Overview and details of the sessions of this conference. Please select a date or location to show only sessions at that day or location. Please select a single session for detailed view (with abstracts and downloads if available).
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Session Overview |
| Date: Monday, 12/June/2023 | |
| 8:00am - 6:30pm | Slides Center Location: Slides Center |
| 8:00am - 6:30pm | Registration Desk Location: Bologna Congress Center |
| 9:00am - 10:45am | Session 2.1: mtDNA maintenance and expression Location: Bologna Congress Center - Sala Europa Session Chair: Zofia Chrzanowska-Lightowers Session Chair: Massimo Zeviani Invited Speakers:
M. Falkemberg; A. Filipovska |
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Invited
ID: 236 Invited Speakers Initiation of mitochondrial DNA replication in mammalian cells. Gothenburg University, Sweden Bibliography
Maria Falkenberg defended her Ph.D. thesis (2000) at the University of Gothenburg, Sweden, after spending three years as a visiting student with Prof. I.R. Lehman, Stanford University School of Medicine. After postdoctoral work with Prof. Nils-Göran Larsson (2001-2002), she was appointed assistant professor at the Karolinska Institutet (2003). Since 2011, she is professor of medical biochemistry at the University of Gothenburg. The Falkenberg laboratory studies DNA replication in mammalian mitochondria, using in-vitro biochemistry, structural biology and and cell biology to study the underlying enzymatic processes. The laboratory also investigates the molecular consequences of disease-causing mutations affecting mitochondrial DNA replication and develops new, rational therapeutic approaches. Invited
ID: 680 Invited Speakers Regulation of mitochondrial gene expression in disease University of Western Australia, Australia Oral presentation
ID: 423 mtDNA maintenance and expression Mitochondrial translation termination at non-canonical stop codons 1Karolinska Institutet, Stockholm, Sweden; 2University of Pennsylvania, Pennsylvania, USA; 3Max-Planck-Institute for Biology of Ageing, Cologne, Germany Bibliography
Krüger A, Remes C, Shiriaev DI, Liu Y, Spåhr H, Wibom R, Atanassov I, Nguyen MD, Cooperman BS, Rorbach J. Human mitochondria require mtRF1 for translation termination at non-canonical stop codons. Nat Commun 14, 30 (2023). Oral presentation
ID: 268 mtDNA maintenance and expression Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability 1Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden; 2Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; 3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; 4Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; 5The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; 6North East and Yorkshire Genomic Laboratory Hub, Central Lab, St. James's University Hospital, Leeds, UK; 7Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, UK; 8Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 9NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK; 10Nuffield Department of Women’s & Reproductive Health, The Women's Centre, University of Oxford, Oxford, UK; 11Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; 12Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil; 13Department of Internal Medicine, Universidade Federal do Rio Grande do Sul - Porto Alegre, Brazil; 14Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul - Porto Alegre, Brazil; 15Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA; 16Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA; 17The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; 18The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; 19The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 20Genomics Unit, The Center for Cancer Research, Sheba Medical Center, Israel; 21Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; 22Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden Bibliography
Menger et al. (2022). Two type I topoisomerases maintain DNA topology in human mitochondria. Nucleic Acids Research; 50(19):11154-11174. Tan et al. (2022). The human mitochondrial genome contains a second light strand promoter. Molecular Cell; 82(19): 3646-3660. Misic et al. (2022). Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Research; 50(15): 8749-8766. Menger et al. (2021). Controlling the topology of mammalian mitochondrial DNA. Open Biology; 11(9): 210168. Jiang et al. (2021). The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Science Advances; 7(27): eabf8631. Oral presentation
ID: 244 mtDNA maintenance and expression The role of replicative exonucleases in mitochondrial DNA replication and degradation University of Miami Miller School of Medicine, United States of America Bibliography
S27 of IFNα1 Contributes to Its Low Affinity for IFNAR2 and Weak Antiviral Activity Nikunj Sharma, Anya J. O'Neal, Christian Gonzalez, Megen Wittling, Erisa Gjinaj, Lisa M. Parsons, Debasis Panda, Alexey Khalenkov, Dorothy Scott, Saurav Misra, and Ronald L. Rabin Journal of Interferon & Cytokine Research 2019 39:5, 283-292 Flash Talk
ID: 127 mtDNA maintenance and expression Processing of mitochondrial RNA in health and disease: the role of FASTKD5. 1The Neuro & McGill University, Montreal, Quebec, Canada; 2Dell School of Medicine, University of Texas at Austin, Austin, TX, USA Bibliography
1.Arguello T, Peralta S, Antonicka H, Gaidosh G, Diaz F, Tu YT, Garcia S, Shiekhattar R, Barrientos A, Moraes CT. (2021) ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly. Cell Rep. 2021 Dec 21;37(12):110139. doi: 10.1016/j.celrep.2021.110139. 2.Go CD, Knight JDR, Rajasekharan A, Rathod B, Hesketh GG, Abe KT, Youn JY, Samavarchi-Tehrani P, Zhang H, Zhu LY, Popiel E, Lambert JP, Coyaud É, Cheung SWT, Rajendran D, Wong CJ, Antonicka H, Pelletier L, Palazzo AF, Shoubridge EA, Raught B, Gingras AC. (2021) A proximity-dependent biotinylation map of a human cell. Nature. 2021 Jul;595(7865):120-124. doi: 10.1038/s41586-021-03592-2. 3.Antonicka H, Lin ZY, Janer A, Aaltonen MJ, Weraarpachai W, Gingras AC, Shoubridge EA. (2020) A High-Density Human Mitochondrial Proximity Interaction Network. Cell Metab. 2020 Sep 1;32(3):479-497.e9. doi: 10.1016/j.cmet.2020.07.017. 4.Maiti P, Antonicka H, Gingras AC, Shoubridge EA, Barrientos A. (2020) Human GTPBP5 (MTG2) fuels mitoribosome large subunit maturation by facilitating 16S rRNA methylation. Nucleic Acids Res. 2020 Aug 20;48(14):7924-7943. doi: 10.1093/nar/gkaa592. 5.Antonicka H, Choquet K, Lin ZY, Gingras AC, Kleinman CL, Shoubridge EA. (2017) A pseudouridine synthase module is essential for mitochondrial protein synthesis and cell viability. EMBO Rep. 2017 Jan;18(1):28-38. doi: 10.15252/embr.201643391. Flash Talk
ID: 524 mtDNA maintenance and expression Mechanisms of mtDNA maintenance and segregation in the female germline 1Karolinska Institutet, Stockholm, Sweden; 2MRC Mitochondrial Biology Unit, Cambridge, United Kingdom; 3Department of Clinical Neurosciences, University of Cambridge, United Kingdom Flash Talk
ID: 116 mtDNA maintenance and expression The human Mitochondrial mRNA Structurome reveals Mechanisms of Gene Expression in Physiology and Pathology 1University of Miami, United States of America; 2Harvard Medical School, United States of America Bibliography
1- Structural basis of LRPPRC-SLIRP-1 dependent translation by the mitoribosome. Vivek Singh, J. Conor Moran, Yuzuru Itoh, Iliana C. Soto, Flavia Fontanesi, Mary Couvillion, Martijn A. Huynen4, Stirling Churchman, Antoni Barrientos*, Alexey Amunts*. Nat Struct Mol Bill. 2023 (in press) 2-Tissue-specific mitochondrial HIGD1C promotes oxygen sensitivity in carotid body chemoreceptors. Timón-Gómez A, Scharr AL, Wong NY, Ni E, Roy A, Liu M, Chau J, Lampert JL, Hireed H, Kim NS, Jan M, Gupta AR, Day RW, Gardner JM, Wilson RJA, Barrientos A, Chang AJ. Elife. 2022 Oct 18;11:e78915. doi: 10.7554/eLife.78915. 2- Coordination of metal center biogenesis in human cytochrome c oxidase. Nývltová E, Dietz JV, Seravalli J, Khalimonchuk O, Barrientos A. Nat Commun. 2022 Jun 24;13(1):3615. doi: 10.1038/s41467-022-31413-1. |
| 10:45am - 11:00am | Coffee Break Location: Bologna Congress Center |
| 11:00am - 12:45pm | Session 2.2: Clinical 1: from new genes to old and novel phenotypes Location: Bologna Congress Center - Sala Europa Session Chair: Agnes Rotig Session Chair: Daniele Ghezzi Invited Speakers: R. Horvath; H. Prokisch |
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Invited
ID: 672 Invited Speakers The role of mitochondria in neuromuscular diseases Cambridge-UK, United Kingdom Bibliography
Van Haute L, et al. Nat Commun 2023 Feb 23;14(1):1009 Invited
ID: 696 Invited Speakers Innovative approaches for the molecular diagnosis of mitochondrial disorders Technical University Munich Institute of Human Genetics Oral presentation
ID: 615 Clinical 1: from new genes to old and novel phenotypes Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing 1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; 2NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK; 3Neurogenetics Unit, Rare and Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, London, UK; 4Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 5Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 6Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 7National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, London, UK; 8Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK; 9Genomics England, One Canada Square London, UK Bibliography
(1) Riley L.G. et al, The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease Genet Med, 2020 Jul;22(7):1254-1261. (2) Davis R.L., Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis, Neurology. 2022 Aug 16;99(7):e730-e742. Oral presentation
ID: 553 Clinical 1: from new genes to old and novel phenotypes Biallelic variants in MCAT in an infant with lactic acidosis, lipoylation disorder, and early death 1University Children's Hospital, Paracelsus Medical University, Salzburg, Austria; 2Institute of Human Genetics, University Medical Center Eppendorf, Hamburg, Germany; 3Current address: Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; 4Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany; 5Amalia Children’s Hospital, Radboudumc, Nijmegen, The Netherlands. Oral presentation
ID: 367 Clinical 1: from new genes to old and novel phenotypes Biallelic PTPMT1 variants impair cardiolipin metabolism and cause mitochondrial myopathy and developmental regression 1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; 2NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK; 3Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge UK; 4Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey; 5Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 6Neurogenetics Unit, Rare and Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, London, UK; 7Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK; 8Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery, London, UK; 9Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle University, Newcastle upon Tyne, UK; 10Genomics England, London, UK; 11Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, Turkey; 12Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt; 13Department of Inherited Metabolic Disease, Division of Women's and Children's Services, University Hospitals Bristol NHS Foundation Trust, Bristol, UK; 14Izmir Biomedicine and Genome Center, Izmir, Turkey; 15Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, Izmir Turkey Flash Talk
ID: 201 Clinical 1: from new genes to old and novel phenotypes Heterozygous missense variants in NUTF2 (nuclear transport factor 2) gene, mapping at the OPA8 locus, cause Dominant Optic Atrophy 1IRCCS - Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica - Bologna (Italy); 2Studio Oculistico d'Azeglio - Bologna (Italy); 3Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele - Milano (Italy); 4Department of Genetics & Genomics, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz University Hospital - Universidad Autónoma de Madrid (IIS-FJD-UAM) - Madrid (Spain); 5Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII - Madrid (Spain); 6Grupo de investigación traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain; Centro de Investigación Biomédica en Red (CIBERER) - Madrid (Spain); 7Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc - Angers (France); 8Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University - Paris (France); 9Departments of Biochemistry and Genetics, University Hospital Angers - Angers (France); 10Molecular Genetics Laboratory, Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany; 11Depart. of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna - Bologna (Italy) Flash Talk
ID: 348 Clinical 1: from new genes to old and novel phenotypes Southern African paediatric patients with King Denborough syndrome are exclusively associated with an autosomal recessive STAC3 variant: is this a highly prevalent secondary mitochondrial disease in this African population? 1Human Metabolomics, North-West University, Potchefstroom, South Africa; 2Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa; 3Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; 4Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; 5https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/global-contributor-list Bibliography
Schoonen, M., Smuts, I., Louw, R., Elson, J. L., van Dyk, E., Jonck, L. M., Rodenburg, R. J. T., van der Westhuizen, F. H. (2019). Panel-Based Nuclear and Mitochondrial Next-Generation Sequencing Outcomes of an Ethnically Diverse Pediatric Patient Cohort with Mitochondrial Disease. The Journal of molecular diagnostics 21, 503–513. Meldau, S., Owen, E. P., Khan, K., & Riordan, G. T. (2022). Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings. Journal of clinical pathology 75, 34–38. Reinecke, C. J., Koekemoer, G., van der Westhuizen, F. H., Louw, R., Lindeque, J. Z., Mienie, L. J., Smuts, I. (2012). Metabolomics of urinary organic acids in respiratory chain deficiencies. Metabolomics 8, 264-283. Terburgh, K., Coetzer, J., Lindeque, J. Z., van der Westhuizen, F. H., Louw, R. (2021). Aberrant BCAA and glutamate metabolism linked to regional neurodegeneration in a mouse model of Leigh syndrome. Biochimica et biophysica acta. Molecular basis of disease 1867, 166082. Flash Talk
ID: 428 Clinical 1: from new genes to old and novel phenotypes AK3, adenylate kinase isozyme 3, is a new gene associated with PEO and multiple mtDNA deletions 1Fondazione IRCCS Istituto Neurologico Besta, Italy; 2Vall d'Hebron Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Autonomous University of Barcelona, Barcelona, Spain; 3Centro Sclerosi Multipla, P.O. Binaghi, ASL Cagliari, Italy; 4Technical University of Munich, School of Medicine, Institute of Human Genetics, 81675 Munich, Germany; 5Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany; 6Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy Flash Talk
ID: 411 mtDNA maintenance and expression Guanylate kinase 1 deficiency: a novel and potentially treatable form of mitochondrial DNA depletion/deletions syndrome 1Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; 2Seattle Children’s Hospital, Seattle, WA, USA; 3Section of Inborn Errors of Metabolism-IBC. Department of Biochemistry and Molecular Genetics. Hospital Clinic de Barcelona-IDIBAPS, Barcelona.; 4Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona; 5Muscle Research and Mitochondrial Function Lab, Cellex - IDIBAPS. Faculty of Medicine and Health Science - University of Barcelona (UB), Barcelona.; 6Department of Internal Medicine, Hospital Clínic of Barcelona.; 7Vall d’Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain.; 8Department of Genome Sciences, University of Washington, Seattle, WA, U.S.A. Bibliography
1DiMauro, S., Schon, E. A., Carelli, V. & Hirano, M. The clinical maze of mitochondrial neurology. Nat Rev Neurol 9, 429-444, doi:10.1038/nrneurol.2013.126 (2013). 2Lopez-Gomez, C., Camara, Y., Hirano, M., Marti, R. & nd, E. W. P. 232nd ENMC international workshop: Recommendations for treatment of mitochondrial DNA maintenance disorders. 16 - 18 June 2017, Heemskerk, The Netherlands. Neuromuscul Disord 32, 609-620, doi:10.1016/j.nmd.2022.05.008 (2022). 3Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 43, 2466-2485, doi:10.1093/nar/gkv047 (2015). 4Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S. & Elpeleg, O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29, 342-344, doi:10.1038/ng751 (2001). 5Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S. & Cohen, N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29, 337-341, doi:10.1038/ng746 (2001). 6Ostergaard, E., Christensen, E., Kristensen, E., Mogensen, B., Duno, M., Shoubridge, E. A. & Wibrand, F. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet 81, 383-387, doi:10.1086/519222 (2007). 7Besse, A., Wu, P., Bruni, F., Donti, T., Graham, B. H., Craigen, W. J., McFarland, R., Moretti, P., Lalani, S., Scott, K. L., Taylor, R. W. & Bonnen, P. E. The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism. Cell Metab 21, 417-427, doi:10.1016/j.cmet.2015.02.008 (2015). 8Sommerville, E. W., Dalla Rosa, I., Rosenberg, M. M., Bruni, F., Thompson, K., Rocha, M., Blakely, E. L., He, L., Falkous, G., Schaefer, A. M., Yu-Wai-Man, P., Chinnery, P. F., Hedstrom, L., Spinazzola, A., Taylor, R. W. & Gorman, G. S. Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance. Clin Genet 97, 276-286, doi:10.1111/cge.13652 (2020). 9Shintaku, J., Pernice, W. M., Eyaid, W., Gc, J. B., Brown, Z. P., Juanola-Falgarona, M., Torres-Torronteras, J., Sommerville, E. W., Hellebrekers, D. M., Blakely, E. L., Donaldson, A., van de Laar, I., Leu, C. S., Marti, R., Frank, J., Tanji, K., Koolen, D. A., Rodenburg, R. J., Chinnery, P. F., Smeets, H. J. M., Gorman, G. S., Bonnen, P. E., Taylor, R. W. & Hirano, M. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J Clin Invest 132, doi:10.1172/JCI145660 (2022). 10Bourdon, A., Minai, L., Serre, V., Jais, J. P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A. & Rotig, A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet 39, 776-780, doi:10.1038/ng2040 (2007). 11Khan, N., Shah, P. P., Ban, D., Trigo-Mourino, P., Carneiro, M. G., DeLeeuw, L., Dean, W. L., Trent, J. O., Beverly, L. J., Konrad, M., Lee, D. & Sabo, T. M. Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer. J Biol Chem 294, 11920-11933, doi:10.1074/jbc.RA119.009251 (2019). 12Li, Y., Zhang, Y. & Yan, H. Kinetic and thermodynamic characterizations of yeast guanylate kinase. J Biol Chem 271, 28038-28044, doi:10.1074/jbc.271.45.28038 (1996). 13Agarwal, K. C., Miech, R. P. & Parks, R. E., Jr. Guanylate kinases from human erythrocytes, hog brain, and rat liver. Methods Enzymol 51, 483-490, doi:10.1016/s0076-6879(78)51066-5 (1978). 14Dummer, R., Duvic, M., Scarisbrick, J., Olsen, E. A., Rozati, S., Eggmann, N., Goldinger, S. M., Hutchinson, K., Geskin, L., Illidge, T. M., Giuliano, E., Elder, J. & Kim, Y. H. Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sezary syndrome). Ann Oncol 25, 1807-1812, doi:10.1093/annonc/mdu231 (2014). |
| 12:45pm - 1:45pm | Lunch Location: Bologna Congress Center - Sala Europa |
| 1:45pm - 3:30pm | Session 2.3: Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Location: Bologna Congress Center - Sala Europa Session Chair: Cristina Ugalde Session Chair: Giovanni Manfredi Invited Speaker: E. Fernandez-Vizarra; A. Prigione |
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Invited
ID: 176 Invited Speakers Metabolic adaptations of respiratory chain organization and function 1Department of Biomedical Sciences, University of Padova, Italy; 2Veneto Institute of Molecular Medicine, Padova, Italy Bibliography
1.Fernandez-Vizarra, E., Lopez-Calcerrada, S., Sierra-Magro, A., Perez-Perez, R., Formosa, L.E., Hock, D.H., Illescas, M., Penas, A., Brischigliaro, M., Ding, S., et al. (2022). Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metab 34, 1792-1808. 10.1016/j.cmet.2022.09.005. 2.Fernandez-Vizarra, E., and Ugalde, C. (2022). Cooperative assembly of the mitochondrial respiratory chain. Trends Biochem Sci 47, 999-1008. 10.1016/j.tibs.2022.07.005. 3.Fernandez-Vizarra, E., Lopez-Calcerrada, S., Formosa, L.E., Perez-Perez, R., Ding, S., Fearnley, I.M., Arenas, J., Martin, M.A., Zeviani, M., Ryan, M.T., and Ugalde, C. (2021). SILAC-based complexome profiling dissects the structural organization of the human respiratory supercomplexes in SCAFI(KO) cells. Biochim Biophys Acta Bioenerg 1862, 148414. 10.1016/j.bbabio.2021.148414. 4.Palenikova, P., Harbour, M.E., Prodi, F., Minczuk, M., Zeviani, M., Ghelli, A., and Fernandez-Vizarra, E. (2021). Duplexing complexome profiling with SILAC to study human respiratory chain assembly defects. Biochim Biophys Acta Bioenerg 1862, 148395. 10.1016/j.bbabio.2021.148395. 5.Protasoni, M., Perez-Perez, R., Lobo-Jarne, T., Harbour, M.E., Ding, S., Penas, A., Diaz, F., Moraes, C.T., Fearnley, I.M., Zeviani, M., Ugalde, C., and Fernandez-Vizarra, E. (2020). Respiratory supercomplexes act as a platform for complex III-mediated maturation of human mitochondrial complexes I and IV. The EMBO journal 39, e102817. 10.15252/embj.2019102817. Invited
ID: 403 Invited Speakers Pluripotent stem cells and brain organoids for drug discovery of mitochondrial diseases Heinrich Heine University, Düsseldorf, Germany Oral presentation
ID: 347 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity High-throughput single cell analysis reveals progressive mitochondrial DNA mosaicism developing throughout life 1Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 2Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 3Biosciences Institute, Faculty of Medical Sciences, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK Bibliography
Burr, S. P., et al. (2023). "Cell lineage-specific mitochondrial resilience during mammalian organogenesis." Cell. Alzaydi, M. M., et al. (2023). "Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension." Am J Respir Cell Mol Biol 68(1): 103-115. Kayhanian, S., et al. (2022). "Cell-Free Mitochondrial DNA in Acute Brain Injury." Neurotrauma Rep 3(1): 415-420. Oral presentation
ID: 238 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy. 1Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY; 2Weill Cornell Medicine, Department of Pharmacology, New York, NY; 3Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy; 4IRCCS, Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy Oral presentation
ID: 520 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Succinylation as a novel pathogenic mechanism in a children's mitochondrial brain disease 1STEMM, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; 2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA; 3Buck Institute for Research on Aging, Novato, CA 94945, USA; 4Gladstone Institutes and University of California, San Francisco, CA 94158, USA; 5Department of Physics, University of Helsinki, Finland; 6HiLIFE Institute of Biotechnology, University of Helsinki, Finland; 7Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark; 8Unit of Cellular Biology and Mitochondrial Diseases, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy; 9Program in Genetics and Genome Biology, The Hospital for Sick Children, Institute of Medical Science University of Toronto, Toronto, Ontario, Canada; 10Division of Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA Bibliography
Gut, P., Matilainen, S., Meyer, J. G., Pällijeff, P., Richard, J., Carroll, C. J., ... & Verdin, E. (2020). SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature communications, 11(1), 5927. Flash Talk
ID: 226 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The levels and activation state of the pyruvate dehydrogenase complex modulate the SCAFI-dependent organization of the mitochondrial respiratory chain 1Instituto de Investigación Hospital 12 de Octubre, Madrid 28041, Spain; 2Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid, Spain Bibliography
Fernández-Vizarra E, López-Calcerrada S, Sierra-Magro A, Pérez-Pérez R, Formosa LE, Hock DH, Illescas M, Peñas A, Brischigliaro M, Ding S, Fearnley IM, Tzoulis C, Pitceathly RDS, Arenas J, Martín MA, Stroud DA, Zeviani M, Ryan MT, Ugalde C. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metab. 2022 Nov 1;34(11):1792-1808.e6. doi: 10.1016/j.cmet.2022.09.005. PMID: 36198313. Flash Talk
ID: 301 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Oxphos deficiency indicates novel functions for the mitochondrial protein import subunit tim50 1Department of Biochemistry and Pharmacology and the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia; 2Queensland Children’s Hospital, Department of Metabolic Medicine, South Brisbane, Brisbane, Queensland, 4001, Australia; 3Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, 3052, Australia; 4Department of Paediatrics, University of Melbourne, Melbourne, Victoria, 3052, Australia; 5Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Victoria, 3052, Australia Flash Talk
ID: 300 Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Microproteins in metabolic regulation 1Duke-NUS Medical School, Singapore; 2University of Melbourne, Australia; 3University of Utah, USA; 4University of Southampton, UK Bibliography
Lena Ho, PhD (lead PI), is regarded as a pioneer in the field of microprotein research with over 30 primary research articles (5991 citations, H-index of 21) in top-tier journals. With more than 12 years of experience in microprotein discovery, functionalization and therapeutic development, Lena and her team have developed a framework of bioinformatic tools for mining ribo-seq data for disease-relevant small ORF peptides, as well as an extensive range of biochemical tools to validate their function and uncover their molecular mechanism. Lena is an EMBO Young Investigator and HHMI international scholar. Recent publications : 1) Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity. Lee CQE, Kerouanton B, Chothani S, Zhang S, Chen Y, Mantri CK, Hock DH, Lim R, Nadkarni R, Huynh VT, Lim D, Chew WL, Zhong FL, Stroud DA, Schafer S, Tergaonkar V, St John AL, Rackham OJL, Ho L. Nat Commun. 2021 Apr 9;12(1):2130. doi: 10.1038/s41467-021-22397-5. 2) Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis. Liang C, Zhang S, Robinson D, Ploeg MV, Wilson R, Nah J, Taylor D, Beh S, Lim R, Sun L, Muoio DM, Stroud DA, Ho L. Cell Rep. 2022 Aug 16;40(7):111204. doi: 10.1016/j.celrep.2022.111204. 3) Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Zhang S, Reljić B, Liang C, Kerouanton B, Francisco JC, Peh JH, Mary C, Jagannathan NS, Olexiouk V, Tang C, Fidelito G, Nama S, Cheng RK, Wee CL, Wang LC, Duek Roggli P, Sampath P, Lane L, Petretto E, Sobota RM, Jesuthasan S, Tucker-Kellogg L, Reversade B, Menschaert G, Sun L, Stroud DA, Ho L. 4) Viral proteases activate the CARD8 inflammasome in the human cardiovascular system. Nadkarni R, Chu WC, Lee CQE, Mohamud Y, Yap L, Toh GA, Beh S, Lim R, Fan YM, Zhang YL, Robinson K, Tryggvason K, Luo H, Zhong F, Ho L. J Exp Med. 2022 Oct 3;219(10):e20212117. doi: 10.1084/jem.20212117. Epub 2022 Sep 21. |
| 3:30pm - 3:50pm | Industry Workshop: Abliva AB Location: Bologna Congress Center - Sala Europa |
| 3:30pm - 4:30pm | Tea Break and poster session Location: Bologna Congress Center Session topics: - Clinical 1: from new genes to old and novel phenotypes - New technological developments and OMICS - Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity |
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ID: 495
Clinical 1: from new genes to old and novel phenotypes Recessive MECR pathogenic variants cause a LHON-like optic neuropathy 1IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; 2Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy; 3Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy; 4Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Italy ID: 213
Clinical 1: from new genes to old and novel phenotypes Variants in ATP5F1B are associated with dominantly inherited dystonia 1Fondazione IRCCS Istituto Neurologico Besta, Milan, Italy; 2Northwestern University, Feinberg School of Medicine, Chicago, USA; 3Helmholtz Zentrum München, Technical University of Munich, Munich, Germany; 4Università di Milano, Milan, Italy ID: 143
Clinical 1: from new genes to old and novel phenotypes Toward clinical implementation of quantitative proteomics in the detection of mitochondrial disorders 1University of Melbourne, Parkville, Australia; 2Victoria University, Footscray, Australia; 3Murdoch Children’s Research Institute, Melbourne, Australia; 4Victorian Clinical Genetics Services, Melbourne, Australia; 5National Metabolic Service Auckland City Hospital, Auckland, New Zealand; 6Starship Children's Hospital, Auckland, New Zealand; 7University of Colorado, Aurora, United States of America; 8Centre for Population Genomics, Melbourne, Australia; 9Garvan Institute of Medical Research, Sydney, Australia Bibliography
Amarasekera S.S.C., Hock D.H., Lake N.J., Calvo S.E., Grønborg S.W., Krzesinski E.I., Amor D.J., Fahey M.C., Simons C., Wibrand F., Mootha V.K., Lek M., Lunke S., Stark Z., Østergaard E., Christodoulou J., Thorburn D.R., *Stroud D.A., *Compton A.G. (2023) Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. In revision. van Bergen N.J., Gunanayagam K., Bournazos A.M., Walvekar A.S., Warmoes M.O., Semcesen L.N., Lunke S., Bommireddipalli S., Sikora T., Jones D.L., Garza D., Sebire D., Gooley S., McLean C.A., Naidoo P., Rajasekaran M., *Stroud D.A., *Linster C.L., *Wallis M., *Cooper S.T., *Christodoulou J. (2023) Severe NAD(P)HX dehydratase (NAXD) neurometabolic syn-drome may present in adulthood after mild head trauma. IJMS 24,4. 10.3390/ijms24043582. Robinson D.R.L., Hock D.H., Muellner-Wong L., Kugapreethan R., Reljic B., Surgenor E.S., Rodrigues C.H.M., Caruana N.J., *Stroud D.A. (2022) Applying Sodium Carbonate Extraction Mass Spectrometry to Investigate Defects in the Mitochondrial Respiratory Chain. Front. Cell Dev. Biol. 10, 786268. Hock D.H., Robinson D.R.L., *Stroud D.A. (2020) Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome. Biochem. J. 477, 4085. Helman G., Compton A.G., Hock D.H., Walkiewicz M., Brett G.R., Pais L., Tan T.Y., De Paoli-Iseppi R., Clark M.B., Christodoulou J., White S.M., Thorburn D.R., Stroud D.A., Stark Z., Simons C. (2021) Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10. Hum. Mutat. 42, 29. Frazier A.E., Compton A.G., Kishita Y., Hock D.H., Welch A.E., Amarasekera S.S.C., Rius R., Formosa L.E., Imai-Okazaki A., Francis D., Wang M., Lake N.J., Tregoning S., Jabbari J.S., Lucattini A., Nitta K.R., Ohtake A., Murayama K., Amor D.J., McGillivray G., Wong F.Y., van der Knaap M.S., Jeroen Vermeulen R., Wiltshire E.J., Fletcher J.M., Lewis B., Baynam G., Ellaway C., Balasubramaniam S., Bhattacharya K., Freckmann M.L., Arbuckle S., Rodriguez M., Taft R.J., Sadedin S., Cowley M.J., Minoche A.E., Calvo S.E., Mootha V.K., Ryan M.T., Okazaki Y., Stroud D.A., Simons C., Christodoulou J., Thorburn D.R. (2021) Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Med 2, 49. Hock D.H., Reljic B., Ang C.S., Muellner-Wong L., Mountford H.S., Compton A.G., Ryan M.T., Thorburn D.R., *Stroud D.A. (2020) HIGD2A Is Required for Assembly of the COX3 Module of Human Mitochondrial Complex IV. Mol. Cell Proteomics. 19, 107541. *, corresponding author ID: 611
Clinical 1: from new genes to old and novel phenotypes A DNM2-related myopathy mimicking a primary mitochondrial disorder 1Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.; 2Department of Neurosciences, Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; 3Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. ID: 594
Clinical 1: from new genes to old and novel phenotypes Assessing the association of mitochondrial DNA genes with Primary Mitochondrial Disease using the ClinGen Clinical Validity Framework 1Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA; 2Illumina Laboratory Services, Illumina Inc., San Diego, CA; 3Center for Personalized Medicine, Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA; 4Keck School of Medicine, University of Southern California, Los Angeles, CA; 5Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; 6Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ID: 282
Clinical 1: from new genes to old and novel phenotypes Functional characterisation of the m.8424T>C MT-ATP8 variant using quantitative proteomics 1University of Melbourne, Parkville, Australia; 2Victoria University, Footscray, Australia; 3Murdoch Children’s Research Institute, Melbourne, Australia; 4Victorian Clinical Genetics Services, Melbourne, Australia; 5Australian Genomics, Melbourne, Australia ID: 493
Clinical 1: from new genes to old and novel phenotypes COX18 variants cause isolated Complex IV deficiency associated with neonatal hypertrophic cardiomyopathy, myopathy and axonal sensory neuropathy 1Dino Ferrari Center, University of Milan, Italy; 2IRCCS Cà Granda Ospedale Maggiore Policlinico Milan, Italy; 3ASST Papa Giovanni XXIII, Bergamo, Italy ID: 255
Clinical 1: from new genes to old and novel phenotypes Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 1Muscular and Neurodegenerative Disorders Unit, Children Hospital Bambino Gesù; 2Cellular biology and mitochondrial diseases diagnostics, Children Hospital Bambino Gesù; 3Department of Chemistry Life Sciences and Environmental Sustainability, University of Parma; 4Metabolism Division, Children Hospital Bambino Gesù, Rome; 5Molecular Medicine, IRCCS Stella Maris, Pisa Bibliography
1) Hypoventilation and sleep hypercapnia in a case of congenital variant-like Rett syndrome. Ghirardo S, Sabatini L, Onofri A, Testa MBC, Paglietti MG, Diodato D, Travaglini L, Stregapede F, Ciofi Degli Atti ML, Cherchi C, Cutrera R. Ital J Pediatr. 2022 Sep 7;48(1):167. doi: 10.1186/s13052-022-01359-7. PMID: 36071486 Free PMC article. 2) Neuropsychological and behavioral profile in a cohort of Becker muscular dystrophy pediatric patients. Cumbo F, Tosi M, Catteruccia M, Diodato D, Nicita F, Capitello TG, Alfieri P, Vicari S, Bertini E, D'Amico A. Neuromuscul Disord. 2022 Sep;32(9):736-742. doi: 10.1016/j.nmd.2022.07.402. Epub 2022 Jul 27. PMID: 35953344 4) Response to: Phenotypic heterogeneity of Leigh syndrome due to NDUFA12 variants is multicausal. Torraco A, Maroofian R, Rötig A, Bertini E, Ghezzi D, Carrozzo R, Diodato D. Hum Mutat. 2022 Jan;43(1):99-100. doi: 10.1002/humu.24303. Epub 2021 Dec 9. PMID: 34888984 No abstract available. 5) Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases. Ardissone A, Bruno C, Diodato D, Donati A, Ghezzi D, Lamantea E, Lamperti C, Mancuso M, Martinelli D, Primiano G, Procopio E, Rubegni A, Santorelli F, Schiaffino MC, Servidei S, Tubili F, Bertini E, Moroni I. Orphanet J Rare Dis. 2021 Oct 9;16(1):413. doi: 10.1186/s13023-021-02029-3. PMID: 34627336 Free PMC article. 6) Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. Zheng WQ, Pedersen SV, Thompson K, Bellacchio E, French CE, Munro B, Pearson TS, Vogt J, Diodato D, Diemer T, Ernst A, Horvath R, Chitre M, Ek J, Wibrand F, Grange DK, Raymond L, Zhou XL, Taylor RW, Ostergaard E. Hum Mol Genet. 2022 Feb 21;31(4):523-534. doi: 10.1093/hmg/ddab257. PMID: 34508595 7) Age-related sensory neuropathy in patients with spinal muscular atrophy type 1. Pro S, Tozzi AE, D'Amico A, Catteruccia M, Cherchi C, De Luca M, Nicita F, Diodato D, Cutrera R, Bertini E, Valeriani M. Muscle Nerve. 2021 Nov;64(5):599-603. doi: 10.1002/mus.27389. Epub 2021 Aug 23. PMID: 34368972 8) Antenatal Membranous Nephropathy and Type 2 (Axonal) Charcot-Marie-Tooth With Mutations in the Metallo-Membrane Endopeptidase Gene: A Call for Family Screening and Pharmacovigilance. Nortier JL, Remiche G, Delrée P, Nauta J, Notermans NC, Vivarelli M, Diodato D, Solé G, Debiec H, Ronco P. Kidney Int Rep. 2021 May 12;6(7):1981-1986. doi: 10.1016/j.ekir.2021.04.034. eCollection 2021 Jul. PMID: 34307994 Free PMC article. No abstract available. 9) Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases. Ticci C, Orsucci D, Ardissone A, Bello L, Bertini E, Bonato I, Bruno C, Carelli V, Diodato D, Doccini S, Donati MA, Dosi C, Filosto M, Fiorillo C, La Morgia C, Lamperti C, Marchet S, Martinelli D, Minetti C, Moggio M, Mongini TE, Montano V, Moroni I, Musumeci O, Pancheri E, Pegoraro E, Primiano G, Procopio E, Rubegni A, Scalise R, Sciacco M, Servidei S, Siciliano G, Simoncini C, Tolomeo D, Tonin P, Toscano A, Tubili F, Mancuso M, Battini R, Santorelli FM. J Clin Med. 2021 May 12;10(10):2063. doi: 10.3390/jcm10102063. PMID: 34065803 Free PMC article. 10) Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation. Torraco A, Nasca A, Verrigni D, Pennisi A, Zaki MS, Olivieri G, Assouline Z, Martinelli D, Maroofian R, Rizza T, Di Nottia M, Invernizzi F, Lamantea E, Longo D, Houlden H, Prokisch H, Rötig A, Dionisi-Vici C, Bertini E, Ghezzi D, Carrozzo R, Diodato D. Hum Mutat. 2021 Jun;42(6):699-710. doi: 10.1002/humu.24195. Epub 2021 Mar 25. PMID: 33715266 ID: 438
Clinical 1: from new genes to old and novel phenotypes Bi-allelic TEFM variants are associated with a treatable mitochondrial myopathy 1Unit of Cellular Biology and Diagnosis of Mitochondrial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome Italy.; 2Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.; 3Dipartimento Di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy. Bibliography
1-Torraco A, Morlino S, Rizza T, Di Nottia M, Bottaro G, Bisceglia L, Montanari A, Cappa M, Castori M, Bertini E, Carrozzo R. A novel homozygous variant in COX5A causes an attenuated phenotype with failure to thrive, lactic acidosis, hypoglycemia, and short stature. Clin Genet. 2022 Jul;102(1):56-60. 2-Torraco A, Nasca A, Verrigni D, Pennisi A, Zaki MS, Olivieri G, Assouline Z, Martinelli D, Maroofian R, Rizza T, Di Nottia M, Invernizzi F, Lamantea E, Longo D, Houlden H, Prokisch H, Rötig A, Dionisi-Vici C, Bertini E, Ghezzi D, Carrozzo R, Diodato D. Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation. Hum Mutat. 2021 Jun;42(6):699-710. 3-Torraco A, Stehling O, Stümpfig C, Rösser R, De Rasmo D, Fiermonte G, Verrigni D, Rizza T, Vozza A, Di Nottia M, Diodato D, Martinelli D, Piemonte F, Dionisi-Vici C, Bertini E, Lill R, Carrozzo R. ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins. Hum Mol Genet. 2018 Oct 15;27(20):3650. ID: 486
Clinical 1: from new genes to old and novel phenotypes TOMM40L as a new causative gene for autosomal recessive mitochondrial disease. 1Laboratorio de Enfermedades Mitocondriales. Instituto de Investigación Hospital 12 de Octubre (i+12), E-28041 Madrid, Spain.; 2Unidad Pediátrica de Enfermedades Raras, Enfermedades Mitocondriales y Metabólicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.; 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041 Madrid, Spain. Bibliography
Rodríguez-García, M. E., Cotrina-Vinagre, F. J., et al., (2022). First splicing variant in HECW2 with an autosomal recessive pattern of inheritance and associated with NDHSAL. Human mutation, 43(10), 1361–1367. https://doi.org/10.1002/humu.24426 Lopes Abath Neto, O., Medne, L., Donkervoort, S., Rodríguez-García, M. E., Bolduc, V., Hu, Y., Guadagnin, E., Foley, A. R., Brandsema, J. F., Glanzman, A. M., Tennekoon, G. I., Santi, M., Berger, J. H., Megeney, L. A., Komaki, H., Inoue, M., Cotrina-Vinagre, F. J.,et al., (2021). MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase. Brain : a journal of neurology, 144(9), 2722–2731. https://doi.org/10.1093/brain/awab275 Cotrina-Vinagre, F. J., et al., (2021). Characterization of a complex phenotype (fever-dependent recurrent acute liver failure and osteogenesis imperfecta) due to NBAS and P4HB variants. Molecular genetics and metabolism, 133(2), 201–210. https://doi.org/10.1016/j.ymgme.2021.02.007 Rodríguez-García, M. E., Cotrina-Vinagre, F. J., et al., (2021). New subtype of PCH1C caused by novel EXOSC8 variants in a 16-year-old Spanish patient. Neuromuscular disorders : NMD, 31(8), 773–782. https://doi.org/10.1016/j.nmd.2021.05.008 Rodríguez-García, M. E., Cotrina-Vinagre, F. J., et al., (2019). A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. European journal of human genetics : EJHG, 27(9), 1369–1378. https://doi.org/10.1038/s41431-019-0418-1 ID: 528
Clinical 1: from new genes to old and novel phenotypes A primary cardiological phenotype caused by an inherited mtDNA single deletion: a case report from an Italian pedigree 1Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy; 2Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; 3Institute of Neurogenomics, Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany; 4Laboratory of Molecular Genetics, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy Bibliography
1) Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Donati MA, Federico A, Minetti C, Moggio M, Mongini T, Santorelli FM, Servidei S, Tonin P, Toscano A, Bruno C, Bello L, Caldarazzo Ienco E, Cardaioli E, Catteruccia M, Da Pozzo P, Filosto M, Lamperti C, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Sauchelli D, Scarpelli M, Sciacco M, Valentino ML, Vercelli L, Zeviani M, Siciliano G. Redefining phenotypes associated with mitochondrial DNA single deletion. J Neurol. 20 2) Grady JP, Campbell G, Ratnaike T, Blakely EL, Falkous G, Nesbitt V, Schaefer AM, McNally RJ, Gorman GS, Taylor RW, Turnbull DM, McFarland R (2014) Disease progression in patients with single, large-scale mitochondrial DNA deletions. Brain 137:323–334 3) Yamashita S, Nishino I, Nonaka I, Goto Y (2008) Genotype and phenotype analyses in 136 patients with single large-scale mitochondrial DNA deletions. J Hum Genet 53:598–606 15 May;262(5):1301-9. doi: 10.1007/s00415-015-7710-y. Epub 2015 Mar 26. Erratum in: J Neurol. 2015 Dec;262(12):2800. PMID: 25808502. 4) Chinnery PF, DiMauro S, Shanske S, Schon EA, Zeviani M, Mariotti C, Carrara F, Lombes A, Laforet P, Ogier H, Jaksch M, Lochmüller H, Horvath R, Deschauer M, Thorburn DR, Bindoff LA, Poulton J, Taylor RW, Matthews JN, Turnbull DM. Risk of developing a mitochondrial DNA deletion disorder. Lancet. 2004 Aug 14-20;364(9434):592-6. doi: 10.1016/S0140-6736(04)16851-7. PMID: 15313359. ID: 150
Clinical 1: from new genes to old and novel phenotypes Genetic characterization of a large cohort of Spanish patients with TK2 deficiency. A founder effect of two TK2 variants partially contributes to a higher prevalence of the disorder in Spain. 1Hospital Universitario 12 de Octubre, imas12 Research Institute, Madrid, Spain; 2Spanish Network for Biomedical Research in Rare Diseases (CIBERER); 3Fundación Galega de Medicina Xenómica, Santiago de Compostela, Spain; 4Instituto de Investigación Sanitaria, Hospital Universitario FundaciónJiménez Díaz, Madrid, Spain; 5Research Group on Neuromuscular and Mitochondrial Diseases, Vall d’Hebron Research Institute, Autonomous University of Barcelona, Barcelona; 6Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia; 7Sant Joan de Déu Research Institute, Sant Joan de Déu Hospital, Barcelona, Spain.; 8Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío, Sevilla, Spain.; 9Center for Biomedical Network Research on Neurodegenerative Disorders (CIBERNED) Bibliography
1.Domínguez-González C, Fernández-Torrón R, Moore U, de Fuenmayor-Fernández de la Hoz CP, Vélez-Gómez B, Cabezas JA, Alonso-Pérez J, González-Mera L, Olivé M, García-García J, Moris G, León Hernández JC, Muelas N, Servian-Morilla E, Martin MA, Díaz-Manera J, Paradas C. Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis. J Neurol. 2022 Jul;269(7):3550-3562. doi: 10.1007/s00415-021-10957-0. Epub 2022 Mar 14. PMID: 35286480; PMCID: PMC9217784. 2.Berardo A, Domínguez-González C, Engelstad K, Hirano M. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. J Neuromuscul Dis. 2022;9(2):225-235. doi: 10.3233/JND-210786. PMID: 35094997; PMCID: PMC9028656. 3.Domínguez-González C, Madruga-Garrido M, Hirano M, Martí I, Martín MA, Munell F, Nascimento A, Olivé M, Quan J, Sardina MD, Martí R, Paradas C. Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency. Orphanet J Rare Dis. 2021 Oct 2;16(1):407. doi: 10.1186/s13023-021-02030-w. PMID: 34600563; PMCID: PMC8487573. 4.Domínguez-González C, Madruga-Garrido M, Mavillard F, Garone C, Aguirre-Rodríguez FJ, Donati MA, Kleinsteuber K, Martí I, Martín-Hernández E, Morealejo-Aycinena JP, Munell F, Nascimento A, Kalko SG, Sardina MD, Álvarez Del Vayo C, Serrano O, Long Y, Tu Y, Levin B, Thompson JLP, Engelstad K, Uddin J, Torres-Torronteras J, Jimenez-Mallebrera C, Martí R, Paradas C, Hirano M. Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy. Ann Neurol. 2019 Aug;86(2):293-303. doi: 10.1002/ana.25506. Epub 2019 Jun 17. PMID: 31125140; PMCID: PMC7586249. 5.Domínguez-González C, Hernández-Laín A, Rivas E, Hernández-Voth A, Sayas Catalán J, Fernández-Torrón R, Fuiza-Luces C, García García J, Morís G, Olivé M, Miralles F, Díaz-Manera J, Caballero C, Méndez-Ferrer B, Martí R, García Arumi E, Badosa MC, Esteban J, Jimenez-Mallebrera C, Encinar AB, Arenas J, Hirano M, Martin MÁ, Paradas C. Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis. 2019 May 6;14(1):100. doi: 10.1186/s13023-019-1071-z. PMID: 31060578; PMCID: PMC6501326. 6.Domínguez-González C, Hernández-Voth A, de Fuenmayor-Fernández de la Hoz CP, Guerrero LB, Morís G, García-García J, Muelas N, León Hernández JC, Rabasa M, Lora D, Blázquez A, Arenas J, Martin MÁ. Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study. Neuromuscul Disord. 2022 Sep;32(9):728-735. doi: 10.1016/j.nmd.2022.07.399. Epub 2022 Jul 16. PMID: 35907766. ID: 198
Clinical 1: from new genes to old and novel phenotypes HSD17B10 interacts with CBR4 to form human mitochondrial 3-ketoacyl-acyl carrier protein reductase 2 (KAR2) in the mitochondrial fatty acid synthesis pathway Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland Bibliography
I.Shvetsova, A., Masud, A. J., Schneider, L., Bergmann, U., Monteuuis, G., Miinalainen, I. J., ... & Kastaniotis, A. J. (2021). A hunt for OM45 synthetic petite interactions in Saccharomyces cerevisiae reveals a role for Miro GTPase Gem1p in cristae structure maintenance. MicrobiologyOpen, 10(5), e1238. doi.org/10.1002/mbo3.1238 II.Masud, A. J., Kastaniotis, A. J., Rahman, M. T., Autio, K. J., & Hiltunen, J. K. (2019). Mitochondrial acyl carrier protein (ACP) at the interface of metabolic state sensing and mitochondrial function. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 118540. doi.org/10.1016/j.bbamcr.2019.118540 III.Monteuuis, G., Suomi, F., Kerätär, J. M., Masud, A. J. & Kastaniotis, A. J. (2017). A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3. Biochemical Journal, 474(22), 3783-3797. doi.org/10.1042/BCJ20170416 IV.Nair, R. R., Kerätär, J. M., Autio, K. J., Masud, A. J., Finnilä, M. A., Autio-Harmainen, H. I., Miinalainen, I. J., Nieminen, P. A., Hiltunen, J. K. & Kastaniotis, A. J. (2017). Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice. Human Molecular Genetics, 26(11), 2104-2117. doi.org/10.1093/hmg/ddx105 V.Masud, A. J. M., Mia, M. A., Islam, M. M., Begum, S. N., & Prodhan, S. H. (2014). Morpho-Molecular Screening of Rice (Oryza Sativa L.) Genotypes At Seedling Stage for Salt Tolerance. The Journal of Microbiology, Biotechnology and Food Sciences, 4(2), 164. doi.org/10.15414/jmbfs.2014.4.2.164-169 ID: 668
Clinical 1: from new genes to old and novel phenotypes Novel atypical variants causing pyruvate dehydrogenase complex deficiency 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 2Centre of inherited metabolic diseases, Karolinska University Hospital, Stockholm, Sweden; 3Neuropediatric Unit, Dept of Women’s, and Children's Health, Karolinska Institutet, Stockholm, Sweden; 4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ID: 492
Clinical 1: from new genes to old and novel phenotypes Novel genetic discoveries detected using diagnostic OMICSs in patients suspected to suffer from multiple acyl-CoA dehydrogenation deficiency 1Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; 2Institute of Neurogenomics, Helmholtz Zentrum München, Germany; 3Institute of Human Genetics, School of Medicine, Technical University Munich, München, Germany.; 4Department of Pediatrics, Graduate School of Medicine, Gifu University Hospital, Gifu, Japan.; 5Department of Informatics, Technical University of Munich, Garching, Germany.; 6Department of Biochemical Genetics, St James's University Hospital, Leeds, UK.; 7Department of Pediatrics, Sheffield Children's Hospital, Sheffield, UK.; 8Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.; 9Department of Inborn Errors of Metabolism and Paediatrics, The Institute of Mother and Child, Warsaw, Poland.; 10Department of Pediatrics, Hannover Medical School, Hannover, Germany.; 11Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.; 12Center for Inherited Metabolic Disorders, Guy’s & St Thomas’ Hospital NHS Foundation Trust, London, UK.; 13University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.; 14Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.; 15Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA; 16Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.; 17UofL Physicians Novak Center for Children's Health, Louisville, USA.; 18Nottingham Children’s Hospital, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK; 19Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK; 20Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; 21Clinical Genetics Center, Gifu University Hospital, Gifu, Japan.; 22Department of Clinical Chemistry, Sheffield Children’s Hospital, Sheffield, UK. Bibliography
First and shared first (3): Mosegaard S*, Dipace G*, Bross P, Carlsen J, Gregersen N, Olsen RKJ. 2020. ”Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism”. International Journal of Molecular Sciences;21(11):3847. doi: 10.3390/ijms21113847. Mosegaard S*, Bruun GH*, Flyvbjerg KF, Bliksrud YT, Gregersen N, Dembic M, Annexstad E, Tangeraas T, Olsen RKJ, Andresen BS. 2017. “An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency”. Molecular Genetics and Metabolism;122(4):182-188. doi: 10.1016/j.ymgme.2017.10.014. Olsen RKJ*, Koňaříková E*, Giancaspero TA*, Mosegaard S*, Boczonadi V*, Mataković L*, ….. Barile M, Prokisch H. 2016. ”Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency”. American Journal of Human Genetics;98(6):1130-1145. doi: 10.1016/j.ajhg.2016.04.006. Co-author (5): V.A. Yépez, M. Gusic, R. Kopajtich, C. Mertes, N.H. Smith, C.L. Alston, R. Ban, S. Beblo, R. Berutti, H. Blessing, E. Ciara, F. Distelmaier, P. Freisinger, J. Häberle, S.J. Hayflick, M. Hempel, Y.S. Itkis, Y. Kishita, T. Klopstock, T.D. Krylova, C. Lamperti, D. Lenz, C. Makowski, S. Mosegaard, M.F. Müller, G. Muñoz-Pujol, A. Nadel, A. Ohtake, Y. Okazaki, E. Procopio, T. Schwarzmayr, J. Smet, C. Staufner, S.L. Stenton, T.M. Strom, C. Terrile, F. Tort, R. Van Coster, A. Vanlander, M. Wagner, M. Xu, F. Fang, D. Ghezzi, J.A. Mayr, D. Piekutowska-Abramczuk, A. Ribes, A. Rötig, R.W. Taylor, S.B. Wortmann, K. Murayama, T. Meitinger, J. Gagneur, H. Prokisch, Clinical implementation of RNA sequencing for Mendelian disease diagnostics, Genome Med. 14 (2022) 38. https://doi.org/10.1186/s13073-022-01019-9. Fogh S, Dipace G, Bie A, Veiga-da-Cunha M, Hansen J, Kjeldsen M, Mosegaard S, Ribes A, Gregersen N, Aagaard L, Van Schaftingen E, Olsen RKJ. “Variants in the ethylmalonyl-CoA decarboxylase (ECHDC1) gene: a novel player in ethylmalonic aciduria?” J Inherit Metab Dis. 2021 Sep;44(5):1215-1225. doi: 10.1002/jimd.12394. Muru K., Reinson K., Künnapas K., Lilleväli H., Nochi Z., Mosegaard S., Pajusalu S., Olsen R. and Õunap K. “FLAD1 Asso-ciated Multiple Acyl-CoA Dehydrogenase Deficiency Identified by Newborn Screening.”. Molecular Genetics & Genomic Medicine;7(9). doi: 10.1002/mgg3.915. García-Villoria J., de Azua B., Tort F., Mosegaard S., Matalonga L., Ugarteburu O., Teixidó L., Olsen R. and Ribes A. “FLAD1, a recently described gene associated to multiple acyl-CoA dehydrogenase deficiency (MADD) is mutated in a patient with myopathy, scoliosis and cataracts.”. Clinical Genetics;94(6):592-593. doi: 10.1111/cge.13452. Auranen M., Paetau A., Piirilä P., Pohju A., Salmi T., Lamminen A., Thure H., Löfberg M., Mosegaard S., Olsen R., Tyni T. “FLAD1 gene mutation causes riboflavin responsive MADD disease”. Neuromuscular Disorders;27(6):581-584. doi: 10.1016/j.nmd.2017.03.003. ID: 439
Clinical 1: from new genes to old and novel phenotypes The Australian genomics mitochondrial flagship: a national program delivering mitochondrial diagnoses 1Murdoch Children's Research Institute, Melbourne, Australia; 2University of Melbourne, Melbourne, Australia; 3Victorian Clinical Genetics Services, Melbourne,; 4Sydney Children’s Hospitals Network, Westmead, Australia; 5Macquarie University, Sydney, Australia; 6Women’s and Children’s Hospital, Adelaide, Australia; 7Tasmanian Clinical Genetics Service, Hobart, Australia; 8Queensland Children’s Hospital, Brisbane, Australia; 9Wesley Hospital, Brisbane, Australia; 10Garvan Institute, Sydney, Australia; 11Royal Melbourne Hospital, Melbourne, Australia; 12Royal Adelaide Hospital, Adelaide, Australia; 13John Hunter Hospital, Newcastle, Australia; 14Harry Perkins Institute of Medical Research, Perth, Australia; 15Perth Children’s Hospital, Perth, Australia; 16Yale School of Medicine, New Haven, CT, USA; 17Royal Perth Hospital, Perth, Australia; 18Royal Children’s Hospital, Melbourne, Australia; 19Mito Foundation, Sydney, Australia; 20Mater Hospital, Brisbane, Australia; 21Genetic Health Queensland, Brisbane, Australia; 22Monash University, Melbourne, Australia; 23Westmead Hospital, Westmead, Australia; 24Royal Hobart Hospital, Hobart, Australia Bibliography
Granata C, Caruana NJ, Botella J, Jamnick NA, Huynh K, Kuang J, Janssen HA, Reljic B, Mellett NA, Laskowski A, Stait TL, Frazier AE, Coughlan MT, Meikle PJ, Thorburn DR, Stroud DA and Bishop DJ (2021) Training-induced bioenergetic improvement in human skeletal muscle is associated with non-stoichiometric changes in the mitochondrial proteome without reorganisation of respiratory chain content. Nat Commun 12:7056 Wu Y, Balasubramaniam S, Rius R, Thorburn DR, Christodoulou J & Goranitis I (2021) Genomic sequencing for the diagnosis of childhood mitochondrial disorders: a health economic evaluation. Eur J Hum Genet 30:577-586 Frazier AE, Compton AG, Kishita Y, Hock DH, Welch AME, Amarasekera SS, Rius R, Formosa LE, Imai-Okazaki A, Francis D, Wang N, Lake NJ, Tregoning S, Jabbari JS, Lucattini A, Nitta KR, Ohtake A, Murayama K, Amor DJ, McGillivray G, Wong FY, van der Knaap MS, Vermeulen RJ, Wiltshire EJ, Fletcher JM, Lewis B, Baynam G, Ellaway C, Balasubramaniam S, Bhattacharya K, Freckmann ML, Arbuckle S, Rodriguez M, Taft RJ, Sadedin S, Cowley MJ, Minoche AE, Calvo SE, Mootha VK, Ryan MT, Okazaki V, Stroud DA, Simons C, Christodoulou J and Thorburn DR (2021) Fatal Perinatal Mitochondrial Cardiac Failure Caused by Recurrent De Novo Duplications in the ATAD3 Locus. Med 2:49-73 Riley LG, Cowley MJ, Gayevskiy V, Minoche AE, Puttick C, Thorburn DR, Rius, Compton AG, Menezes MJ, Battacharya K, Coman D, Ellaway C, Alexander IE, Adams L, Kava M, Robinson J, Sue CM, Balasubramaniam S and Christodoulou J (2020) The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease. Genet Med 22:1254-1261 ID: 649
Clinical 1: from new genes to old and novel phenotypes A new family with a case of severe early-onset muscle fatigue and a peculiar maternally inherited painful swelling in chewing muscles associated with homoplasmic m.15992A>T mutation in mitochondrial tRNAPro 1Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy; 2Department of Medicine, Surgery, and Health Sciences, University of Trieste, Trieste, Italy; 3Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. Bibliography
1. Auré K, Fayet G, Chicherin I, Rucheton B, Filaut S, Heckel AM, Eichler J, Caillon F, Péréon Y, Entelis N, Tarassov I, Lombès A. Homoplasmic mitochondrial tRNAPro mutation causing exercise-induced muscle swelling and fatigue. Neurol Genet. 2020 Jul 15;6(4):e480. ID: 358
Clinical 1: from new genes to old and novel phenotypes A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies. 1Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta; 2Department of Pathophysiology and Transplantation (DEPT), University of Milan ID: 618
Clinical 1: from new genes to old and novel phenotypes Biallelic pathogenic variants of PARS2 cause Developmental and Epileptic Encephalopathy with Spike-and-Wave Activation in Sleep 1IRCCS, Istituto delle Scienze Neurologiche di Bologna, Italy; 2Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy; 3Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Italy. ID: 548
Clinical 1: from new genes to old and novel phenotypes Novel KARS1 mutation causes early-onset lethal cardiomyopathy 1IRCCS Istituto Giannina Gaslini, Genoa; 2IRCCS Fondazione Stella Maris, Calambrone (PI); 3IRCCS Ospedale Bambin Gesù, Rome ID: 277
Clinical 1: from new genes to old and novel phenotypes The ER-MITO (Emilia Romagna-Mitochondrial) project: prevalence and genetics of Chronic Progressive External Ophthalmoplegia (CPEO) in an Italian region 1IRCCS Institute of Neurological Sciences of Bologna, Italy; 2Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy Bibliography
Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort. J Neurol. 2022; 269(12): 6555–6565. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Res. 2022 Aug 26; 50(15): 8749–8766 Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys. Mol Med. 2022; 28: 90. Published online 2022 Aug 3. doi: 10.1186/s10020-022-00519-z ID: 504
Clinical 1: from new genes to old and novel phenotypes UCHL1 missense and loss-of-function variants as an emerging cause of autosomal dominant optic atrophy (ADOA) 1IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; 2Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Italy; 3Ospedale Oftalmico Roma, Rome, Italy; 4Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy ID: 345
Clinical 1: from new genes to old and novel phenotypes Mitochondrial dysfunction in patients with early-onset UFM1-linked encephalopathy 1National Centre for Mitochondrial Diseases, Nice Teaching Hospital (CHU de Nice), Department of Medical Genetics, Nice, France; 2Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, France; 3APHM, La Timone Hospital, Department of Neuropediatrics, Marseille, France Bibliography
UQCRC2-related mitochondrial complex III deficiency, about 7 patients. Bansept C, Gaignard P, Lebigot E, Eyer D, Delplancq G, Hoebeke C, Mazodier K, Ledoyen A, Rouzier C, Fragaki K, Ait-El-Mkadem Saadi S, Philippe C, Bruel AL, Faivre L, Feillet F, Abi Warde MT. Mitochondrion. 2022 Dec 9;68:138-144. doi: 10.1016/j.mito.2022.12.001. ABEILLE: a novel method for ABerrant Expression Identification empLoying machine LEarning from RNA-sequencing data. Labory J, Le Bideau G, Pratella D, Yao JE, Ait-El-Mkadem Saadi S, Bannwarth S, El-Hami L, Paquis-Fluckinger V, Bottini S. Bioinformatics. 2022 Oct 14;38(20):4754-4761. doi: 10.1093/bioinformatics/btac603. Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability. Ait-El-Mkadem Saadi S, Kaphan E, Morales Jaurrieta A, Fragaki K, Chaussenot A, Bannwarth S, Maues De Paula A, Paquis-Flucklinger V, Rouzier C. Eur J Med Genet. 2022 Dec;65(12):104643. doi: 10.1016/j.ejmg.2022.104643. A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases. Pratella D, Ait-El-Mkadem Saadi S, Bannwarth S, Paquis-Fluckinger V, Bottini S. Int J Mol Sci. 2021 Oct 8;22(19):10891. doi: 10.3390/ijms221910891. Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders. Bris C, Goudenège D, Desquiret-Dumas V, Gueguen N, Bannwarth S, Gaignard P, Rucheton B, Trimouille A, Allouche S, Rouzier C, Saadi S, Jardel C, Slama A, Barth M, Verny C, Spinazzi M, Cassereau J, Colin E, Armelle M, Pereon Y, Martin-Negrier ML, Paquis-Flucklinger V, Letournel F, Lenaers G, Bonneau D, Reynier P, Amati-Bonneau P, Procaccio V. Genet Med. 2021 Sep;23(9):1769-1778. doi: 10.1038/s41436-021-01206-w. CHCHD10-Related Disorders. Ait-El-Mkadem Saadi S, Chaussenot A, Bannwarth S, Rouzier C, Paquis-Flucklinger V. 2015 Jul 1 [updated 2021 May 27]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Multi-Omics Approaches to Improve Mitochondrial Disease Diagnosis: Challenges, Advances, and Perspectives. Labory J, Fierville M, Ait-El-Mkadem S, Bannwarth S, Paquis-Flucklinger V, Bottini S. Front Mol Biosci. 2020 Nov 2;7:590842. doi: 10.3389/fmolb.2020.590842. Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases. Zereg E, Chaussenot A, Morel G, Bannwarth S, Sacconi S, Soriani MH, Attarian S, Cano A, Pouget J, Bellance R, Tranchant C, Lannes B, de Paula AM, Saadi Ait-El-Mkadem S, Chafino B, Berthet M, Fragaki K, Paquis-Flucklinger V, Rouzier C. Hum Mutat. 2020 Aug;41(8):1394-1406. doi: 10.1002/humu.24037. NDUFS6 related Leigh syndrome: a case report and review of the literature. Rouzier C, Chaussenot A, Fragaki K, Serre V, Ait-El-Mkadem S, Richelme C, Paquis-Flucklinger V, Bannwarth S. J Hum Genet. 2019 Jul;64(7):637-645. doi: 10.1038/s10038-019-0594-4. MT-CYB deletion in an encephalomyopathy with hyperintensity of middle cerebellar peduncles. Chaussenot A, Rouzier C, Fragaki K, Sacconi S, Ait-El-Mkadem S, Paquis-Flucklinger V, Bannwarth S. Neurol Genet. 2018 Sep 19;4(5):e268. doi: 10.1212/NXG.0000000000000268. eCollection 2018 Oct. PMID: 30294674 Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases. Plutino M, Chaussenot A, Rouzier C, Ait-El-Mkadem S, Fragaki K, Paquis-Flucklinger V, Bannwarth S. BMC Med Genet. 2018 Apr 7;19(1):57. doi: 10.1186/s12881-018-0568-y. PMID: 29625556 ID: 580
Clinical 1: from new genes to old and novel phenotypes A novel dominant variant in the ISCU gene is associated with mitochondrial myopathy 1Maria Sklodowska-Curie, Medical Academy in Warsaw, Poland; 2MedGen Medical Center, Warsaw, Poland; 3Institute of Psychiatry and Neurology, Warsaw, Poland Bibliography
1. Mochel F, Knight MA, Tong WH, Hernandez D, Ayyad K, Taivassalo T, Andersen PM, Singleton A, Rouault TA, Fischbeck KH, Haller RG. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet 2008;82:652–60. 2. Olsson A, Lind L, Thornell LE, Holmberg M. Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum Mol Genet 2008;17:1666–72. 3. Legati A., Reyes A., Ceccatelli Berti C., Stehling O., Marchet S., Lamperti C., Ferrari A., Robinson A.J., Mühlenhoff U., Lill R., et al. A Novel de Novo Dominant Mutation in ISCU Associated with Mitochondrial Myopathy. J. Med. Genet. 2017;54:815–824. ID: 499
Clinical 1: from new genes to old and novel phenotypes Expanding the spectrum of clinical presentations associated with COA8 pathogenic 1IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 2Dino Ferrari Center, University of Milan, Milan, Italy ID: 332
Clinical 1: from new genes to old and novel phenotypes A novel mitochondrial DNA variant, m.14430A>C, in MT-ND6 as the likely cause of Leigh syndrome with mitochondrial complex I deficiency. 1University of Cape Town, Cape Town, South Africa; 2National Health Laboratory Sevices, South Africa; 3Red Cross War Memorial Children's Hospital, Cape Town, South Africa; 4Constantiaberg Mediclinic, Cape Town, South Africa; 5Grootte Schuur Hospital, Cape Town, South Africa; 6Neuroscience Institute, University of Cape Town, Cape Town, South Africa; 7Human Metabolomics, North-West University, Potchefstroom, South Africa Bibliography
Meldau S, Owen EP, Khan K, Riordan GT. “Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings.” J Clin Pathol. 2022 [https://doi.org/10.1136/jclinpath-2020-207026] A.C. Muller-Nedebock, S. Meldau, C. Lombard, S. Abrahams, F.H. van der Westhuizen, S. Bardien, Increased blood-derived mitochondrial DNA copy number in African ancestry individuals with Parkinson's disease Parkinsonism Relat Disord 101 (2022) 1-5. DOI: 10.1016/j.parkreldis.2022.06.003 Meldau S, Fratter C, Bhengu LN, et al. Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa. Mol Genet Metab Rep 2020;24:100629 doi: 10.1016/j.ymgmr.2020.100629. Roberts L, Julius S, Dawlat S, Yildiz S, Rebello G, Meldau S, Pillay K, Esterhuizen A, Vorster A, Benefeld G, Da Rocha J, Beighton P, Sellars SL, Thandrayen K, Pettifor JM, Ramesar RS. Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B. Hum Mutat 2020 doi: 10.1002/humu.24094 Meldau, S., De Lacy R, Riordan G, Goddard L, Pillay K, Fieggen K, Marais D, Van der Watt G, “Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.” Clin Genet, 2018 [PMID:29318572 DOI:10.1111/cge.13208] O’Keefe, H., Queen, R.A., Meldau, S., Lord, P., Elson, J.L. (2018) “Haplogroup context is less important in the penetrance of Mitochondrial DNA complex I mutations compared to mt-tRNA mutations.” J Mol Evol 86:395-403. Ng, Y. S., Lax, N. Z., Maddison, P., Alston, C. L., Blakely, E. L., Hepplewhite, P. D., Riordan, G., Meldau, S., Chinnery, P. F., Pierre, G., Chronopoulou, E., Du, A., Hughes, I., Morris, A. A., Kamakari, S., Chrousos, G., Rodenburg, R. J., Saris, C. G. J., Feeney, C., Hardy, S. A., Sakakibara, T., Sudo, A., Okazaki, Y., Murayama, K., Mundy, H., Hanna, M. G., Ohtake, A., Schaefer, A. M., Champion, M. P., Turnbull, D. M., Taylor, R. W., Pitceathly, R. D. S., McFarland, R. and Gorman, G. S., MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load. EBioMedicine 2018. Meldau, S., G. Riordan, F. Van der Westhuizen, J. L. Elson, I. Smuts, M. S. Pepper and H. Soodyall (2016). "Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease?" S Afr Med J 106(3): 234-236. (Invited editorial) Van der Westhuizen, F. H., P. Z. Sinxadi, C. Dandara, I. Smuts, G. Riordan, S. Meldau, A. N. Malik, M. G. Sweeney, Y. Tsai, G. W. Towers, R. Louw, G. S. Gorman, B. A. Payne, H. Soodyall, M. S. Pepper and J. L. Elson (2015). "Understanding the Implications of Mitochondrial DNA Variation in the Health of Black Southern African Populations: The 2014 Workshop." Hum Mutat 36(5): 569-571. ID: 379
Clinical 1: from new genes to old and novel phenotypes Leigh syndrome and Fanconi renotubular syndrome are the main clinical phenotype due to mutations in NDUFAF6 gene. 1Bambino Gesù Children Hospital, Italy; 2UCL Queen Square Institute of Neurology; 3Université Paris Descartes, Sorbonne Paris Cité ID: 544
Clinical 1: from new genes to old and novel phenotypes Mitochondrial encephalomyopathy associated with the m.618T>C in MT-TF 1Hospital Municipal Dr. José de Carvalho, Brazil; 2Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil ID: 296
Clinical 1: from new genes to old and novel phenotypes TWNK in Parkinson's disease: a Movement Disorder and Mitochondrial Disease Center perspective study 1School of Medicine and Surgery and Milan Center for Neuroscience, University of Milan-Bicocca.; 2Foundation IRCCS San Gerardo dei Tintori, Monza; 3Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan 20122, Italy; 4Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy; 5IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 6Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; 7Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy; 8Neurology Unit, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari (APSS) di Trento, Trento, Italy; 9Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Audiology Unit, Milan, Italy; 10University of Milan, Milan, Italy; 11Department of Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas, Research Hospital, Milan, Italy; 12Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, SE 405 30 Gothenburg, Sweden; 13Department of Molecular Medicine, University of Pavia, Pavia, Italy. ID: 394
Clinical 1: from new genes to old and novel phenotypes Novel pathogenic MT-ND3 variant causing a particular MELAS phenotype 1CHU de Nice, France; 2Université Côte d'Azur, CNRS, INSERM, IRCAN; 3Service de Neurologie- Hôpital Pasteur 2, CHU de Nice; 4Centre de référence des Maladies neuromusculaires ID: 474
Clinical 1: from new genes to old and novel phenotypes Mitochondrial molecular genetic findings in the South African diagnostic setting 1University of Cape Town, Cape Town, South Africa; 2National Health Laboratory Sevices, South Africa; 3Red Cross War Memorial Children's Hospital, Cape Town, South Africa Bibliography
Meldau S, Owen EP, Khan K, Riordan GT. “Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings.” J Clin Pathol. 2022 [https://doi.org/10.1136/jclinpath-2020-207026] A.C. Muller-Nedebock, S. Meldau, C. Lombard, S. Abrahams, F.H. van der Westhuizen, S. Bardien, Increased blood-derived mitochondrial DNA copy number in African ancestry individuals with Parkinson's disease Parkinsonism Relat Disord 101 (2022) 1-5. DOI: 10.1016/j.parkreldis.2022.06.003 Meldau S, Fratter C, Bhengu LN, et al. Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa. Mol Genet Metab Rep 2020;24:100629 doi: 10.1016/j.ymgmr.2020.100629. Roberts L, Julius S, Dawlat S, Yildiz S, Rebello G, Meldau S, Pillay K, Esterhuizen A, Vorster A, Benefeld G, Da Rocha J, Beighton P, Sellars SL, Thandrayen K, Pettifor JM, Ramesar RS. Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B. Hum Mutat 2020 doi: 10.1002/humu.24094 Meldau, S., De Lacy R, Riordan G, Goddard L, Pillay K, Fieggen K, Marais D, Van der Watt G, “Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.” Clin Genet, 2018 [PMID:29318572 DOI:10.1111/cge.13208] O’Keefe, H., Queen, R.A., Meldau, S., Lord, P., Elson, J.L. (2018) “Haplogroup context is less important in the penetrance of Mitochondrial DNA complex I mutations compared to mt-tRNA mutations.” J Mol Evol 86:395-403. Ng, Y. S., Lax, N. Z., Maddison, P., Alston, C. L., Blakely, E. L., Hepplewhite, P. D., Riordan, G., Meldau, S., Chinnery, P. F., Pierre, G., Chronopoulou, E., Du, A., Hughes, I., Morris, A. A., Kamakari, S., Chrousos, G., Rodenburg, R. J., Saris, C. G. J., Feeney, C., Hardy, S. A., Sakakibara, T., Sudo, A., Okazaki, Y., Murayama, K., Mundy, H., Hanna, M. G., Ohtake, A., Schaefer, A. M., Champion, M. P., Turnbull, D. M., Taylor, R. W., Pitceathly, R. D. S., McFarland, R. and Gorman, G. S., MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load. EBioMedicine 2018. Meldau, S., G. Riordan, F. Van der Westhuizen, J. L. Elson, I. Smuts, M. S. Pepper and H. Soodyall (2016). "Could we offer mitochondrial donation or similar assisted reproductive technology to South African patients with mitochondrial DNA disease?" S Afr Med J 106(3): 234-236. (Invited editorial) Van der Westhuizen, F. H., P. Z. Sinxadi, C. Dandara, I. Smuts, G. Riordan, S. Meldau, A. N. Malik, M. G. Sweeney, Y. Tsai, G. W. Towers, R. Louw, G. S. Gorman, B. A. Payne, H. Soodyall, M. S. Pepper and J. L. Elson (2015). "Understanding the Implications of Mitochondrial DNA Variation in the Health of Black Southern African Populations: The 2014 Workshop." Hum Mutat 36(5): 569-571. ID: 183
Clinical 1: from new genes to old and novel phenotypes Known genes, new genes and new phenotypes in inherited mitochondrial eye diseases 1Moorfields Eye Hospital NHS Foundation Trust, London, UK; 2Institute of Ophthalmology, University College London, London, UK; 3The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK; 4North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 5John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 6Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK Bibliography
Jurkute N et al. Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches. Eur J Hum Genet. 2018. doi:10.1038/s41431-018-0235-y. PMID: 30143805. Jurkute N et al. SSBP1 mutations in dominant optic atrophy with variable retinal degeneration. Ann Neurol. 2019 Sep;86(3):368-383. doi: 10.1002/ana.25550. Epub 2019 Jul 31. PMID: 31298765. Jurkute N et al. SSBP1-Disease Update: Expanding the Genetic and Clinical Spectrum, Reporting Variable Penetrance and Confirming Recessive Inheritance. Invest Ophthalmol Vis Sci. 2021 Dec 1;62(15):12. doi: 10.1167/iovs.62.15.12. PMID: 34905022. Jurkute N et al. Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature. Invest Ophthalmol Vis Sci. 2021 May 3;62(6):2. doi: 10.1167/iovs.62.6.2. PMID: 33938912. Jurkute N et al. Whole Genome Sequencing Identifies a Partial Deletion of RTN4IP1 in a Patient With Isolated Optic Atrophy. J Neuroophthalmol. 2022 Apr 19. doi: 10.1097/WNO.0000000000001589. PMID: 35439212. Jurkute N et al. Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model. Brain Commun. 2021 Jul 20;3(3):fcab162. doi: 10.1093/braincomms/fcab162. PMID: 34466801. Jurkute N et al. Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype. NPJ Genom Med. 2022 Oct 20;7(1):60. doi: 10.1038/s41525-022-00330-z. PMID: 36266294; PMCID: PMC9581764. Other publications available at: https://pubmed.ncbi.nlm.nih.gov/?term=jurkute. ID: 652
Clinical 1: from new genes to old and novel phenotypes LHON spectrum disorder: new phenotypes and genotypes 1San Raffaele Hospital, Italy; 2IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica (Bologna, Italy); 3Studio Oculistico d’Azeglio (Bologna, Italy); 4Department of Clinical Science and Community Health, University of Milan, (Milan, Italy); 5Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna (Bologna, Italy) ID: 218
Clinical 1: from new genes to old and novel phenotypes Chronic asymmetric progressive external ophthalmoplegia without eyelid weakness Seoul National University Hospital, Korea, Republic of (South Korea) ID: 586
New technological developments and OMICS Bayesian inference enables discovery of functional effects of heteroplasmic mitochondrial mutations in the developing brain Imperial College London, United Kingdom ID: 337
New technological developments and OMICS Cell lineage-specific mitochondrial gene expression is established in the early embryo, prior to organ maturation 1Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 2Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 3Novo Nordisk Research Centre Oxford, Innovation Building, University of Oxford, Old Road Campus, Oxford, UK; 4Functional Genomics Centre, Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK; 5Max Planck Institute for Biology of Ageing, Cologne, Germany; 6Biosciences Institute, Faculty of Medical Sciences, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK Bibliography
1. Burr et al., Cell, 2023, DOI: 10.1016/j.cell.2023.01.034 ID: 563
New technological developments and OMICS Identifying mitochondrial methyltransferases using unbiased proteome-ligand profiling 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden, Sweden; 2Centre of Inherited metabolic diseases, Karolinska University Hospital, Stockholm, Sweden ID: 185
New technological developments and OMICS Engineering mitochondrial aminoacyl-tRNA synthetases as a tool to investigate mitochondrial protein synthesis Newcastle University, United Kingdom Bibliography
Albus CA, Berlinguer-Palmini R, Hewison C, McFarlane F, Savu EA, Lightowlers RN, Chrzanowska-Lightowlers ZM, Zorkau M. Mitochondrial Translation Occurs Preferentially in the Peri-Nuclear Mitochondrial Network of Cultured Human Cells. Biology (Basel). 2021 Oct 15; 10 (10):1050. Zorkau M, Albus CA, Berlinguer-Palmini R, Chrzanowska-Lightowlers ZMA, Lightowlers RN. High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells. Proc Natl Acad Sci U S A.2021 Feb 9; 118(6):e2008778118. ID: 405
New technological developments and OMICS Short-read NGS for the screening of structural and copy number alterations in mtDNA as powerful diagnostic tool. 1Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, (Munich, Germany); 2Institute of Neurogenomics, Helmholtz Zentrum München (Neuherberg, Germany); 3Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy); 4Department of Neurology, Friedrich-Baur-Institute, LMU Hospital, Ludwig Maximilians University (Munich, Germany); 5Department of Pathophysiology and Transplantation, University of Milan (Milan, Italy) ID: 613
New technological developments and OMICS Ethical dilemmas and diagnostic uplifts; primary mitochondrial disease the era of first line whole genome sequencing 1UCL Queen Square Institute of Neurology, United Kingdom; 2NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK.; 3Centre for Personalised Medicine, and Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK; 4Clinical Ethics, Law and Society, Faculty of Medicine, University of Southampton, Southampton, UK Bibliography
(1) Raymond, F. L., Horvath, R. & Chinnery, P. F. First-line genomic diagnosis of mitochondrial disorders. Nat. Rev. Genet. 19, 399–400 (2018). (2) Macken, W. L., Vandrovcova, J., Hanna, M. G. & Pitceathly, R. D. S. Applying genomic and transcriptomic advances to mitochondrial medicine. Nat. Rev. Neurol. 0123456789, (2021). (3) Macken WL et al Mitochondrial DNA variants in genomic data: diagnostic uplifts and predictive implications. Nat Rev Genet. 2021 Sep;22(9):547-548. ID: 506
New technological developments and OMICS Analysis of mitochondrial metabolism using 13C-labeled mass isotopologue analysis and mass spectrometry as a new approach for the diagnostics of mitochondrial disorders 1Department of Genetics, Translational Metabolic Laboratory, Radboudumc, Nijmegen, The Netherlands.; 2Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, The Netherlands Bibliography
Barbosa-Gouveia S, Vázquez-Mosquera ME, Gonzalez-Vioque E, Hermida-Ameijeiras Á, Valverde LL, Armstrong-Moron J, Fons-Estupiña MDC, Wintjes LT, Kappen A, Rodenburg RJ, Couce ML. Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome. Int J Mol Sci. 2021 Dec 15;22(24):13484. doi: 10.3390/ijms222413484. PMID: 34948281; PMCID: PMC8708263. Wintjes LTM, Kava M, van den Brandt FA, van den Brand MAM, Lapina O, Bliksrud YT, Kulseth MA, Amundsen SS, Selberg TR, Ybema-Antoine M, Tutakhel OAZ, Greed L, Thorburn DR, Tangeraas T, Balasubramaniam S, Rodenburg RJT. A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction. Hum Mutat. 2021 Feb;42(2):135-141. doi: 10.1002/humu.24137. Epub 2020 Nov 30. PMID: 33169484; PMCID: PMC7898715. ID: 421
New technological developments and OMICS Subcellular metabolomics: a pipeline for compartment-specific metabolic investigations in a mouse model of Leigh syndrome North-West University, South Africa Bibliography
Terburgh K, Lindeque JZ, van der Westhuizen FH, Louw R (2021) Cross‑comparison of systemic and tissue‑specific metabolomes in a mouse model of Leigh syndrome. Metabolomics. 17:101 (IF 4.290 Van der Walt G, Lindeque JZ, Mason S, Louw R (2021) Sub-cellular metabolomics contributes mitochondria-specific metabolic insights to a mouse model of Leigh syndrome. Metabolites 11, 658 (IF 4.932). Terburgh K, Coetzer J, Lindeque JZ, van der Westhuizen FH, Louw R (2021) Aberrant BCAA and glutamate metabolism linked to regional neurodegeneration in a mouse model of Leigh syndrome. BBA Molecular Basis of Disease. 1867 (5) 166082 (IF 4.352). ID: 480
New technological developments and OMICS High‐content screening for modulators of mitochondria‐ER contact sites and identification of their protein targets 1Department of Biology, University of Padova, Italy; 2Department of Biomedical Sciences, University of Padova, Italy ID: 617
New technological developments and OMICS A novel Approach to assess the pathogenicity of mtDNA Variants RadboudUMC, Translational Metabolic Laboratory, Dept of Pediatrics, Nijmegen, The Netherlands ID: 508
New technological developments and OMICS At the core of the apoptotic foci CECAD, Germany ID: 167
New technological developments and OMICS Clinical utility of ultra-rapid genomic testing for infants and children with a suspected mitochondrial disorder 1Murdoch Children's Research Institute, Melbourne, Australia; 2University of Melbourne, Melbourne, Australia; 3Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; 4University of Sydney, Sydney, Australia; 5Australian Genomics, Melbourne, Australia; 6Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia; 7Sydney Children’s Hospitals Network – Westmead, Sydney, Australia; 8Sydney Children’s Hospitals Network – Randwick, Sydney, Australia; 9University of New South Wales, Sydney, Australia; 10Monash Genetics, Monash Health, Melbourne, Australia; 11Department of Paediatrics, Monash University, Melbourne, Australia; 12Paediatric and Reproductive Genetics Unit, Women’s and Children’s Hospital, North Adelaide, Australia; 13Adelaide Medical School, The University of Adelaide, Adelaide, Australia; 14Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia; 15Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, Australia; 16School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; 17Genetic Services of Western Australia, Perth, Australia; 18Department of Clinical Genetics, The Canberra Hospital, Canberra, Australia; 19Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; 20Randwick Genomics Laboratory, NSW Health Pathology, Prince of Wales Hospital, Sydney, Australia; 21Neuroscience Research Australia (NeuRA) and Prince of Wales Clinical School, UNSW, Sydney, Australia Bibliography
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St John, M., Thauvin-Robinet, C., Traficante, G., van der Sluijs, P.J., Vergano, S.A., Vos N., Walden, K.K., Azmanov, D., Balci, T., Banka, S., Gecz, J., Henneman, P., Lee, J.A., Mannens, M.M.A.M., Roscioli, T., Siu, V., Amor, D.J., Baynam, G., Bend, E.G., Boycott, K., Brunetti-Pierri, N., Campeau, P.M., Christodoulou, J., Dyment, D., Esber, N. Fahrner, J.A., Fleming M.D., Genevieve, D., Kerrnohan, K.D., McNeill, A., Menke, L.A., Merla, G., Prontera, P., Rockman-Greenberg, C., Schwartz, C., Skinner, S.A., Stevenson, R.E., Vitobello, A., Tartaglia, M., Tedder, M.L., Alders, M., Sadikovic, B. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders. Human Mutation. 2022: 43(11); 1609-1628. 13.Rius R., Bennett, N.K., Bhattacharya, K., Riley. L.G., Yüksel, Z., Formosa. L.E., Compton, A.G., Dale, R.C., Cowley, M.J., Gayevskiy, V., Al Tala, S., Almehery, A.A., Ryan, M.T., Thorburn, D.R., Nakamura, K., Christodoulou, J. Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy. Human Mut. 2022: 43 (12); 1970-1978. 14.Long, J., Best, S., Nic Giolla Easpaig, B., Hatem, S., Fehlberg, Z., Christodoulou, J., Braithwaite, J. Needs of people with rare diseases that can be supported by electronic resources: a scoping review. Published by BMJ Open 2022 Sep 1;12(9):e060394. doi: 10.1136/bmjopen-2021-060394. 15.Temple, S.E.L., Ho, G., Bennetts, B., Gayagay, T., Boggs, K., Buckley, M., Roscioli, T., Zhu, Y., Mowat, D., Christodoulou, J., Schultz, A., Vidic, N., Lunke, S., Stark, Z., Jaffe,A. The role of exome sequencing in interstitial or diffuse lung disease of childhood. Orphanet J Rare Dis. 2022: 17(1); 350 16.Tudini E, Andrews J, Lawrence D, King-Smith SL, Baker N, Baxter L, Beilby J, Bennetts B, Beshay V, Black M, Boughtwood TF, Brion K, Cheong PL, Christie M, Christodoulou J, Chong B, Cox K, Davis MR, Dejong L, Dinger ME, Doig KD, Douglas E, Dubowsky A, Ellul M, Fellowes A, Fisk K, Fortuno C, Friend K, Gallagher RL, Gao S, Hackett E, Hadler J, Hipwell M, Ho G, Hollway G, Hooper AJ, Kassahn K, Krishnaraj R, Lau C, Le H, Leong HS, Lundie B, Lunke S, Marty A, McPhillips M, Nguyen LT, Nones K, Palmer K, Pearson JV, Quinn MCJ, Rawlings LH, Sadedin S, Sanchez L, Schreiber AW, Sigalas E, Simsek A, Soubrier J, Stark Z, Thompson BA, James U J, Vakulin CG, Wells AV,Wise CA, Woods R, Ziolkowski A, Brion M-J, Scott HS,Thorne NP, Spurdle AB, on behalf of the Shariant Consortium. Shariant platform: enabling evidence sharing across Australian clinical genetic testing laboratories to support variant interpretation. Amer J Human Genet 2022: 109(11); 1960-197. 17.Vogel GF, Mozer-Glassberg Y, Landau YE, Schlieben LD, Prokisch H, Brennenstuhl H, Pechlaner A, Baker JJ, Morrison K, Marina AD, Khan A, Burnyte B, Coman D, Soler-Alfonso C, Scaglia F, Ciara E, M Das AM, Teles EL, Nicastro E, Distelmaier F, Gaignard P, Gonzales E, Baric I, Margolis MG, Christodoulou J, Thorburn DR, Murayama K, Darin N, Pennisi A, Schiff M, Rötig A, Ganetzky RD, Santer R, Konstantopoulou V, Fang W, Wang J-S, McFarland R, Taylor RW, Shagrani MA, Alkuraya FS, Braverman N, Ersoy M Kose M, Feichtinger R, Mayr J, Weghuber D, Wortmann S. Genotypic diversity and phenotypic spectrum of infantile liver failure due to variants in TRMU. Genet Med accepted 26th September 2022. 18.Kline BL, Sylvie Jaillard S, Bell KM, Bakhshalizadeh S, 1 Robevska G, van den Bergen J, Dulon J, Ayers KL, Christodoulou J, Tchan MC, Touraine P, Sinclair AH, Tucker EJ. Integral role of the mitochondrial ribosome in supporting ovarian function: MRPS7 variants in syndromic premature ovarian insufficiency. Genes, accepted 11th November 2022. 19.Neyroud, A.S., Rudinger-Thirion, J., Frugier, M., Riley, L.G., Bidet, M., Akloul, L., Gilot, D., Christodoulou, J., Ravel, C., Sinclair, A.H., Belaud-Rotureau, M-A., Tucker, E.J., Jaillard, S. LARS2 variants can present as isolated premature ovarian insufficiency in the absence of overt hearing loss. Eur J Human Genet, 1 December 2022, Online ahead of print doi: 10.1038/s41431-022-01252-1 ID: 511
New technological developments and OMICS Contribution of RNA-seq to diagnosis and determination of functional impact of candidate variants in 45 patients suspected of mitochondrial disease. 1Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, Barcelona, Spain; 2Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; 3CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology and Universitat Pompeu Fabra, Barcelona, Spain ID: 560
New technological developments and OMICS Dynamics of NAD and glutathione metabolites in blood during aging, in disease and upon supplementation with NAD-booster 1University of Helsinki, Finland; 2NADMED Ltd, Finland; 3HUS Diagnostic Centre, Finland ID: 446
New technological developments and OMICS Enzymatic assay for UDP-GlcNAc and its application in the parallel assessment of substrate availability and protein O-GlcNAcylation 1Folkhalsan Research Center, Finland; 2Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Finland; 3Viikki Metabolomics Unit, University of Helsinki, Finland; 4Children’s Hospital, Helsinki University Hospital, Finland ID: 307
New technological developments and OMICS Genetic testing for mitochondrial disease: The United Kingdom best practice guidelines 1NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 2Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 3Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; 4Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Bibliography
PMID: 36513735 PMID: 35700042 PMID: 34732400 ID: 432
New technological developments and OMICS Identification of uncharacterized genes involved in mitochondrial OXPHOS function and integrity. Centro de Biología Molecular Severo Ochoa, Spain ID: 388
New technological developments and OMICS Investigating the role of mito-nuclear genetic variation in determining m.3243A>G variant heteroplasmy 1Wellcome Centre for Mitochondrial Research and Institute for Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK; 2NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 3Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU Klinikum), Munich, Germany; 4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK; 5Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; 6Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; 7Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 8German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 9Department of Neurology, University Hospital Bonn, Bonn, Germany; 10Neurological Institute of Pisa, Italy; 11Institute of Human Genetics, School of Medicine, Technische Universität München, München, Germany; 12Institute of Neurogenomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; 13Department of Neurology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 14Department of Neurology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany; 15Neurogenetics Unit, The National Hospital for Neurology and Neurosurgery, London, UK; 16Population Health Sciences Institute, Newcastle University, UK ID: 424
New technological developments and OMICS Mitochondrial DNA depletion and deletion analysis using smMIPs 1Translational Metabolic Laboratory, Radboudumc, Nijmegen, The Netherlands; 2Radboud Center for Mitochondrial Medicine (RCMM), Radboudumc, Nijmegen, The Netherlands; 3Department of Pediatrics, Radboudumc, Nijmegen, The Netherlands ID: 513
New technological developments and OMICS Ultrastructure of mitochondria in 3D from volume electron microscopy 1Department of Computer Science, University of Copenhagen, Denmark; 2Center for Quantification of Imaging Data from MAX IV; 3Department of Clinical Medicine, Aarhus University, Denmark; 4Center of Functionally Integrative Neuroscience ID: 304
New technological developments and OMICS Visualizing ATP dynamics in living mice National Cerebral and Cardiovascular Center, Japan ID: 184
New technological developments and OMICS Applying sodium carbonate extraction mass spectrometry to investigate defects in the mitochondrial respiratory chain 1Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Australia; 2Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia; 3Department of Biochemistry and Molecular Biology, Monash University, Melbourne,Australia; 4The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; 5Baker Heart and Diabetes Institute, Melbourne, Australia; 6Institute for Health and Sport (IHES), Victoria University, Melbourne, Australia Bibliography
[1]Hock D, Robinson D and Stroud D (2020), “Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome”, Biochemical Journal, 477(21):4085-4132. [2]Robinson D, Hock D, Muellner-Wong L, Kugapreethan R, Reljic B, Surgenor E, Rodrigues C, Caruana N and Stroud D (2022), “Applying Sodium Carbonate Extraction Mass Spectrometry to Investigate Defects in the Mitochondrial Respiratory Chain”, Front Cell Dev Biol, 10:786268 ID: 587
New technological developments and OMICS Global analysis of protein methylation in the mitochondrial compartment of cancer cells: a proteomic approach 1Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS Milano, Italy; 2European School of Molecular Medicine (SEMM); 3Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy; 4Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy Bibliography
[1]S.C. Larsen, K.B. Sylvestersen, A. Mund, D. Lyon, M. Mullari, M. V. Madsen, J.A. Daniel, L.J. Jensen, M.L. Nielsen, Proteome-wide analysis of arginine monomethylation reveals widespread occurrence in human cells, Sci. Signal. 9 (2016). https://doi.org/10.1126/SCISIGNAL.AAF7329/SUPPL_FILE/9_RS9_TABLES_S1_TO_S5.ZIP. [2]J.M. Małecki, E. Davydova, P. Falnes, Protein methylation in mitochondria, J. Biol. Chem. 298 (2022). https://doi.org/10.1016/J.JBC.2022.101791. [3]M. Maniaci, F.L. Boffo, E. Massignani, T. Bonaldi, Systematic Analysis of the Impact of R-Methylation on RBPs-RNA Interactions: A Proteomic Approach, Front. Mol. Biosci. 8 (2021) 818. https://doi.org/10.3389/FMOLB.2021.688973/BIBTEX. [4]W. juan Li, Y. hui He, J. jing Yang, G. sheng Hu, Y. an Lin, T. Ran, B. ling Peng, B. lan Xie, M. feng Huang, X. Gao, H. hua Huang, H.H. Zhu, F. Ye, W. Liu, Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth, Nat. Commun. 2021 121. 12 (2021) 1–20. https://doi.org/10.1038/s41467-021-21963-1. [5]V. Spadotto, R. Giambruno, E. Massignani, M. Mihailovich, M. Maniaci, F. Patuzzo, F. Ghini, F. Nicassio, T. Bonaldi, PRMT1-mediated methylation of the microprocessor-associated proteins regulates microRNA biogenesis, Nucleic Acids Res. 48 (2020) 96–115. https://doi.org/10.1093/NAR/GKZ1051. [6]D. Musiani, R. Giambruno, E. Massignani, M.R. Ippolito, M. Maniaci, S. Jammula, D. Manganaro, A. Cuomo, L. Nicosia, D. Pasini, T. Bonaldi, PRMT1 Is Recruited via DNA-PK to Chromatin Where It Sustains the Senescence-Associated Secretory Phenotype in Response to Cisplatin, Cell Rep. 30 (2020) 1208-1222.e9. https://doi.org/10.1016/J.CELREP.2019.12.061/ATTACHMENT/17FA0EA5-8E2C-4786-AFA1-3008203E27DB/MMC5.XLSX. [7]Q. Wu, M. Schapira, C.H. Arrowsmith, D. Barsyte-Lovejoy, Protein arginine methylation: from enigmatic functions to therapeutic targeting, Nat. Rev. Drug Discov. 20 (2021). https://doi.org/10.1038/s41573-021-00159-8. [8]M. Bremang, A. Cuomo, A.M. Agresta, M. Stugiewicz, V. Spadotto, T. Bonaldi, Mass spectrometry-based identification and characterisation of lysine and arginine methylation in the human proteome, Mol. Biosyst. 9 (2013) 2231–2247. https://doi.org/10.1039/C3MB00009E. [9]E. Massignani, A. Cuomo, D. Musiani, S.G. Jammula, G. Pavesi, T. Bonaldi, hmSEEKER: Identification of hmSILAC Doublets in MaxQuant Output Data, Proteomics. 19 (2019). https://doi.org/10.1002/PMIC.201800300. [10]E. Massignani, M. Maniaci, T. Bonaldi, Heavy Methyl SILAC Metabolic Labeling of Human Cell Lines for High-Confidence Identification of R/K-Methylated Peptides by High-Resolution Mass Spectrometry, Methods Mol. Biol. 2603 (2023) 173–186. https://doi.org/10.1007/978-1-0716-2863-8_14. ID: 344
New technological developments and OMICS MITODIAG : The French network of diagnostic laboratories for mitochondrial diseases 1Service de génétique médicale, Centre de référence des maladies mitochondriales, CHU Nice, Université Cote d’Azur, CNRS, INSERM, IRCAN, Nice; 2Filnemus, laboratoire de génétique moléculaire, CHU Montpellier; 3Service de génétique, Institut de Biologie en santé, Centre National de référence Maladies Neurodégénératives et Mitochondriales, CHU Angers; 4Fédération de génétique médicale, Service de génétique moléculaire du GH Necker-enfants malades, Hôpital Necker-Enfants Malades, Paris; 5Laboratoire de Biochimie, Pôle BPP, CHU Paris Sud, Hôpital Bicêtre-le Kremlin Bicêtre, Paris; 6Pôle de biologie et pathologie, CHU Bordeaux; 7Unité fonctionnelle d’histologie moléculaire, Service de pathologie, CHU Bordeaux-GU Pellegrin, Bordeaux; 8Service de biochimie et biologie moléculaire Grand Est, UM Maladies Héréditaires du Métabolisme, Centre de biologie et pathologie Est, CHU Lyon HCL, GH Est, Lyon; 9Laboratoire de génétique, Hématologie et Immunologie, CHU Reims; 10Laboratoire de génétique moléculaire: maladies héréditaires et oncologie, Service de biochimie, biologie moléculaire et toxicologie environnementale, CHU Grenoble et des Alpes, Institut de biologie et pathologie, Grenoble; 11Service de biochimie, Pôle Biologie, Pharmacie et Hygiène, CHU Caen, Hôpital de la Côte de Nacre, Caen; 12Laboratoire de Génétique Moléculaire, CHU Montpellier, PhyMedExp, Université de Montpellier, INSERM, CNRS, Montpellier; 13Filnemus, Assistance Publique Hôpitaux Marseille, Service de Neurologie, Hôpital La Timone, Marseille Bibliography
Claire B, Pauline G, Elise L, Didier E, Geoffroy D, Célia H, Karin M, Anaïs L, Cécile R, Konstantina F, Saadi Samira AE, Christophe P, Ange-Line Christophe B, Laurence F, François F, Warde Marie-Thérèse A.UQCRC2-related mitochondrial complex III deficiency, about 7 patients. Mitochondrion. 2022 Dec 9:S1567-7249(22)00105-2. doi: 10.1016/j.mito.2022.12.001. Ait-El-Mkadem Saadi S., Kaphan E., Jaurrieta A., Fragaki K., Chaussenot A., Bannwarth S., Maues De Paula A., Paquis-Flucklinger V., Rouzier C. Splicing variants in NARS2 are associated with milder phenotypes and intra-familial variability. Eur J Med Genet. 2022 Dec;65(12):104643. doi: 10.1016/j.ejmg.2022.104643. Epub 2022 Oct 14. Bris C, Goudenège D, Desquiret-Dumas V, Gueguen N, Bannwarth S, Gaignard P, Rucheton B, Trimouille A, Allouche S, Rouzier C, Saadi S, Jardel C, Slama A, Barth M, Verny C, Spinazzi M, Cassereau J, Colin E, Armelle M, Pereon Y, Martin-Negrier ML, Paquis-Flucklinger V, Letournel F, Lenaers G, Bonneau D, Reynier P, Amati-Bonneau P, Procaccio V. Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders. Genet Med. 2021 Sep;23(9):1769-1778 Elamine Zereg, Annabelle Chaussenot, Godelieve Morel, Sylvie Bannwarth, Sabrina Sacconi , Marie-Hélène Soriani, Shahram Attarian, Aline Cano, Jean Pouget, Rémi Bellance, Christine Tranchant, Béatrice Lannes, André Maues de Paula, Samira Saadi Ait-El-Mkadem, Bernadette Chafino, Mathieu Berthet, Konstantina Fragaki, Véronique Paquis-Flucklinger, Cécile Rouzier. Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases. Hum Mutat . 2020 Aug;41(8):1394-1406. doi: 10.1002/humu.24037. Epub 2020 Jun 12. ID: 331
New technological developments and OMICS Multiomic mitochondrial and metabolic screening reveals potential biomarkers in inclusion body myositis 1Hereditary Metabolic Diseases and Muscular Diseases Lab, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 2Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain; 3CIBERER— Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain; 4Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu; Esplugues de Llobregat, Barcelona, Spain ID: 465
New technological developments and OMICS Network analysis of protein-protein interactions identifies intermediate filaments as a novel mitochondrial dynamics related structure Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, The Netherlands ID: 170
New technological developments and OMICS Establishment of mitochondrial proline metabolic disorder patient-derived induced pluripotent stem cells as a new cellular model for aging associated disease study Mackay Memorial Hospital, Taiwan Bibliography
Huang YW, Chiang MF, Ho CS, Hung PL, Hsu MH, Lee TH, Chu LJ, Liu H, Tang P, Victor Ng W*, Lin DS*. A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder. Aging Dis 2018;9(6),1043-1057. ID: 659
New technological developments and OMICS Mitochondrial disorders unraveled by NGS technologies 1Research centre for medical genetics, Russian Federation; 2Morozov's Moscow City Child Clinical Hospital, Moscow, Russia Bibliography
Chinnery PF, Hudson G. Mitochondrial genetics. Br Med Bull. 2013;106(1):135-59. doi: 10.1093/bmb/ldt017. Epub 2013 May 22. PMID: 23704099; PMCID: PMC3675899. Rahman J, Rahman S. Mitochondrial medicine in the omics era. Lancet. 2018 Jun 23;391(10139):2560-2574. doi: 10.1016/S0140-6736(18)30727-X. Epub 2018 Jun 18. PMID: 29903433. Legati A, Reyes A, Nasca A, Invernizzi F, Lamantea E, Tiranti V, Garavaglia B, Lamperti C, Ardissone A, Moroni I, Robinson A, Ghezzi D, Zeviani M. New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. Biochim Biophys Acta. 2016 Aug;1857(8):1326-1335. doi: 10.1016 /j.bbabio.2016.02.022. Epub 2016 Mar 8. PMID: 26968897. ID: 427
New technological developments and OMICS Incorporation of exogenous mitochondria into cells and their effects on the cells 1LUCA Science, Japan; 2Biological Drug Development based DDS technology, Hokkaido Univ. Bibliography
Tateno M., Enami, A., Fujinami K., Ohta H. Polymorphisms in Cha o 1 and Cha o 2, major allergens of Japanese cypress (Chamaecyparis obtuse) pollen from a restricted region in Japan. PLos One 16: e0261327, 2021 Fujimura T, Fujinami K, Ishikawa R, Tateno M, Tahara Y, Okumura Y, Ohta H, Miyazaki H, Taniguchi M. Recombinant Fusion Allergens, Cry j 1 and Cry j 2 from Japanese Cedar Pollen, Conjugated with Polyethylene Glycol Potentiate the Attenuation of Cry j 1-Specific IgE Production in Cry j 1-Sensitized Mice and Japanese Cedar Pollen Allergen-Sensitized Monkeys. Int Arch Allergy Immunol.;168:32-43, 2015 ID: 336
New technological developments and OMICS Mitochondrial encapsulation technology for mitochondrial transplantation therapy 1Pharmaceutical Sciences Laboratory, Åbo Akademi University, Finland; 2Turku Bioscience Centre, University of Turku and Åbo Akademi University ID: 130
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Inhibition of mtDNA transcription in liver reverses diet-induced obesity and hepatosteatosis in the mouse 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Sweden; 2Max-Planck Institute of Biochemistry, Martinsried, Germany; 3Metabolomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany ID: 126
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The mitochondrial phenotype of Leigh syndrome SURF1 mutant patient-derived fibroblasts and recovery using small molecules 1Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom; 2Nanna Therapeutics, Cambridge, United Kingdom ID: 133
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Knockout of Complex III subunit Uqcrh decreases respiratory capacity and impairs cardiac contractile function independent of mitochondrial ROS production 1Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich, German Research Center for Environmental Health, Germany; 2Jena University Hospital, Friedrich-Schiller University of Jena, Germany; 3Oroboros Instruments, Innsbruck, Austria; 4Department of Biochemistry and Molecular Biology, Semmelweis University Budapest, Hungary; 5Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Germany; 6Member of German Center for Diabetes Research (DZD), Germany; 7Chair of Experimental Genetics Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Germany; 8BioMediTech & Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Finland; 9Contributed equally ID: 134
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Molecular insights into the role of complex V deficiency in heart development, function and disease 1Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; 2German Center for Cardiovascular Research (DZHK), partner site Göttingen, Germany; 3Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; 4Research Group Mitochondrial Structure and Dynamics, Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany Bibliography
1. Pavez-Giani MG and Cyganek L. Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells. Front Cell Dev Biol. 2022 Jan 10;9:800529. 2. Bomer N*, Pavez-Giani MG*, Grote Beverborg N, Cleland J, van Veldhuisen DJ, van der Meer P. Micronutrient deficiencies in heart failure: mitochondrial dysfunction as a common pathophysiological mechanism? J Intern Med. 2022 Jun;291(6):713-731. 3. Bomer N*, Pavez-Giani MG*, Hoes MF, Deiman FE, Piek A, Simonides W, Boer RA, Berezikov E, Westenbrink D, Silljé HWH, van der Meer P. Identification of DIO2 as a regulator of metabolic reprogramming and mitochondrial function in heart failure. Int J Mol Sci. 2021 Nov 2;22(21):11906. 4. Pavez-Giani MG, Sánchez-Aguilera PI, Bomer N, Miyamoto S, Booij HG, Giraldo P, Oberdorf-Maass SU, Nijholt KT, Yurista SR, Milting H, van der Meer P, Boer RA de, Heller Brown J, Sillje HWH, Westenbrink BD. ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ. Int J Mol Sci 2021;22. ID: 147
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Establishing mammalian cell models for research of NDUFS1-associated diseases 1Heinrich Heine University Düsseldorf, Germany; 2IUF- Leibniz Research Institute for Environmental Medicine ID: 149
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A neuronal model of mtDNA disease reveals a compensatory reprogramming of the electron transfer chain during neuronal maturation 1Wellcome Centre for Mitochondrial Research, Newcastle University, United Kingdom; 2Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles (UCLA), CA, USA Bibliography
Gorman, G. S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Annals of Neurology 77, 753–759 (2015). Russell, O.M., Fruh, I., Rai, P.K. et al. Preferential amplification of a human mitochondrial DNA deletion in vitro and in vivo. Sci Rep 8, 1799 (2018). ID: 156
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Development of mutant mtDNA-targeted TALENs and their application to iPSC-based mitochondrial disease model. Fujita Health University School of Medicine, Japan Bibliography
Yahata, N., Boda, H. and Hata, R. Elimination of Mutant mtDNA by an Optimized mpTALEN Restores Differentiation Capacities of Heteroplasmic MELAS-iPSCs (2021) Mol Ther Methods Clin Dev. 20, 54-68 ID: 165
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Deficits in mitochondrial oxidative phosphorylation enhance SARS-CoV-2 replication 1Children's Hospital of Philadelphia, USA; 2University of Pennsylvania, USA; 3Boston University, USA; 4National Emerging Infectious Diseases Laboratories, Boston, USA ID: 175
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Metabolic analysis of mouse sarcopenic skeletal muscle identifies new strategies to increase lifespan in C. elegans 1Karolinska Institutet, Sweden; 2Centre for Vision Research Duke-NUS & Singapore National Eye Centre, Singapore; 3Save Sight Institute at the University of Sydney, Australia; 4The University of Melbourne, Australia. ID: 181
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Delineating mitochondrial pathology using a genome-wide CRISPR/Cas9 activation screen 1Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH; 2NHS Highly Specialised Rare Mitochondrial Disorders Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH ID: 188
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Cancer and cellular senescence – two complementary stress models to study turnover and quality control of mitochondrial respiratory complexes. 1IMol Polish Academy of Sciences, Poland; 2ReMedy International Research Agenda ID: 189
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Proteotoxicity induced mitochondrial integrated stress response in CHCHD10-linked adult-onset spinal muscular atrophy 1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki; 2Helsinki Institute of Life Science HiLIFE, University of Helsinki; 3Genetically Modified Rodents Unit, Laboratory Animal Center, University of Helsinki; 4Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki; 5Faculty of Biological and Environmental Sciences, University of Helsinki; 6Division of Clinical Neurosciences, Turku University Hospital and University of Turku; 7Department of Neurology, Neuromuscular Research Center, Tampere University Hospital and Tampere University; 8Clinical Neurosciences, Neurology, Helsinki University Hospital Bibliography
1. Harjuhaahto S, Rasila TS, Molchanova SM, Woldegebriel R, Kvist J, Konovalova S, Sainio MT, Pennonen J, Torregrosa-Muñumer R, Ibrahim H, Otonkoski T, Taira T, Ylikallio E, Tyynismaa H (2020) ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. Neurobiol Dis. 2020 Jul;141:104940. doi: 10.1016/j.nbd.2020.104940. Epub 2020 May 11. PMID: 32437855. Cover story. 2. Järvilehto J, Harjuhaahto S, Palu E, Auranen M, Kvist J, Zetterberg H, Koskivuori J, Lehtonen M, Saukkonen AM, Jokela M, Ylikallio E, Tyynismaa H (2022) Serum creatine but not neurofilament light is elevated in CHCHD10-linked spinal muscular atrophy. Front. Neurology, 2022. https://doi.org/10.3389/FNEUR.2022.793937 3. Sainio MT, Rasila T, Molchanova SM, Järvilehto J, Torregrosa-Muñumer R, Harjuhaahto S, Pennonen J, Huber N, Herukka S-K Haapasalo A, Zetterberg H, Taira T, Palmio J, Ylikallio E and Tyynismaa H (2022) Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons. Front. Cell Dev. Biol. 2022, 9:820105. doi: 10.3389/fcell.2021.820105 4. Neupane N, Rajendran J, Kvist J, Harjuhaahto S, Hu B, Kinnunen V, Yang Y, Nieminen A I, Tyynismaa H. (2022) Inter-organellar and systemic survival responses to impaired mitochondrial matrix protein import in skeletal muscle. Commun Biol. 2022 Oct 5;5(1):1060. doi: 10.1038/s42003-022-04034-z. 5. Woldegebriel R, Kvist J, White M, Sinkko M, Hänninen S, Sainio MT, Torregrosa-Munumer R, Harjuhaahto S, Huber N, Herukka K, Haapasalo A, Carpen O, Bassett A, Ylikallio E, Sreedharan J, Tyynismaa H. (2021) Peripheral neuropathy linked mRNA export factor GANP 1 reshapes gene regulation in human motor neurons. bioRxiv 2021.05.18.444636. https://doi.org/10.1101/2021.05.18.444636 ID: 190
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Protective role of mitochondrial stress signaling and fragmentation in mitochondrial cardiomyopathy Max Planck Institute for Biology of Ageing, Cologne, Germany ID: 591
Clinical 1: from new genes to old and novel phenotypes The Italian reappraisal on the most frequent genetic defects in hereditary optic neuropathies and the global top 10 1IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 2Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 3Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy; 4Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy; 5Ospedale Oftalmico Roma, Rome, Italy; 6Ophthalmology Unit, University Hospital of Parma, Parma, Italy; 7Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy; 8Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, Bari, Italy; 9Neuroophthalmology Service and Ocular Electrophysiology laboratory, Department of Ophthalmology, IRCCS Istituto Auxologico Italiano, Milan, Italy Bibliography
Rocatcher, Aude et al. “The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.” Brain : a journal of neurology vol. 146,2 (2023): 455-460. doi:10.1093/brain/awac395 ID: 117
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Aberrant ER-mitochondria communication in human mitochondrial disease 1Columbia University, USA; 2Centro de Investigaciones Biológicas “Margarita Salas”, Madrid, Spain Bibliography
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg ZZ, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez E (2017). Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 36, 3356-3371. ID: 161
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial F0F1-ATP synthase conditions the responsiveness of mitochondria to fission 1MITOVASC Université d'Angers, France; 2Departments of Biochemistry and Molecular Biology, University Hospital Angers, Angers, France; 3Laboratoire de Neurobiologie et Neuropathologie, Centre Hospitalier Universitaire d'Angers, Angers, France Bibliography
Thirty-year progression of an EMPF1 encephalopathy due to defective mitochondrial and peroxisomal fission caused by a novel de novo heterozygous DNM1L variant 2022 Frontiers neurology PMID: 36212643 DOI: 10.3389/fneur.2022.937885 Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure 2022 Biomedicines PMID: 35884972 DOI: 10.3390/biomedicines10071665 STochastic Optical Reconstruction Microscopy (STORM) reveals the nanoscale organization of pathological aggregates in human brain 2020 Neuropathology and Applied Neurobiology PMID: 32688444 DOI: 10.1111/nan.12646 Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy 2017 Journal of Cellular and Molecular Medicine PMID: 28378518 DOI: 10.1111/jcmm.13149 ID: 199
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A screening method for mitochondrial disorders by high-resolution respirometry 1National Institute of Chemical Physics and Biophysics, Estonia; 2Clinic of Internal Medicine, East-Tallinn Central Hospital, Estonia Bibliography
1.Tepp, Kersti; Aid-Vanakova, Jekaterina; Puurand, Marju; Timohhina, Natalja; Reinsalu, Leenu; Tein, Karin; Plaas, Mario; Shevchuk, Igor; Terasmaa, Anton; Kaambre, Tuuli; (2022). Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles. Biochemistry and Biophysics Reports, 30, 101250. DOI: 10.1016/j.bbrep.2022.101250. 2. Tepp, Kersti; Puurand, Marju; Timohhina, Natalja; Aid-Vanakova, Jekaterina; Reile, Indrek; Shevchuk, Igor; Chekulayev, Vladimir; Eimre, Margus; Peet, Nadežda; Kadaja, Lumme; Paju, Kalju; Kaambre, Tuuli (2020). Adaptation of mice striated muscles to wolframin deficiency: alterations in cellular bioenergetics. Biochemica et Biophysica Acta. DOI: 10.1016/j.bbagen.2020.129523. 3. Kaup, Karl Kristjan; Toom, Lauri; Truu, Laura; Miller,Sten; Puurand, Marju; Tepp, Kersti; Kaambre Tuuli; Reile, Indrek (2021). A line-broadening free real-time 31P Pure Shift NMR method for phosphometabolomic analysis. The Analyst, 1−5. DOI: 10.1039/D1AN01198G. 4. Rebane-Klemm, Egle; Truu, Laura; Reinsalu, Leenu; Puurand, Marju; Shevchuk, Igor; Chekulayev, Vladimir; Timohhina, Natalja; Tepp, Kersti; Bogovskaja, Jelena; Afanasjev, Vladimir; Suurmaa, Külliki; Valvere, Vahur; Kaambre, Tuuli (2020). Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps. Cancers, 12 (4), ARTN 815. DOI: 10.3390/cancers12040815. ID: 1428
Clinical 1: from new genes to old and novel phenotypes AK3, adenylate kinase isozyme 3, is a new gene associated with PEO and multiple mtDNA deletions 1Fondazione IRCCS Istituto Neurologico Besta, Italy; 2Vall d'Hebron Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Autonomous University of Barcelona, Barcelona, Spain; 3Centro Sclerosi Multipla, P.O. Binaghi, ASL Cagliari, Italy; 4Technical University of Munich, School of Medicine, Institute of Human Genetics, 81675 Munich, Germany; 5Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany; 6Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy ID: 1201
Clinical 1: from new genes to old and novel phenotypes Heterozygous missense variants in NUTF2 (nuclear transport factor 2) gene, mapping at the OPA8 locus, cause Dominant Optic Atrophy 1IRCCS - Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica - Bologna (Italy); 2Studio Oculistico d'Azeglio - Bologna (Italy); 3Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele - Milano (Italy); 4Department of Genetics & Genomics, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz University Hospital - Universidad Autónoma de Madrid (IIS-FJD-UAM) - Madrid (Spain); 5Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII - Madrid (Spain); 6Grupo de investigación traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain; Centro de Investigación Biomédica en Red (CIBERER) - Madrid (Spain); 7Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc - Angers (France); 8Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University - Paris (France); 9Departments of Biochemistry and Genetics, University Hospital Angers - Angers (France); 10Molecular Genetics Laboratory, Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany; 11Depart. of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna - Bologna (Italy) ID: 1348
Clinical 1: from new genes to old and novel phenotypes Southern African paediatric patients with King Denborough syndrome are exclusively associated with an autosomal recessive STAC3 variant: is this a highly prevalent secondary mitochondrial disease in this African population? 1Human Metabolomics, North-West University, Potchefstroom, South Africa; 2Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa; 3Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; 4Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; 5https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/global-contributor-list Bibliography
Schoonen, M., Smuts, I., Louw, R., Elson, J. L., van Dyk, E., Jonck, L. M., Rodenburg, R. J. T., van der Westhuizen, F. H. (2019). Panel-Based Nuclear and Mitochondrial Next-Generation Sequencing Outcomes of an Ethnically Diverse Pediatric Patient Cohort with Mitochondrial Disease. The Journal of molecular diagnostics 21, 503–513. Meldau, S., Owen, E. P., Khan, K., & Riordan, G. T. (2022). Mitochondrial molecular genetic results in a South African cohort: divergent mitochondrial and nuclear DNA findings. Journal of clinical pathology 75, 34–38. Reinecke, C. J., Koekemoer, G., van der Westhuizen, F. H., Louw, R., Lindeque, J. Z., Mienie, L. J., Smuts, I. (2012). Metabolomics of urinary organic acids in respiratory chain deficiencies. Metabolomics 8, 264-283. Terburgh, K., Coetzer, J., Lindeque, J. Z., van der Westhuizen, F. H., Louw, R. (2021). Aberrant BCAA and glutamate metabolism linked to regional neurodegeneration in a mouse model of Leigh syndrome. Biochimica et biophysica acta. Molecular basis of disease 1867, 166082. ID: 1356
New technological developments and OMICS Long-read NGS for detection of mitochondrial DNA large-scale deletions and complex rearrangements 1Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy); 2University of Milan (Milan, Italy) ID: 1374
New technological developments and OMICS Quantification of all 12 canonical ribonucleotides by real-time fluorogenic in vitro transcription 1Folkhalsan Research Center, Finland; 2Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki Bibliography
1. Banerjee R, Purhonen J, Kallijärvi J. The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology. FEBS J (2021) 2. Purhonen J, Banerjee R, McDonald AE, Fellman V, Kallijärvi J. A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye and inhibitor-resistant high-fidelity DNA polymerase. Nucleic Acids Res 48(15), e87 (2020) 3. Purhonen J, Grigorjev V, Ekiert R, Aho N, Rajendran J, Pietras R, Truvé K, Wikström M, Sharma V, Osyczka A, Fellman V, Kallijärvi J. A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nat Commun 11:322 (2020) ID: 1125
New technological developments and OMICS Quantifying mitochondrial proteome remodeling during macrophage polarization University of Lausanne, Switzerland Bibliography
1. C. L. Strelko, et al. J Am Chem Soc. 2011, 133, 16386-16389 2. A. K. Jha, et al. Immunity. 2015, 42, 419-430 3. P. S. Liu, et al. Nat Immunol. 2017, 18, 985-994 4. D. Vats, et al. Cell Metab. 2006, 4, 13-24 5. S. Rath, et al. Nucleic Acids Res. 2021, 49, D1541-D1547 6. A. Michelucci, et al. Proc Natl Acad Sci U S A. 2013, 110, 7820-7825 7. Z. Zhong, et al. Nature. 2018, 560, 198-203 8. S. A. Clayton, et al. Sci Adv. 2021, 7, eabl5182 ID: 158
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial injury in warm ischemia studied by high-resolution respirometry Oroboros Instruments GmBH, Austria ID: 648
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity MitoCluster: integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction 1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; 2Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge UK; 3Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, UK; 4NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK; 5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK; 6Cancer Research UK Beatson Institute, Glasgow, UK; 7Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; 8Mary Lyon Centre MRC Harwell, UK; 9University of Padua, Italy |
| 4:30pm - 6:00pm | Session 2.4: New technological developments and OMICS Location: Bologna Congress Center - Sala Europa Session Chair: Holger Prokisch Session Chair: Leonid Sazanov Invited Speaker: :S. Churchman; :H. Hillen |
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ID: 683 Invited Speakers Decoding the regulatory principles of mitochondrial DNA: packaging, expression, and impact on cellular metabolism Harvard Medical School, United States of America Invited
ID: 705 Invited Speakers Mechanisms of mitochondrial RNA biogenesis in health and disease 1Department of Cellular Biochemistry, University Medical Center Göttingen, Germany; 2Research Group Structure and Function of Molecular Machines, Max-Planck-Institute for Multidisciplinary Sciences Göttingen, Germany Bibliography
Bhatta A, Dienemann C, Cramer P, Hillen HS (2021) Structural basis of RNA processing by human mitochondrial RNase P. Nature Structural & Molecular Biology 28, 713-723. Bonekamp NA, Peter B, Hillen HS, Felser A, Bergbrede T, Choidas A, Horn M, Unger A, Di Lucrezia R, Atanassov I, Li X, Koch U, Menninger S, Boros J, Habenberger P, Giavalisco P, Cramer P, Denzel MS, Nussbaumer P, Klebl B, Falkenberg M, Gustafsson CM, Larsson N-G (2020) Small-molecule inhibitors of human mitochondrial DNA transcription. Nature 588, 712-716 Hillen HS, Temiakov D, Cramer P (2018) Structural basis of mitochondrial transcription. Nature Structural & Molecular Biology 25, 754–765 Hillen HS, Parshin AV, Agaronyan K, Morozov YI, Graber JJ, Chernev A, Schwinghammer K, Urlaub H, Anikin M, Cramer P, Temiakov D (2017) Mechanism of Transcription Anti-termination in Human Mitochondria. Cell 171, 1082-1093.e13 Hillen HS, Morozov YI, Sarfallah A, Temiakov D, Cramer P (2017) Structural Basis of Mitochondrial Transcription Initiation. Cell 171, 1072-1081.e10 Oral presentation
ID: 338 New technological developments and OMICS Disruption of mitochondrial function induces cell lineage-specific compensatory transcriptional responses during early embryonic development 1Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 2Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK; 3Novo Nordisk Research Centre Oxford, Innovation Building, University of Oxford, Old Road Campus, Oxford, UK; 4Functional Genomics Centre, Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK; 5Department of Medical Biochemistry and Cell Biology, University of Gothenburg, PO Box 440, Gothenburg 405 30, Sweden; 6Max Planck Institute for Biology of Ageing, Cologne, Germany; 7Biosciences Institute, Faculty of Medical Sciences, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK Bibliography
1. Burr et al., Cell, 2023, DOI: 10.1016/j.cell.2023.01.034 Oral presentation
ID: 120 New technological developments and OMICS Single-cell multi-omics reveals dynamics of purifying selection of pathogenic mitochondrial DNA across human immune cells 1Department of Pathology, Stanford University, Stanford, CA 94305, USA; 2Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA; 3Department of Genetics, Stanford University, Stanford, CA 94305, USA; 4Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 5Division of Hematology / Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; 6Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; 7Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany; 8Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany; 9Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany; 10Technology Innovation Lab, New York Genome Center, New York, NY 10013, USA; 11Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02134, USA; 12Center for Pediatric Neurosciences, Mitochondrial Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; 13Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; 14Department of Pediatric Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany; 15Department of Computer Science, Stanford University, Stanford, CA 94305, USA; 16Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; 17Current address: Immunai, New York, NY 10114, USA; 18Current address: 10x Genomics, San Francisco, CA 94111, USA; 19Current address: Genentech, San Francisco, CA 94080, USA Bibliography
Preprint of the manuscript: https://www.biorxiv.org/content/10.1101/2022.11.20.517242v1 Related prior work: https://www.nejm.org/doi/full/10.1056/NEJMoa2001265 https://www.nature.com/articles/s41587-020-0645-6 https://www.nature.com/articles/s41587-021-00927-2 Flash Talk
ID: 125 New technological developments and OMICS Quantifying mitochondrial proteome remodeling during macrophage polarization University of Lausanne, Switzerland Bibliography
1. C. L. Strelko, et al. J Am Chem Soc. 2011, 133, 16386-16389 2. A. K. Jha, et al. Immunity. 2015, 42, 419-430 3. P. S. Liu, et al. Nat Immunol. 2017, 18, 985-994 4. D. Vats, et al. Cell Metab. 2006, 4, 13-24 5. S. Rath, et al. Nucleic Acids Res. 2021, 49, D1541-D1547 6. A. Michelucci, et al. Proc Natl Acad Sci U S A. 2013, 110, 7820-7825 7. Z. Zhong, et al. Nature. 2018, 560, 198-203 8. S. A. Clayton, et al. Sci Adv. 2021, 7, eabl5182 Flash Talk
ID: 374 New technological developments and OMICS Quantification of all 12 canonical ribonucleotides by real-time fluorogenic in vitro transcription 1Folkhalsan Research Center, Finland; 2Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki Bibliography
1. Banerjee R, Purhonen J, Kallijärvi J. The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology. FEBS J (2021) 2. Purhonen J, Banerjee R, McDonald AE, Fellman V, Kallijärvi J. A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye and inhibitor-resistant high-fidelity DNA polymerase. Nucleic Acids Res 48(15), e87 (2020) 3. Purhonen J, Grigorjev V, Ekiert R, Aho N, Rajendran J, Pietras R, Truvé K, Wikström M, Sharma V, Osyczka A, Fellman V, Kallijärvi J. A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nat Commun 11:322 (2020) Flash Talk
ID: 356 New technological developments and OMICS Long-read NGS for detection of mitochondrial DNA large-scale deletions and complex rearrangements 1Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy); 2University of Milan (Milan, Italy) |
| 6:00pm - 7:00pm | Poster session Location: Bologna Congress Center Session topics: - Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity |
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ID: 564
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Maintenance on mitochondrial complexes ensures bioenergetic function in differentiated cells 1Institute for Cardiovascular Physiology, Goethe University Frankfurt, Germany; 2Molecular Bioinformatics, Goethe University, Frankfurt, Germany Bibliography
[1] H. Heide, L. Bleier, M. Steger, J. Ackermann, S. Dröse, B. Schwamb, M. Zörnig, A.S. Reichert, I. Koch, I. Wittig, U.Brandt, Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex, Cell Metab. 16 (2012) 538–549. [2] B. Schwanhäusser, M. Gossen, G. Dittmar, M. Selbach, Global analysis of cellular protein translation by pulsed SILAC, Proteomics 9 (2009) 205–209. ID: 462
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Investigating pathogenicity and tissue-specificity of mitochondrial aminoacyl-tRNA synthetase defects AARS2, EARS2 and RARS2 in neurons Department of Clinical Neurosciences, University of Cambridge, United Kingdom ID: 253
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mutations in Coq2 leads to severe developmental delay and early death in both zebrafish and mouse 1Ibs.Granada, Granada, Spain; 2Physiology Department, Biomedical Research Center, University of Granada, Granada, Spain; 3Biofisika Institute (CSIC,UPV-EHU) and Department of Biochemistry and Molecular Biology, University of Basque Country, Leioa, Spain Bibliography
1.Alcázar-Fabra, M., Rodríguez-Sánchez, F., Trevisson, E., & Brea-Calvo, G. (2021). Primary Coenzyme Q deficiencies: A literature review and online platform of clinical features to uncover genotype-phenotype correlations. Free Radical Biology and Medicine, 167, 141-180. https://doi.org/10.1016/j.freeradbiomed.2021.02.046 2.Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy. (2013). New England Journal of Medicine, 369(3), 233-244. https://doi.org/10.1056/nejmoa1212115 3.Jakobs, B. S., Van Den Heuvel, L. P., Smeets, R., De Vries, M., Hien, S., Schaible, T., Smeitink, J. A., Wevers, R. A., Wortmann, S. B., & Rodenburg, R. J. (2013). A novel mutation in COQ2 leading to fatal infantile multisystem disease. Journal of the Neurological Sciences, 326(1-2), 24-28. https://doi.org/10.1016/j.jns.2013.01.004 4.Herebian, D., Seibt, A., Smits, S. H. J., Rodenburg, R. J., & Mayatepek, E. (2017). 4-Hydroxybenzoic acid restores CoQ10biosynthesis in human COQ2 deficiency. Annals of clinical and translational neurology, 4(12), 902-908. https://doi.org/10.1002/acn3.486 ID: 297
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Pathogenic variants of the mitochondrial metallochaperone SCO1 result in a severe, combined COX and copper deficiency that causes a dilated cardiomyopathy in the murine heart. 1University of Saskatchewan, Canada; 2Auburn University Bibliography
Glerum DM, Shtanko A, Tzagoloff A. Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J Biol Chem. 1996 Jun 14;271(24):14504-9. doi: 10.1074/jbc.271.24.14504. PMID: 8662933. Srinivasan C, Posewitz MC, George GN, Winge DR. Characterization of the copper chaperone Cox17 of Saccharomyces cerevisiae. Biochemistry. 1998 May 19;37(20):7572-7. doi: 10.1021/bi980418y. PMID: 9585572. Hlynialuk CJ, Ling B, Baker ZN, Cobine PA, Yu LD, Boulet A, Wai T, Hossain A, El Zawily AM, McFie PJ, Stone SJ, Diaz F, Moraes CT, Viswanathan D, Petris MJ, Leary SC. The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis. Cell Rep. 2015 Feb 17;10(6):933-943. doi: 10.1016/j.celrep.2015.01.019. Epub 2015 Feb 13. PMID: 25683716. Baker ZN, Jett K, Boulet A, et al. The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart. Hum Mol Genet. 2017;26(23):4617-4628. doi:10.1093/hmg/ddx344 Leary, S.C., Antonicka, H., Sasarman, F., Weraarpachai, W., Cobine, P.A., Pan, M., Brown, G.K., Brown, R., Majewski, J., Ha, K.C.H., et al. (2013a). Novel mutations in SCO1 as a cause of fatal infantile encephalopathy and lactic acidosis. Hum. Mutat. 34, 1366–1370. ID: 196
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Tissue-specific adaptation of stress responses upon COX10 deficiency 1CECAD Research Center, Germany; 2Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne ID: 269
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Using iPSC-derived neurons to unravel the pathomechanisms of Leber’s hereditary optic neuropathy 1Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; 2IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 3Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy; 4National Research Council (CNR), Institute of Neuroscience, Milan, Italy; 5Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy; 6Maria Cecilia Hospital, GVM Care & Research, 48033, Cotignola, Ravenna, Italy; 7Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy Bibliography
Danese A, Patergnani S, Maresca A, Peron C, Raimondi A, Caporali L, Marchi S, La Morgia C, Del Dotto V, Zanna C, Iannielli A, Segnali A, Di Meo I, Cavaliere A, Lebiedzinska-Arciszewska M, Wieckowski MR, Martinuzzi A, Moraes-Filho MN, Salomao SR, Berezovsky A, Belfort R Jr, Buser C, Ross-Cisneros FN, Sadun AA, Tacchetti C, Broccoli V, Giorgi C, Tiranti V, Carelli V, Pinton P. Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy. Cell Rep. 2022 Jul 19;40(3):111124. doi: 10.1016/j.celrep.2022.111124. PMID: 35858578; PMCID: PMC9314546. Peron C, Maresca A, Cavaliere A, Iannielli A, Broccoli V, Carelli V, Di Meo I, Tiranti V. Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives. Front Neurol. 2021 Jun 8;12:648916. doi: 10.3389/fneur.2021.648916. PMID: 34168607; PMCID: PMC8217617. Peron C, Mauceri R, Cabassi T, Segnali A, Maresca A, Iannielli A, Rizzo A, Sciacca FL, Broccoli V, Carelli V, Tiranti V. Generation of a human iPSC line, FINCBi001-A, carrying a homoplasmic m.G3460A mutation in MT-ND1 associated with Leber's Hereditary optic Neuropathy (LHON). Stem Cell Res. 2020 Oct;48:101939. doi: 10.1016/j.scr.2020.101939. Epub 2020 Aug 3. PMID: 32771908. ID: 418
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Stem cell modelling of mitochondrial disease-linked cardiomyopathy 1Murdoch Children’s Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia; 2Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia; 3Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia; 4Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia; 5Victorian Clinical Genetics Services, The Royal Children’s Hospital, Melbourne, VIC, Australia; 6The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Murdoch Children's Research Institute, Melbourne, VIC, Australia; 7Melbourne Centre for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia; 8Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, Australia ID: 316
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Biochemical and computational approaches to dissect the effect of MT-CYB pathogenic mutations on respiratory chain activity and assembly Department of Pharmacy and Biotechnology, University of Bologna, Italy Bibliography
1 Fernández-Vizarra E, Ugalde C. Cooperative assembly of the mitochondrial respiratory chain. Trends Biochem Sci. 2022 2 Rugolo M, Zanna C, Ghelli AM. Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences. Life (Basel). 2021 3 Mishra SK. PSP-GNM: Predicting Protein Stability Changes upon Point Mutations with a Gaussian Network Model. Int J Mol Sci. 2022 ID: 565
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Exploring the assembly and maintenance of mitochondrial complex I by complexome profiling-based approaches 1Institute for Cardiovascular Physiology, Goethe University Frankfurt, Germany; 2Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands Bibliography
[1] S. Guerrero-Castillo, F. Baertling, D. Kownatzki, H.J. Wessels, S. Arnold, U. Brandt, L. Nijtmans, The Assembly Pathway of Mitochondrial Respiratory Chain Complex I, Cell metabolism, 25 (2017) 128-139. [2] H. Heide, L. Bleier, M. Steger, J. Ackermann, S. Drose, B. Schwamb, M. Zornig, A.S. Reichert, I. Koch, I. Wittig, U. Brandt, Complexome profiling identifies TMEM126B as a component of the mitochondrial complex I assembly complex, Cell metabolism, 16 (2012) 538-549. [3] A. Cabrera-Orefice, A. Potter, F. Evers, J.F. Hevler, S. Guerrero-Castillo, Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease, Front Cell Dev Biol, 9 (2022) 796128. ID: 225
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Functional involvement of actin-binding Gelsolin on mitochondrial Oxphos dysfunction Fundación Hospital 12 de Octubre, Spain Bibliography
García-Bartolomé, A., Peñas, A., Illescas, M., Bermejo, V., López-Calcerrada, S., Pérez-Pérez, R., et al. (2020). Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction. Cells 9, 1922–21. doi:10.3390/cells9091922 Peñas, A., Fernández-De la Torre, M., Laine-Menéndez, S., Lora, D., Illescas, M., García-Bartolomé, A., et al. (2021). Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders. Ijms 22, 6396. doi:10.3390/ijms22126396 Illescas M, Peñas A, Arenas J, Martín MA and Ugalde C. 2021. Regulation of Mitochondrial Function by the Actin Cytoskeleton. Front. Cell Dev. Biol. 9:795838. doi: 10.3389/fcell.2021.795838. Fernández-Vizarra E, López-Calcerrada S, Sierra-Magro A, Pérez-Pérez R, Formosa LE, Hock DH, Illescas M, Peñas A, Brischigliaro M, Ding S, Fearnley IM, Tzoulis C, Pitceathly RDS, Arenas J, Martín MA, Stroud DA, Zeviani M, Ryan MT, Ugalde C. 2022 Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metab. doi: 10.1016/j.cmet.2022.09.005 ID: 472
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity In vivo role of respiratory complex I NDUFA10 subunit in dNTP homeostasis 1Research Group on Neuromuscular and Mitochondrial Disorders, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; 3BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona 08028, Spain. and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona 08036, Spain.; 4Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia; 5Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041 Madrid, Spain.; 6Laboratory of Metabolism and Obesity, Vall d'Hebron - Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBERDEM, CIBER on Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Barcelona, Spain Bibliography
Molina-Granada D, González-Vioque E, Dibley MG, Cabrera-Pérez R, Vallbona-Garcia A, Torres-Torronteras J, Sazanov LA, Ryan MT, Cámara Y, Martí R. Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit. Commun Biol. 2022 Jun 23;5(1):620. doi: 10.1038/s42003-022-03568-6. PMID: 35739187; PMCID: PMC9226000. ID: 247
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Modeling POLRMT pathogenic variants in the mouse 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 2Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden; 3Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ID: 425
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The role of the CCR4 family member ANGEL1 in the expression of mitochondrial-targeted proteins 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden Bibliography
Chang, K§., Liu, P§., Requejo, G & Bai, H. (2022). mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila. Front. Cell Dev. Biol., 2022. https://doi.org/10.3389/fcell.2022.866210 §These authors contributed equally to this work Birnbaum, A., Chang, K., & Bai, H. (2020). FOXO regulates neuromuscular junction homeostasis during Drosophila aging. Front Aging Neurosci, 2021 Jan 27; 12:567861. DOI: 10.3389/fnagi.2020.567861. Huang, K., Miao, T., Chang, K. et al. Impaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine. Nat Commun 11, 2943 (2020). https://doi.org/10.1038/s41467-020-16781-w Kai Chang§, Ping Kang§, Ying Liu, Kerui Huang, Ting Miao, Antonia P. Sagona, Ioannis P. Nezis, Rolf Bodmer, Karen Ocorr & Hua Bai (2019) TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2, Autophagy, DOI: 10.1080/15548627.2019.1704117 §These authors contributed equally to this work Kang, P., Chang, K., Liu, Y. et al. Drosophila Kruppel homolog 1 represses lipolysis through interaction with dFOXO. Sci Rep 7, 16369 (2017) doi:10.1038/s41598-017-16638-1 ID: 600
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Tissue-specific bioenergetics in mouse models of mitochondrial disease 1Università di Padova; 2Semmelweis University; 3Universität Innsbruck; 4University of Sussex ID: 490
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Yeast as a tool to investigate variants in mtARS genes associated with mitochondrial diseases 1Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy; 2Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; 3Department of Medical Physiopathology and Transplantation, University of Milan, Milan, Italy ID: 227
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A mutation in mouse mt-Atp6 gene induces respiration defects and opposed effects on the cell tumorigenic phenotype 1University of Zaragoza, Spain; 2University of Zaragoza, Peaches Biotech Group, Spain; 3Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Spain Bibliography
1.Moreno-Loshuertos, R.; Marco-Brualla, J.; Meade, P.; Soler-Agesta, R.; Enriquez, J. A.; Fernandez-Silva, P., How hot can mitochondria be? Incubation at temperatures above 43 degrees C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria. Mitochondrion 2023, 69, 83-94. 2.Moreno-Loshuertos, R.; Movilla, N.; Marco-Brualla, J.; Soler-Agesta, R.; Ferreira, P.; Enriquez, J. A.; Fernandez-Silva, P., A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype. Int J Mol Sci 2023, 24, (2). 3.Novo, N.; Romero-Tamayo, S.; Marcuello, C.; Boneta, S.; Blasco-Machin, I.; Velázquez-Campoy, A.; Villanueva, R.; Moreno-Loshuertos, R.; Lostao, A.; Medina, M.; Ferreira, P., Beyond a platform protein for the degradosome assembly: The Apoptosis-Inducing Factor as an efficient nuclease involved in chromatinolysis. PNAS Nexus 2022, 2, (2). 4.Soler-Agesta, R.; Marco-Brualla, J.; Minjarez-Saenz, M.; Yim, C. Y.; Martinez-Julvez, M.; Price, M. R.; Moreno-Loshuertos, R.; Ames, T. D.; Jimeno, J.; Anel, A., PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies. Cancers (Basel) 2022, 14, (16). 5.Pinol, R.; Zeler, J.; Brites, C. D. S.; Gu, Y.; Tellez, P.; Carneiro Neto, A. N.; da Silva, T. E.; Moreno-Loshuertos, R.; Fernandez-Silva, P.; Gallego, A. I.; Martinez-Lostao, L.; Martinez, A.; Carlos, L. D.; Millan, A., Real-Time Intracellular Temperature Imaging Using Lanthanide-Bearing Polymeric Micelles. Nano Lett 2020, 20, (9), 6466-6472. 6.Gu, Y.; Yoshikiyo, M.; Namai, A.; Bonvin, D.; Martinez, A.; Pinol, R.; Tellez, P.; Silva, N. J. O.; Ahrentorp, F.; Johansson, C.; Marco-Brualla, J.; Moreno-Loshuertos, R.; Fernandez-Silva, P.; Cui, Y.; Ohkoshi, S. I.; Millan, A., Magnetic hyperthermia with epsilon-Fe(2)O(3) nanoparticles. RSC Adv 2020, 10, (48), 28786-28797. 7.Delavallee, L.; Mathiah, N.; Cabon, L.; Mazeraud, A.; Brunelle-Navas, M. N.; Lerner, L. K.; Tannoury, M.; Prola, A.; Moreno-Loshuertos, R.; Baritaud, M.; Vela, L.; Garbin, K.; Garnier, D.; Lemaire, C.; Langa-Vives, F.; Cohen-Salmon, M.; Fernandez-Silva, P.; Chretien, F.; Migeotte, I.; Susin, S. A., Mitochondrial AIF loss causes metabolic reprogramming, caspase-independent cell death blockade, embryonic lethality, and perinatal hydrocephalus. Mol Metab 2020, 40, 101027. ID: 242
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A systemic Muscle-WAT crosstalk progressively depletes protein and fat stores aggravating mitochondrial myopathy. 1Weill Cornell Medicine, Brain and Mind Research Institute, New York, NY; 2Weill Cornell Medicine, Department of Pharmacology, New York, NY; 3Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy. ID: 646
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A novel mitochondrial assembly factor RTN4IP1 has an essential role in the final stages of Complex I assembly 1Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2Department of Applied Sciences, Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK; 3Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; 4Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; 5Functional Proteomics Group, Institute for Cardiovascular Physiology, Goethe University Frankfurt, 60590, Frankfurt am Main, Germany Bibliography
1 Charif M et al. Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults. JAMA Neurol. 2017 ID: 599
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity ETFDH supports OXPHOS efficiency in skeletal muscle by regulating coenzyme Q homeostasis 1Department of Molecular Biology, Centro de Biología Molecular "Severo Ochoa" (CBMSO-UAM-CSIC), Madrid, Spain; 2Instituto Universitario de Biología Molecular (IUBM), Autonomous University of Madrid, Madrid, Spain; 3Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; 4Instituto de Investigación Hospital 12 de octubre, i+12, Universidad Autónoma de Madrid, Madrid, Spain ID: 559
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Metabolic rewiring as an adaptive mechanism in COX null cells 1Department of Bioenergetics, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic; 2Faculty of Science, Charles University, 12800 Prague, Czech Republic; 3Laboratory of Translational Metabolomics, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic ID: 383
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Metabolic rewiring due to progressive increase in mtDNA mutation heteroplasmy reveals markers of disease severity 1North-West University, South Africa; 2Osaka University, Japan; 3Radboud University Medical Center, Netherlands; 4University of Tsukuba, Japan ID: 442
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Novel or rare AIFM1 pathogenic variants: their impact on mitochondrial metabolism and clinical manifestation in eight patients, including 3 girls 1Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague; 2Institute of Molecular and Clinical Pathology and Medical Genetics, University Hospital Ostrava ID: 558
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Pathological molecular mechanisms underlying COA8 loss of function 1Department of Biomedical Sciences, University of Padova, Padova, Italy; 2Veneto Institute of Molecular Medicine, Padova, Italy; 3Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; 4University of Texas Southwestern Medical Center, Dallas, TX, USA; 5Department of Chemical Sciences, University of Padova, Padova, Italy; 6Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany; 7Department of Neurosciences, University of Padova, Padova, Italy Bibliography
Hedberg-Oldfors, C., Darin, N., Thomsen, C., Lindberg, C., and Oldfors, A. (2020). COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation. Neurol Genet 6, e464. Melchionda, L., Haack, T.B., Hardy, S., Abbink, T.E., Fernandez-Vizarra, E., Lamantea, E., Marchet, S., Morandi, L., Moggio, M., Carrozzo, R., et al. (2014). Mutations in APOPT1, Encoding a Mitochondrial Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency. Am J Hum Genet 95, 315-325. Pei, J., Zhang, J., and Cong, Q. (2022). Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling. Bioinformatics. Sharma, S., Singh, P., Fernandez-Vizarra, E., Zeviani, M., Van der Knaap, M.S., and Saran, R.K. (2018). Cavitating Leukoencephalopathy With Posterior Predominance Caused by a Deletion in the APOPT1 Gene in an Indian Boy. J Child Neurol 33, 428-431. Signes, A., Cerutti, R., Dickson, A.S., Beninca, C., Hinchy, E.C., Ghezzi, D., Carrozzo, R., Bertini, E., Murphy, M.P., Nathan, J.A., et al. (2019). APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS. EMBO molecular medicine 11. ID: 366
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Retinal pathophysiology characterisation of the novel mitochondrial heteroplasmy mouse model 1University of Cambridge, United Kingdom; 2Newcastle University, United Kingdom ID: 666
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Impaired spermatogenesis driven by mitochondrial dysfunction and ferroptosis in primary spermatocytes in a mouse model of Leigh syndrome 1University of Pennsylvania,USA; 2University of Angers, SFR ICAT, SCIAM, 49000 Angers, France; 3MITOLAB, University of Angers, INSERM U1083, France; 4Pablo de Olavide University, Spain; 5Neuromuscular Reference Center CHU Angers, France ID: 574
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitophagy dysfunction in mitochondrial myopathy and therapy by mitophagy activator CAP1902 1STEMM Research Program, Biomedicum Helsinki, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 3Department of Pharmacology, Center for Innovations in Brain Science, University of Arizona, Tucson, AZ, USA; 4Department of Medicine, Endocrinology, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA ID: 192
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mtfp1 controls oxidative phosphorylation and cell death in liver disease 1Institut Pasteur, Mitochondrial Biology Group, CNRS UMR 3691, Université Paris Cité, Paris, France.; 2Institut Pasteur, Biomics Technological Platform, Université Paris Cité, Paris, France.; 3Institut Pasteur, Bioinformatics and Biostatistics Hub, Université Paris Cité, Paris, France.; 4Institut Pasteur, Proteomics Core Facility, MSBio UtechS, UAR CNRS 2024, Université Paris Cité, Paris, France.; 5Institut Pasteur Ultrastructural Bio Imaging, UTechS, Université Paris Cité, Paris, France.; 6Platform for Metabolic Analyses, SFR Necker, INSERM US24/CNRS UMS 3633, Paris, France.; 7Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia. ID: 319
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Non-canonical function of succinate dehydrogenase assembly factor 2 (SDHAF2) during OXPHOS dysfunction 1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia; 2Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia; 3Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; 4Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia; 5Victorian Clinical Genetics Services, Royal Children's Hospital, Parkville, VIC, Australia ID: 502
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity NUAK1-dependent metabolic underpinnings of adult muscle stem cells Physiopathology and Genetics of Neurons and Muscles Laboratory, Institut NeuroMyoGène, Lyon, France ID: 415
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates 1Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095 USA; 2Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA; 3Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA; 4Molecular & Cellular Integrative Physiology, University of California, Los Angeles, CA, 90095, USA.; 5Institut de Biologia Molecular de Barcelona, IBMB-CSIC, Barcelona, Catalonia, 08028, Spain ID: 440
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity OxPhos defects cause cell-autonomous and whole-body signs of hypermetabolism in cells and in patients with mitochondrial diseases 1Columbia University Irving Medical Center, United States of America; 2University of Florida, United States of America; 3Angers University, UMR CNRS 6015 - INSERM U1083, MitoVasc Institute, Angers, France; 4Yale University, United States of America; 5University of Pennsylvania, United States of America; 6Stanford University, United States of America; 7University of California San Francisco, United States of America; 8Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; 9University of Copenhagen, Denmark; 10University of Udine, Italy; 11Altos labs, United States of America; 12University of Texas Southwestern Medical Center, United States of America; 13University of Pittsburgh, United States of America; 14Thomas Jefferson University, United States of America Bibliography
Sturm G et al. A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations. Sci Data 9, 751 (2022). https://doi.org/10.1038/s41597-022-01852-y Sturm G. et al. OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Commun Biol 6, 22 (2023). https://doi.org/10.1038/s42003-022-04303-x ID: 605
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Dysfunction of mitochondrial chaperone HSP60 triggers disruption of mitochondrial pathways activating multiple regulatory responses 1Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; 3Department of Forensic Medicine, Aarhus University, Aarhus, Denmark; 4Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Bibliography
1. Bie AS, Cömert C, Körner R, et al. An inventory of interactors of the human HSP60/HSP10 chaperonin in the mitochondrial matrix space. Cell Stress Chaperones. 2020;25(3):407-416. 2. Bross P, Naundrup S, Hansen J, et al. The Hsp60-(p.V98I) mutation associated with hereditary spastic paraplegia SPG13 compromises chaperonin function both in vitro and in vivo. J Biol Chem. 2008;283(23):15694-15700. 3. Magen D, Georgopoulos C, Bross P, et al. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet. 2008;83(1):30-42. 4. Cömert C, Brick L, Ang D, et al. A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy. Cold Spring Harb Mol Case Stud. 2020;6(3):a004879. Published 2020 Jun 12. ID: 365
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Generation of iPSCs derived neural progenitors and cardiomyocytes as cellular models to study the pathophysiology of Pearson Syndrome 1Unit of Medical genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; 2Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy; 3Department of Biotechnology and Biosciences, University of Milano - Bicocca, Milan, Italy ID: 476
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity High aerobic exercise capacity predicts increased mitochondrial response to exercise training 1Department of Cardiothoracic Surgery, University Hospital of Friedrich-Schiller-University Jena, Germany; 2Department of Physiology and Pharmacology, University of Toledo, Toledo, OH, United States; 3Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States Bibliography
Heyne E, Schrepper A, Doenst T, Schenkl C, Kreuzer K, Schwarzer M. High-fat diet affects skeletal muscle mitochondria comparable to pressure overload-induced heart failure. J Cell Mol Med. 2020 Jun;24(12):6741-6749. doi: 10.1111/jcmm.15325. Epub 2020 May 4. PMID: 32363733; PMCID: PMC7299710. Schwarzer M, Molis A, Schenkl C, Schrepper A, Britton SL, Koch LG, Doenst T. Genetically determined exercise capacity affects systemic glucose response to insulin in rats. Physiol Genomics. 2021 Sep 1;53(9):395-405. doi: 10.1152/physiolgenomics.00014.2021. Epub 2021 Jul 23. PMID: 34297615; PMCID: PMC8530732. ID: 488
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Investigating the role of LONP1 in heart and skeletal muscle metabolism 1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany; 2Department III of Internal Medicine, Heart Center, University Hospital of Cologne, 50931 Cologne, Germany; 3Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany ID: 229
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial dysfunction promotes liver fibrosis through the ACOT2-MCT6-OXCT1 axis. 1Karolinska Institutet, Sweden; 2Zhengzhou University, China; 3Norwegian Veterinary Institute, Norway Bibliography
Zhou X, Mikaeloff F, Curbo S, Zhao Q, Kuiper R, Végvári Á, Neogi U, Karlsson A.Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.Hum Mol Genet. 2021 Oct 13;30(21):2012-2026 ID: 655
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity PNC2 (SLC25A36) deficiency associated with the hyperinsulinism/hyperammonemia syndrome 1Università degli Studi di Bari Aldo Moro, Italy; 2Libera Università Mediterranea Giuseppe Degennaro, Italy; 3Department of Pediatrics and Genetics, Al Makassed Hospital and Al-Quds University, Palestine.; 4Department of Genetics, Hadassah, Hebrew University Medical Center, Israel Bibliography
[1] M.A. Shahroor, F.M. Lasorsa, V. Porcelli V, I. Dweikat, M.A. Di Noia, M. Gur, G. Agostino, A . Shaag A, T. Rinaldi, G. Gasparre, F. Guerra, A. Castegna, S. Todisco, B. Abu-Libdeh, O. Elpeleg, L. Palmieri, PNC2 (SLC25A36) Deficiency Associated With the Hyperinsulinism/Hyperammonemia Syndrome, J Clin Endocrinol Metab, 107(2022):1346-1356. [2] L. Jasper, P. Scarcia, S. Rust, J. Reunert, F. Palmieri, T. Marquardt, Uridine Treatment of the First Known Case of SLC25A36 Deficiency, Int J Mol Sci. 22(2021) 9929. [3] Safran A, Proskorovski-Ohayon R, Eskin-Schwartz M, Yogev Y, Drabkin M, Eremenko E, Aharoni S, Freund O, Jean MM, Agam N, Hadar N, Loewenthal N, Staretz-Chacham O, Birk OS.Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation. J Inherit Metab Dis. 2023 Jan 25. doi: 10.1002/jimd.12594. Online ahead of print ID: 397
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Cultured neurons with CoQ10 deficiency reveal alterations of lipid metabolism 1Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, United States; 2IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 3Institute of Biotechnology, Biomedical Research Center (CIBM), Health Science Technological Park (PTS), University of Granada, Armilla, Granada, 18100, Spain; 4Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, 986145 Nebraska Medical Center, Omaha, NE; 5Unita` di Genetica delle Malattie Neurodegenerative e Metaboliche, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, 20126, Italy Bibliography
1. Turunen, M.; Olsson, J.; Dallner, G. Metabolism and function of coenzyme Q. Biochim. Biophys. Acta - Biomembr. 2004, 1660, 171–199, doi:10.1016/j.bbamem.2003.11.012. 2. Quinzii, C.M.; López, L.C.; Gilkerson, R.W.; Dorado, B.; Coku, J.; Naini, A.B.; Lagier-Tourenne, C.; Schuelke, M.; Salviati, L.; Carrozzo, R.; et al. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 2010, 24, 3733–3743, doi:10.1096/fj.09-152728. 3. Emma, F.; Montini, G.; Parikh, S.M.; Salviati, L. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. 2016, doi:10.1038/nrneph.2015.214. 4. Ernster, L.; Dallner, G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys. Acta 1995, 1271, 195–204. ID: 426
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; 2Biocenter Oulu, University of Oulu, Oulu, Finland; 3Faculty of Physics, University of Warsaw, Warsaw, Poland; 4Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany; 5Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany; 6Zentrum für Molekulare Biologie (ZMBH), DKFZ-ZMBH Alliance and Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany Bibliography
Rahman M.T., Koski M.K., Panecka-Hofman J., Schmitz W, Kastaniotis A.J., Wade R.C., Wierenga R.K., Hiltunen J.K. & Autio K.J. (2023) An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration. Nature Communications 14(1):619. doi: 10.1038/s41467-023-36358-7 Alam J., Sah-Teli S.K., Venkatesan R., Koski M.K., Autio K.J., Hiltunen J K. & Kastaniotis A.J. (2021) Biophysical and structural analysis of the SAM-dependent Saccharomyces cerevisiae methyltransferase family protein Rsm22. Acta Crystallographica Section D. 77:840-853 Kastaniotis A.J., Autio K.J. & Nair R.R. (2021) Mitochondrial fatty acids and neurodegenerative disorders. Neuroscientist 27(2):143-158 ID: 561
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Antibiotics directly affect mitochondrial respiration 1Technische Universität München, Germany; 2Oroboros Instruments GmbH, Innsbruck, Austria; 3Helmholtz Zentrum München, Germany Bibliography
[1] Tarantino G. et al. (2017): Hepatol Res. 37:410‐415 [2] O'Reilly M. et al. (2019):. Front Cell Neurosci. 13;13:416. doi: 10.3389/fncel.2019.00416. [3] Oyebode OT. et al. (2018) Toxicology Mechanisms and Methods, 1–31.doi:10.1080/15376516.2018.1528651 ID: 471
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Can transmission of mitochondria over the species barrier promote climate change adaptation? 1Tampere University, Finland; 2University of Eastern Finland Bibliography
Gaertner K, Michell C, Tapanainen R, et al. Molecular phenotyping uncovers differences in basic housekeeping functions among closely related species of hares (Lepus spp., Lagomorpha: Leporidae) [published online ahead of print, 2022 Nov 1]. Mol Ecol. 2022; doi:10.1111/mec.16755 ID: 626
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Developing an in vitro model to study the impact of the m.3243A>G mutation in iPSC-derived myofibers University College London, United Kingdom ID: 334
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Discordant phenotype in fibroblast cell lines generated from the same MELAS patient 1IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; 2Department of Biomedical and Neuromuscular Sciences (DIBINEM), University of Bologna ID: 531
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Generation of a novel CoQ deficient mouse model to elucidate the role of COQ4 Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA. Bibliography
1.Guerra, R.M. and D.J. Pagliarini, Coenzyme Q biochemistry and biosynthesis. Trends Biochem Sci, 2023. 2.Alcázar-Fabra, M., E. Trevisson, and G. Brea-Calvo, Clinical syndromes associated with Coenzyme Q. Essays Biochem, 2018. 62(3): p. 377-398. 3.Belogrudov, G.I., et al., Yeast COQ4 encodes a mitochondrial protein required for coenzyme Q synthesis. Arch Biochem Biophys, 2001. 392(1): p. 48-58. 4.Casarin, A., et al., Functional characterization of human COQ4, a gene required for Coenzyme Q10 biosynthesis. Biochem Biophys Res Commun, 2008. 372(1): p. 35-9. 5.Marbois, B., et al., Coq3 and Coq4 define a polypeptide complex in yeast mitochondria for the biosynthesis of coenzyme Q. J Biol Chem, 2005. 280(21): p. 20231-8. 6.Marbois, B., et al., The yeast Coq4 polypeptide organizes a mitochondrial protein complex essential for coenzyme Q biosynthesis. Biochim Biophys Acta, 2009. 1791(1): p. 69-75. ID: 414
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Perivascular adipose tissue remodeling impairs mitochondrial function in thermoneutral-housed rats 1University of Colorado/Rocky Mountain Regional VA Medical Center, United States of America; 2Cornell College, United States of America Bibliography
1. Chun J.H., Henckel M.M., Knaub L.A., Hull S.E., Pott G.B., Ramirez D.G., Reusch J.E.-B., Keller A.C. (-)-Epicatechin Reverses Glucose Intolerance in Rats Housed at Thermoneutrality. Planta Med. 2022 Aug;88(9-10):735-744. doi: 10.1055/a-1843-9855. 2. Keller A.C., Chun J.H., Knaub L.A., Henckel M.M., Hull S.E., Scalzo R.L., Pott G.B., Walker L.A., Reusch J.E.-B. Thermoneutrality induces vascular dysfunction and impaired metabolic function in male Wistar rats: a new model of vascular disease. J Hypertens. 2022 Nov 1;40(11):2133-2146. doi: 10.1097/HJH.0000000000003153. 3. Vaughan O.R., Rosario F.J., Chan J., Cox L.A., Ferchaud-Roucher V., Zemski-Berry K.A., Reusch J.E.- B., Keller A.C., Powell T.L., Jansson T. Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice. J Physiol. 2022 Jul;600(13):3169-3191. doi: 10.1113/JP282462. 4. Chun J.H., Henckel M.M., Knaub L.A., Hull S.E., Pott G., Walker, L.A., Reusch J.E.B., Keller A.C. (–)-Epicatechin improves vasoreactivity and mitochondrial respiration in thermoneutral-housed Wistar rat vasculature. Nutrients. 2022 14(5), 1097;doi.org/10.3390/nu14051097. 5. Keller, A.C., Hull, S.E., Elajaili, H., Johnston, A., Knaub, L.A., Chun, J.H., Walker, L.A., Nozik-Grayck, E., Reusch, J.E.-B. (–)-Epicatechin Modulates Mitochondrial Redox in Vascular Cell Models of Oxidative Stress. Oxidative Medicine and Cellular Longevity. 2020. doi.org/10.1155/2020/6392629 ID: 595
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Temporal analysis of mitochondrial complexome profiling coupled to multi-omics analysis unveils implications of CIV remodelling in postnatal heart development University of Cologne, Germany Bibliography
1. Porter Jr G., et al. (2011) Bioenergetics, mitochondria, and cardiac myocyte differentiation. Prog. Pediatr. Cardiol. 31, 75–81. doi: 10.1016/j.ppedcard.2011.02.002; 2. Gan J., Sonntag H-J., Tang Mk., Cai D., Lee KKH. (2015) Integrative Analysis of the Developing Postnatal Mouse Heart Transcriptome. PLoS ONE 10 (7): e0133288. doi:10.1371/journal.pone.0133288 3. Gu Y., et al. (2022) Multi-omics profiling visualizes dynamics of cardiac development and functions, Cell Reports, Volume 41, Issue 13,111891, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2022.111891. 4.Talman V., et al. (2018). Molecular Atlas of Postnatal Mouse Heart Development. J Am Heart Assoc. 2018;7:e010378. DOI: 10.1161/JAHA.118.010378 ID: 258
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial dysfunction in immune cells leads to distinct transcriptome profile and improved immune competence in Drosophila 1Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 2Department of Molecular Biology, Umeå University, Umeå, Sweden; 3Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, United Kingdom ID: 376
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Molecular mechanisms of extraocular muscle manifestation in mitochondrial myopathy STEMM, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland Bibliography
Forsström, S., Jackson, C. B., Carroll, C. J., Kuronen, M., Pirinen, E., Pradhan, S., … Suomalainen, A. (2019). Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions. Cell Metabolism, 1–15. https://doi.org/10.1016/j.cmet.2019.08.019. Khan, N. A., Nikkanen, J., Yatsuga, S., Jackson, C., Wang, L., Pradhan, S., … Suomalainen, A. (2017). mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression. Cell Metabolism, 26(2), 419-428.e5. https://doi.org/10.1016/j.cmet.2017.07.007 Pradhan, S...Lopus M (2017) “Elucidation of the Tubulin-Targeted Mechanism of Action of 9-(3-Pyridyl) Noscapine.” Cur. Top. in Medicinal Chemistry, vol. 17, no. 22, 2017, pp. 2569–74, doi:http://dx.doi.org/10.2174/1568026617666170104150304. ID: 572
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Redox metabolites and transporters: Differential expression and ratios in specific Ndufs4 knockout mice organs. Human Metabolomics, North-West University, South Africa ID: 475
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity What makes folding of a mitochondrial protein dependent on the HSP60/HSP10 chaperone complex? Aarhus University and Aarhus University Hospital, Denmark Bibliography
1.Henriques, B. J., Katrine Jentoft Olsen, R., Gomes, C. M., andBross, P. (2021) Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease Gene 145407 10.1016/j.gene.2021.145407 2.Cömert, C., Brick, L., Ang, D., Palmfeldt, J., Meaney, B. F., Kozenko, M. et al. (2020) A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy Cold Spring Harb Mol Case Stud 6, 10.1101/mcs.a004879 3.Bie, A. S., Comert, C., Korner, R., Corydon, T. J., Palmfeldt, J., Hipp, M. S. et al. (2020) An inventory of interactors of the human HSP60/HSP10 chaperonin in the mitochondrial matrix space Cell Stress Chaperones 25, 407-416 10.1007/s12192-020-01080-6 4.Palmfeldt, J., andBross, P. (2017) Proteomics of human mitochondria Mitochondrion 33, 2-14 10.1016/j.mito.2016.07.006 ID: 385
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity OXPHOS composition is altered in the FXNI151F mouse model of Friedreich Ataxia in a progressive and a tissue-specific way Dept. Ciències Mèdiques Bàsiques, Fac. Medicina, Universitat de Lleida. IRB Lleida. Bibliography
Medina-Carbonero M, Sanz-Alcázar A, Britti E, Delaspre F, Cabiscol E, Ros J, Tamarit J. Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations. Cell Mol Life Sci. 2022 Jan 17;79(2):74. ID: 482
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Disease causing-Mfn2 mutations alter mitochondrial fusion and fission dynamics and metabolism. 1Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.; 2School of Biological Sciences, Department of Cellular and Molecular Biology, Pontificia Universidad Catolica de Chile, Santiago, Chile. ID: 284
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Dissecting the mitochondrial disease-associated ATAD3 gene cluster and its pathogenic variants 1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria,Australia; 2Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; 3Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia; 4Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia; 5Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia; 6Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia; 7Harry Perkins Institute of Medical Research and The University of Western Australia Centre for Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia; 8ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre and University of Western Australia, Nedlands, Western Australia, Australia; 9Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, Western Australia, Australia; 10Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia ID: 340
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Dynamics of adenine nucleotides in colorectal cancer clinical material 1National Institute of Chemical Physics and Biophysics, Estonia; 2Tallinn University of Technology, Estonia; 3North Estonia Medical Centre Bibliography
Klepinin, A., Miller, S., Reile, I., Puurand, M., Rebane-Klemm, E., Klepinina, L., Vija, H., Zhang, S., Terzic, A., Dzeja, P., & Kaambre, T. (2022). Stable Isotope Tracing Uncovers Reduced γ/β-ATP Turnover and Metabolic Flux Through Mitochondrial-Linked Phosphotransfer Circuits in Aggressive Breast Cancer Cells. Frontiers in oncology, 12, 892195. https://doi.org/10.3389/fonc.2022.892195 Reinsalu, L., Puurand, M., Chekulayev, V., Miller, S., Shevchuk, I., Tepp, K., Rebane-Klemm, E., Timohhina, N., Terasmaa, A., & Kaambre, T. (2021). Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis. Frontiers in oncology, 11, 698951. https://doi.org/10.3389/fonc.2021.698951 Kaup, K. K., Toom, L., Truu, L., Miller, S., Puurand, M., Tepp, K., Käämbre, T., & Reile, I. (2021). A line-broadening free real-time 31P pure shift NMR method for phosphometabolomic analysis. The Analyst, 146(18), 5502–5507. https://doi.org/10.1039/d1an01198g ID: 521
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The role of SURF1 protein in cytochrome c oxidase biogenesis 1Institute of Physiology of the Czech Academy of Sciences, Czech Republic; 2Institute of Microbiology, Czech Academy of Sciences, Trebon, Czech Republic; 3Departement of Biomedical Sciences, University of Padova, Padova, Italy; 4Departement of Neurosciences, University of Padova, Padova, Italy Bibliography
N. Kovářová, P. Pecina, H. Nůsková, M. Vrbacký, M. Zeviani, T. Mráček, C. Viscomi, J. Houštěk, Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects, BBA, 1862 (2016), 705-15. ID: 447
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Depicting inclusion body myositis using a patient-derived fibroblast model 1Laboratory of Inherited Metabolic Disorders and Muscle Disease, Centre de Recerca Biomèdica CELLEX - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 2Department of Internal Medicine, Hospital Clinic of Barcelona, Barcelona, Spain; 3CIBERER— Spanish Biomedical Research Centre in Rare Diseases, Madrid, Spain; 4CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; 5Universitat Pompeu Fabra (UPF), Barcelona, Spain; 6Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu; Esplugues de Llobregat, Barcelona, Spain; 7Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Liver Unit-HCB-IDIBAPS, Barcelona, Spain; 8CIBEREHD-Spanish Biomedical Research Centre in Hepatic and Digestive Diseases, Madrid, Spain; 9Department of Biomedicine, Cell Biology Unit, CELLEX-IDIBAPS, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain ID: 223
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Effect of physiological cell culture media on cell viability and NRF2 activation National Institute of Chemical and Biological Physics, Estonia ID: 637
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Genetic and functional characterization of a new patient with COX4I1 deficiency 1Hospital Clinic, IDIBAPS, CIBERER, Barcelona, Spain; 2Hospital Universitario de Cruces, Spain ID: 233
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Application of the Escherichia coli Model System to Study the Human Polyribonucleotide Phosphorylase Università degli Studi di Milano, Italy ID: 523
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Phase two biotransformation is highly affected by mitochondrial disease: considerations for pharmacological therapies. Human Metabolomics, North-West University, South Africa Bibliography
1.Kühn, S., Williams, M. E., Dercksen, M., Sass, J. O., & van der Sluis, R. (2023). The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA-an in-silico and in vitro validation. Computational and Structural Biotechnology Journal, 21, 1236-1248. https://doi.org/10.1016/j.csbj.2023.01.041 2.Gruosso, F., Montano, V., Simoncini, C., Siciliano, G., & Mancuso, M. (2020). Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020. Journal of Clinical Medicine, 10(1), 94. MDPI AG. Retrieved from http://dx.doi.org/10.3390/jcm10010094 3.Fouché, B. R. (2021). Differential expression of genes involved in phase two biotransformation in an NDUFS4 deficient mouse model (Master’s dissertation, North-West University (South Africa)). http://hdl.handle.net/10394/38596 ID: 436
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial phenotyping of fibroblasts from Kearns Sayre’s patients to model the disease 1Laboratory of Inherited Metabolic Disorders and Muscle Disease, Centre de Recerca Biomèdica CELLEX - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Sciences - Universitat de Barcelona (UB); Barcelona, Spain.; 2Internal Medicine Department - Hospital Clínic de Barcelona; Barcelona, Spain.; 3CIBERER—Spanish Biomedical Research Centre in Rare Diseases; Madrid, Spain.; 4Hospital Sant Joan de Déu (HSJdD) de Barcelona, Barcelona, Spain.; 5Grupo de Enfermedades Mitocondriales, Instituto de Investigación Hospital 12 de Octubre (imas12). Madrid. Spain.; 6Centro de Biología Molecular S.O., Universidad Autónoma de Madrid (UAM); Madrid, Spain. ID: 343
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Effect of various mutations in the GTPase and middle domain of Drp1 on the mitochondrial network, nucleoids, and peroxisomes 1Department of Paediatrics and Inherited Metabolic Disorders, Charles University and General University Hospital in Prague, Prague, Czech Republic; 2Institute of Physiology, The Czech Academy of Sciences, Prague, Czech Republic ID: 317
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Importance of human ClpXP protease for mitochondrial function First Faculty of Medicine, Charles University; and General University Hospital in Prague ID: 581
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Ketogenic diet mitigates the pathogenic phenotype in TMEM70 deficient animal models 1Institute of Physiology of the Czech Acad. Sci., Prague, Czech Republic; 2Institute of Molecular Genetics of the Czech Acad. Sci., Prague, Czech Republic; 3Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic ID: 276
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mutation in Coq5 leads to CoQ10 deficiency, developmental delay and early death in zebrafish 1Physiology Department, Biomedical Research Center, University of Granada, Granada, Spain; 2Ibs.Granada, Granada, Spain Bibliography
[1] Malicdan MCV, Vilboux T, Ben-Zeev B, et al. A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency. Hum Mutat. 2018;39(1):69-79 ID: 364
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Omega-3 supplementation effects on mitochondrial and metabolic profile in a rabbit model of intrauterine growth restriction 1Inherited metabolic diseases and muscular disorders Lab, Cellex - Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Science - University of Barcelona (UB), 08036 Barcelona, Spain; 2Internal Medicine Unit, Medicine Department, Hospital Clínic of Barcelona, 08036 Barcelona, Spain; 3Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain; 4BCNatal—Barcelona Centre for Maternal-Foetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), IDIBAPS, University of Barcelona, 08036 Barcelona, Spain; 5Department of Clinical Biochemistry, Institut de Recerca de Sant Joan de Deu, Esplugues de Llobregat, 08036 Barcelona, Spain ID: 616
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Redundant and divergent roles of COQ8A and COQ8B in cell metabolism. 1Clinical Genetics Unit, Department of Women and Children’s Health, University of Padova and “Fondazione Istituto di Ricerca Pediatrica Città Della Speranza”, 35127 Padova, Italy.; 2Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, 70121 Bari, Italy; 3Department of Biomedical and Neuromotor Sciences, University of Bologna, I-40126 Bologna, Italy. ID: 305
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Loss of CHCHD8 (COA4) caused mitochondrial respiratory Complex IV deficiency National Defense Academy, Japan ID: 341
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Delving into the phenotypic heterogeneity of Coenzyme Q biosynthesis defects 1Centro Andaluz de Biología del Desarrollo/Universidad Pablo de Olavide-CSIC-JA, Seville, Spain; 2CIBERER, Instituto de Salud Carlos III, Madrid, Spain; 3Laboratorio de Fisiopatología Celular y Bioenergética, Seville, Spain. ID: 654
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Investigating the impact of mtDNA point mutations on mitochondrial function and bioenergetics using patient fibroblasts and hiPSC derived neuronal models University College London, United Kingdom ID: 632
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Human COQ10A and COQ10B genes are essential for Coenzyme Q function in mitochondrial respiration 1University of Padova, Italy; 2Isituto di Ricerca Pediatrica - Cittá della Speranza, Italy; 3Pablo de Olavide University, Sevilla, Spain Bibliography
[1] Stefely JA, Pagliarini DJ. Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. Trends Biochem Sci. 2017 Oct;42(10):824-843. doi: 10.1016/j.tibs.2017.06.008. Epub 2017 Sep 17. PMID: 28927698; PMCID: PMC5731490. [2] Tsui HS, Pham NVB, Amer BR, Bradley MC, Gosschalk JE, Gallagher-Jones M, Ibarra H, Clubb RT, Blaby-Haas CE, Clarke CF. Human COQ10A and COQ10B are distinct lipid-binding START domain proteins required for coenzyme Q function. J Lipid Res. 2019 Jul;60(7):1293-1310. doi: 10.1194/jlr.M093534. Epub 2019 May 2. PMID: 31048406; PMCID: PMC6602128. ID: 286
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The use of β-RA in leptin-deficient mice reveals novel mechanisms of this compound for the treatment of obesity 1Physiology Department, Biomedical Research Center, University of Granada, Granada, Spain; 2Ibs.Granada, Granada, Spain Bibliography
Santos AL, Sinha S. Obesity and aging: Molecular mechanisms and therapeutic approaches. Ageing Res Rev. 2021;67:101268 Hidalgo-Gutiérrez A, Barriocanal-Casado E, Díaz-Casado ME, et al. β-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight. Biomedicines. 2021;9(10):1457 ID: 274
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Oocyte-specific mitofusin 2 knockout enhances the metabolic disfunction of offspring born to obese mothers Federal University of Sao Carlos, Brazil Bibliography
GARCIA, B.M.; MACHADO, T.S.; CARVALHO, K.F.; NOLASCO, P.; NOCITI, R.P.; DEL COLLADO, M.; CAPO BIANCO, M.J.D.; GREJO, M.P.; AUGUSTO NETO, J.D.; SUGIYAMA, F.H.C.; TOSTES, K.; PANDEY, A.K.; GONÇALVES, L.M.; PERECIN, F.; MEIRELLES, F.V.; FERRAZ, J.B.S.; VANZELA, E.C.; BOSCHERO, A.C.; GUIMARÃES, F.E.G.; ABDULKADER, F.; LAURINDO, F.R. M.; KOWALTOWSKI, A.J.; CHIARATTI, M.R. Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis. Molecular Human Reproduction, v. 26, p. 938-952, 2020. ID: 489
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Off-target effects of etomoxir: inhibition of mitochondrial Complex I and fatty acid oxidation 1Oroboros Instruments, Innsbruck, Austria; 2Dept Biochem, Semmelweis Univ, Budapest, Hungary; 3CNC-Center Neurosci and Cell Biol, Univ Coimbra, Portugal; 4IIUC-Inst Interdisciplinary Research, Univ Coimbra, Portugal; 5CIBB-Center for Innovative Biomed Biotechnol, Univ Coimbra, Portugal; 6PDBEB-PhD Programme in Exp Biol Biomed, IIUC, Univ Coimbra, Portugal; 7Lab Pharmaceut Pharmacol, Latvian Inst Organic Synthesis, Riga, Latvia Bibliography
Fischer C, Valente de Souza L, Komlódi T, Garcia-Souza LF, Volani C, Tymoszuk P, Demetz E, Seifert M, Auer K, Hilbe R, Brigo N, Petzer V, Asshoff M, Gnaiger E, Weiss G (2022) Mitochondrial respiration in response to iron deficiency anemia. Comparison of peripheral blood mononuclear cells and liver. https://doi.org/10.3390/metabo12030270 Komlódi T, Tretter L (2022) The protonmotive force – not merely membrane potential. Bioenerg Commun 2022.16. https://doi.org/10.26124/bec:2022-0016 Pallag G, Nazarian S, Ravasz D, Bui D, Komlódi T, Doerrier C, Gnaiger E, Seyfried TN, Chinopoulos C (2022) Proline oxidation supports mitochondrial ATP production when Complex I is inhibited. https://doi.org/10.3390/ijms23095111 Komlódi T, Cardoso LHD, Doerrier C, Moore AL, Rich PR, Gnaiger E (2021) Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria. https://doi.org/10.26124/bec:2021-0003 Komlódi T, Sobotka O, Gnaiger E (2021) Facts and artefacts on the oxygen dependence of hydrogen peroxide production using Amplex UltraRed. https://doi.org/10.26124/bec:2021-0004 ID: 542
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Mitochondrial alterations in sirtuin1 heterozygous mice fed high fat diet and melatonin 1Dept Biomedical Sciences for Health, University of Milan, Milan, Italy; 2Laboratorio Morfologia Umana Applicata, IRCCS Policlinico San Donato, Milan, Italy; 3Dept Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; 4Center for Electron Microscopy, University of Belgrade, Belgrade, Serbia; 5Instituto de Investigaciones Biomedicas “Alberto Sols” (CSIC-UAM), Madrid, Spain Bibliography
1. Paramesha B. et al. Antioxidants (2021) 10: 338; 2. Stacchiotti A. et al. Cells (2019) 8: 1053. 3. Stacchiotti A et al. Nutrients (2017) 9:1323. ID: 1300
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Microproteins in metabolic regulation 1Duke-NUS Medical School, Singapore; 2University of Melbourne, Australia; 3University of Utah, USA; 4University of Southampton, UK Bibliography
Lena Ho, PhD (lead PI), is regarded as a pioneer in the field of microprotein research with over 30 primary research articles (5991 citations, H-index of 21) in top-tier journals. With more than 12 years of experience in microprotein discovery, functionalization and therapeutic development, Lena and her team have developed a framework of bioinformatic tools for mining ribo-seq data for disease-relevant small ORF peptides, as well as an extensive range of biochemical tools to validate their function and uncover their molecular mechanism. Lena is an EMBO Young Investigator and HHMI international scholar. Recent publications : 1) Coding and non-coding roles of MOCCI (C15ORF48) coordinate to regulate host inflammation and immunity. Lee CQE, Kerouanton B, Chothani S, Zhang S, Chen Y, Mantri CK, Hock DH, Lim R, Nadkarni R, Huynh VT, Lim D, Chew WL, Zhong FL, Stroud DA, Schafer S, Tergaonkar V, St John AL, Rackham OJL, Ho L. Nat Commun. 2021 Apr 9;12(1):2130. doi: 10.1038/s41467-021-22397-5. 2) Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis. Liang C, Zhang S, Robinson D, Ploeg MV, Wilson R, Nah J, Taylor D, Beh S, Lim R, Sun L, Muoio DM, Stroud DA, Ho L. Cell Rep. 2022 Aug 16;40(7):111204. doi: 10.1016/j.celrep.2022.111204. 3) Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly. Zhang S, Reljić B, Liang C, Kerouanton B, Francisco JC, Peh JH, Mary C, Jagannathan NS, Olexiouk V, Tang C, Fidelito G, Nama S, Cheng RK, Wee CL, Wang LC, Duek Roggli P, Sampath P, Lane L, Petretto E, Sobota RM, Jesuthasan S, Tucker-Kellogg L, Reversade B, Menschaert G, Sun L, Stroud DA, Ho L. 4) Viral proteases activate the CARD8 inflammasome in the human cardiovascular system. Nadkarni R, Chu WC, Lee CQE, Mohamud Y, Yap L, Toh GA, Beh S, Lim R, Fan YM, Zhang YL, Robinson K, Tryggvason K, Luo H, Zhong F, Ho L. J Exp Med. 2022 Oct 3;219(10):e20212117. doi: 10.1084/jem.20212117. Epub 2022 Sep 21. ID: 1301
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Oxphos deficiency indicates novel functions for the mitochondrial protein import subunit tim50 1Department of Biochemistry and Pharmacology and the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia; 2Queensland Children’s Hospital, Department of Metabolic Medicine, South Brisbane, Brisbane, Queensland, 4001, Australia; 3Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Victoria, 3052, Australia; 4Department of Paediatrics, University of Melbourne, Melbourne, Victoria, 3052, Australia; 5Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, Victoria, 3052, Australia ID: 1226
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity The levels and activation state of the pyruvate dehydrogenase complex modulate the SCAFI-dependent organization of the mitochondrial respiratory chain 1Instituto de Investigación Hospital 12 de Octubre, Madrid 28041, Spain; 2Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy; 3Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid, Spain Bibliography
Fernández-Vizarra E, López-Calcerrada S, Sierra-Magro A, Pérez-Pérez R, Formosa LE, Hock DH, Illescas M, Peñas A, Brischigliaro M, Ding S, Fearnley IM, Tzoulis C, Pitceathly RDS, Arenas J, Martín MA, Stroud DA, Zeviani M, Ryan MT, Ugalde C. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metab. 2022 Nov 1;34(11):1792-1808.e6. doi: 10.1016/j.cmet.2022.09.005. PMID: 36198313. ID: 631
Modelling pathogenic mechanisms: OXPHOS, metabolic rewiring and tissue specificity Development of a yeast model to characterize OPA1 mutations associated with different neuromuscular disorders 1Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padua, and Istituto di Ricerca Pediatrica (IRP) Città della Speranza, Padua, Italy; 2Department of Biomedical Sciences, University of Padua, Padua, Italy ID: 263
Clinical 1: from new genes to old and novel phenotypes An ultra-special family with an ultra-rare condition: three children with mithochondrial complex III deficiency due to homozygous mutations in Lyrm7 Bolzano Hospital, Italy Bibliography
Invernizzi, Federica et al. “A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.” Human mutation. 2013. Sánchez E et al. LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial Complex III assembly in human cells. Biochim Biophys Acta. 2013. Dallabona C. et al. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain. 2016. Hempel M. et al. LYRM7 - associated complex III deficiency: A clinical, molecular genetic, MR tomographic, and biochemical study. Mitochondrion. 2017. Cherian A. et al. Multifocal cavitating leukodystrophy-A distinct image in mitochondrial LYRM7 mutations. Mult Scler Relat Disord. 2021. Peruzzo R et al. Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction. Nat Commun. 2021. |