Time: Wednesday, 14/June/2023: 2:45pm - 4:15pm |
Location: Bologna Congress Center Address: Piazza della Costituzione, 4/a, Bologna (BO), Italy |
- Late Breaking News
- mtDNA maintenance and expression
- Therapy 1: preclinical developments
- Therapy 2: clinical trials
Late breaking news
Precision Medicine Applied to Leigh Syndrome: development of an In Utero fetal gene therapy approach
1Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy; 2Fetal Medicine and Surgery Service, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.; 3Department of Biomedical Sciences, University of Padova, Italy; 4Department of Neurosciences, University of Padova, Italy; 5Laboratorio di Tecnologie della Riproduzione, Avantea, Cremona, Italy; 6Department of Medical Biotechnology and Translational Medicine, University of Milan, Italy
Late breaking news
AAV-based liver-targeted gene therapy for MNGIE: proposal for a clinical trial
1MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK; 2Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; 3Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Catalonia
Late breaking news
Experimental model for studying clinical variability of Thymidine Kinase 2 deficiency with induced pluripotent stem cells
1Alma Mater Studiorum University of Bologna, Department of Medical and Surgical Sciences, Bologna, Italy; 2Alma Mater Studiorum University of Bologna, University of Bologna, Department of Pharmacy and Biotechnology, Bologna, Italy; 3IRCCS Istituto delle Scienze Neurologiche, Programma di Neurogenetica, Bologna, Italy; 4IRCCS Istituto delle Scienze Neurologiche, UOC Neuropsichiatia dell'età pediatrica, Bologna, Italy
Late breaking news
Mitochondrial genome variability in COVID-19 patients
1Azienda USL di Bologna - IRCCS Istituto delle scienze Neurologiche di Bologna, Italy, Italy; 2Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, BO, Italy; 3Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 4Unit of Infectious Diseases and Clinical Microbiology, University Hospital Virgen Macarena, Institute of Biomedicine of Seville (IBIS)/CSIC, Seville, Spain; 5Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 6Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
Late breaking news
Decoding the role of optic atrophy1 (OPA1) non-synonymous single nucleotide polymorphisms in mitochondrial DNA maintenance defects
Jawaharlal Nehru Centre for Advanced Scientific Research, India
1.Gavin Hudson, Patrizia Amati-Bonneau, Emma L. Blakely, Joanna D. Stewart, Langping He, Andrew M. Schaefer, Philip G. Griffiths, Kati Ahlqvist, Anu Suomalainen, Pascal Reynier, Robert McFarland, Douglass M. Turnbull, Patrick F. Chinnery, Robert W. Taylor, Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance, Brain, Volume 131, Issue 2, February 2008, Pages 329–337, https://doi.org/10.1093/brain/awm272
2.Ayman W. El-Hattab, William J. Craigen, Fernando Scaglia, Mitochondrial DNA maintenance defects, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1863, Issue 6, 2017, Pages 1539-1555, ISSN 0925-4439, https://doi.org/10.1016/j.bbadis.2017.02.017.
Late breaking news
Feasibility, safety, and efficacy of Ketogenic Diet in patients with mitochondrial myopathy
1Department of Gastroenterology and Hepatology-Dietetics, Radboudumc, Nijmegen, The Netherlands; 2Radboud Centre for Mitochondrial Medicine (RCMM) , Nijmegen, The Netherlands; 3Department of Physiology, Radboudumc, Nijmegen, The Netherlands; 4Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands; 5University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria; 6Human and Animal Physiology, Wageningen University, The Netherlands; 7Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands
1. Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety.
Zweers H, van Wegberg AMJ, Janssen MCH, Wortmann SB.
Orphanet J Rare Dis. 2021 Jul 3;16(1):295.
mtDNA maintenance and expression
Degrading factors of mitoribosome quality control and their mitigation of translation-induced stress
1Wellcome Centre for Mitochondrial Research, United Kingdom; 2University of Helsinki
mtDNA maintenance and expression
Mitochondrial DNA Double-Strand Breaks lead to the formation of mtDNA deletions which are increased by MgmeI knockout in vivo.
University of Miami, United States of America
•ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly. Arguello T, Peralta S, Antonicka H, Gaidosh G, Diaz F, Tu YT, Garcia S, Shiekhattar R, Barrientos A, Moraes CT. Cell Rep. (2021) Dec 21;37(12):110139.
•Metformin delays neurological symptom onset in a mouse model of neuronal complex I deficiency. Peralta S, Pinto M, Arguello T, Garcia S, Diaz F, Moraes CT. (2020) JCI Insight. Nov 5;5(21):141183
•Myopathy reversion in mice after restauration of mitochondrial complex I. Pereira CV, Peralta S, Arguello T, Bacman SR, Diaz F, Moraes CT. (2020). EMBO Mol Med. Jan 9:e10674.
mtDNA maintenance and expression
Mutating the binding interphases of SLIRP and LRPPRC uncover specific roles for these proteins in optimizing mitochondrial translation.
1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; 2National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Lund University, Lund 223 87, Sweden
Diana Rubalcava-Gracia, Rodolfo García-Villegas, Nils-Göran Larsson. No role for nuclear transcription regulators in mammalian mitochondria? Molecular Cell, 2022. PMID: 36182692.
mtDNA maintenance and expression
A disease-causing mutation (p.F907I) reveals a novel pathogenic mechanism for POLG-related diseases.
1University of Gothenburg, Sweden; 2Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; 3Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
1. TWNK in Parkinson's Disease: A Movement Disorder and Mitochondrial Disease Center Perspective Study.
Percetti M, Franco G, Monfrini E, Caporali L, Minardi R, La Morgia C, Valentino ML, Liguori R, Palmieri I, Ottaviani D, Vizziello M, Ronchi D, Di Berardino F, Cocco A, Macao B, Falkenberg M, Comi GP, Albanese A, Giometto B, Valente EM, Carelli V, Di Fonzo A.
Mov Disord. 2022 Sep;37(9):1938-1943. doi: 10.1002/mds.29139.
2. The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication.
Jiang M, Xie X, Zhu X, Jiang S, Milenkovic D, Misic J, Shi Y, Tandukar N, Li X, Atanassov I, Jenninger L, Hoberg E, Albarran-Gutierrez S, Szilagyi Z, Macao B, Siira SJ, Carelli V, Griffith JD, Gustafsson CM, Nicholls TJ, Filipovska A, Larsson NG, Falkenberg M.
Sci Adv. 2021 Jul 2;7(27):eabf8631. doi: 10.1126/sciadv.abf8631.
3.DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion.
Silva-Pinheiro P, Pardo-Hernández C, Reyes A, Tilokani L, Mishra A, Cerutti R, Li S, Rozsivalova DH, Valenzuela S, Dogan SA, Peter B, Fernández-Silva P, Trifunovic A, Prudent J, Minczuk M, Bindoff L, Macao B, Zeviani M, Falkenberg M, Viscomi C.
Nucleic Acids Res. 2021 May 21;49(9):5230-5248. doi: 10.1093/nar/gkab282.
mtDNA maintenance and expression
Mitoribosome intrinsic GTPase mS29 acts as a non-canonical molecular switch to facilitate mitochondrial translation
1University of Miami, United States of America; 2Stockholm University, Sweden
mtDNA maintenance and expression
Nucleoside supplementation in a zebrafish model of RRM2B mitochondrial DNA depletion syndrome alleviates disease associated symptoms.
Department of Clinical Neurosciences, University of Cambridge, United Kingdom
Van Haute, L., O’Connor, E., Díaz-Maldonado, H., Munro, B. et al. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease. Nat Commun 14, 1009 (2023). https://doi.org/10.1038/s41467-023-36277-7
Benjamin Munro, Rita Horvath, Juliane S Müller, Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok −/− zebrafish, Human Molecular Genetics, Volume 28, Issue 5, 1 March 2019, Pages 796–803, https://doi.org/10.1093/hmg/ddy389
mtDNA maintenance and expression
Non-stop mRNAs generate a ground state of mitochondrial gene expression noise
Institute of Biotechnolgy, University of Helsinki, Finland
K.Y. Ng, G. Lutfullahoglu Bal, U. Richter, O. Safronov, L. Paulin, C.D. Dunn, V. Paavilainen, Julie Richer, W.G. Newman, R.W. Taylor, B.J. Battersby. (2022). Non-stop mRNAs generate the ground state of mitochondrial gene expression noise. Science Advances. 8(46).
mtDNA maintenance and expression
Biochemical characterisation of pathological TOP3A variants associated with adult-onset mitochondrial disease
1Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden; 2Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne; 3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne; 4Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne; 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; 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; 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, 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.
mtDNA maintenance and expression
How hot can mitochondria be? Incubation at temperatures above 43 ºC induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria
1Department of Biochemistry and Molecualr and Cellular Biology, Universidad de Zaragoza, Spain; 2Institute for Biocomputation and Physics of Complex Systems (BIFI), Zaragoza, Spain; 3Peaches Biotech Group, Madrid, Spain; 4Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; 5Centro de Investigaciones Biomédicas en Red en Fragilidad y Envejecimiento Saludable, Madrid, Spain
1.- Moreno-Loshuertos, R., Marco-Brualla, J., Meade, P., Soler-Agesta, R., Enriquez, J. A., & Fernández-Silva, P. (2023). How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria. Mitochondrion, 69, 83–94. Advance online publication. https://doi.org/10.1016/j.mito.2023.02.002
mtDNA maintenance and expression
Inhibition of mitochondrial protein Synthesis induces Biosynthesis of oxidative phosphorylation Complex V
University College London, United Kingdom
mtDNA maintenance and expression
Linear DNA driven recombination in human mitochondria.
1University of Eastern Finland, Finland; 2King Abdullah University of Science and Technology (KAUST); 3University of Miami Miller School of Medicine; 4University of North Carolina at Chapel Hill
mtDNA maintenance and expression
Mitochondrial Topoisomerase 1 in ribonucleotide removal and mtDNA stability
Umeå University, Sweden
mtDNA maintenance and expression
The (in)fidelity of human mitochondrial gene expression
University of Helsinki, Finland
PEER-REVIEWED PUBLICATIONS (*** corresponding authorship)
Tomoda, E., A. Nagao, Y. Shirai, T. Suzuki, B.J. BATTERSBY, T. Suzuki. 2023. Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases. Nucleic Acids Research. In press
Jett, K. A., Z.N. Baker, A. Hossain, A. Boulet, P.A. Cobine, S. Ghosh, P. Ng, O. Yilmaz, K. Barreto, J. DeCoteau, K. Mochoruk, G.N. Ioannou, C. Savard, S. Yuan, C. Lowden, B.E. Kim, H.Y.M. Cheng, B.J. BATTERSBY, Gohil, V. M., & Leary, S. C. 2023. Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein. Journal of Clinical Investigation. 133:e154684
Ng, K.Y., G. Lutfullahoglu Bal, U. Richter, O. Safronov, L. Paulin, C.D. Dunn, V.O. Paavilainen, J. Richer, W.G. Newman, R.W. Taylor and B.J. BATTERSBY***. 2022. Non-stop mRNAs generate a ground state of mitochondrial gene expression noise. Science Advances. 8:eabq5234
Ng, K.Y. and B.J. BATTERSBY***. 2022. Sucrose gradient analysis of human mitochondrial ribosomes and RNA. Methods in Molecular Biology. In press.
Ng, K.Y., U. Richter, C.B. Jackson, S. Seneca, and B.J. BATTERSBY ***. 2022. Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis. Human Molecular Genetics. 31:1230-1241
Hochberg, I., L.A.M. Demain, J. Richer, K. Thompson, J.E. Urquhart, A. Rea, W. Pagarkar, A. Rodríguez-Palmero, A. Schlüter, E. Verdura, A. Pujol, P. Quijada-Fraile, A. Amberger, A.J. Deutschmann, S. Demetz, M. Gillespie, I.A. Belyantseva, H.J. McMillan, M. Barzik, G.M. Beaman, R. Motha, K.Y. Ng, J. O’Sullivan, S.G. Williams, S.S. Bhaskar, I.R. Lawrence, E.M. Jenkinson, J.L. Zambonin, Z. Blumenfeld, S. Yalonetsky, S. Oerum, W. Rossmanith, Genomics England Research Consortium, W.W. Yue, J. Zschocke, K.J. Munro, B.J. BATTERSBY, T.B. Friedman, R.W. Taylor, R.T. O’Keefe, W.G. Newman. 2021. Biallelic Variants in the Mitochondrial RNase P Subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. American Journal of Human Genetics. 108: 2195-2204
Itoh, Y., J. Andréll, A. Choi, U. Richter, P. Maiti, A. Barrientos, B.J. BATTERSBY***, A. Amunts. 2021. Mechanism of membrane-tethered mitochondrial protein synthesis. Science. 371:846-849.
Gorski, K., A. Spoljaric, T. Nyman, K. Kaila, B.J. BATTERSBY, A.E. Lehesjoki. 2020. Quantitative changes in the mitochondrial proteome of cerebellar synaptosomes from preclinical cystatin B-deficient mice. Frontiers in Molecular Neuroscience. 13:570640.
BATTERSBY, B.J.***, U. Richter, and O. Safronov. 2019. Mitochondrial nascent chain quality control determines organelle form and function. ACS Chemical Biology. 14:2396-2405.
Forsström, S., C.B. Jackson, C.J. Carroll, M. Kuronen, E. Pirinen, S Pradhan, A. Marmyleva, M. Auranen, I.M. Kleine, N.A. Khan, A. Roivainen, P. Marjamäki, H. Liljenbäck, L. Wang, B.J. BATTERSBY, U. Richter, V. Velagapudi, J. Nikkanen, L. Euro, A. Suomalainen. 2019. Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metabolism. 30:1040-1054.
Richter U., K.Y. Ng, F. Suomi, P. Marttinen, T. Turunen, C. Jackson, A. Suomalainen, H. Vihinen, E. Jokitalo, T.A. Nyman, M.A. Isokallio, J.B. Stewart, C. Mancini, A. Brusco, S. Seneca, A. Lombès, R.W. Taylor, B.J. BATTERSBY***. 2019. Mitochondrial stress response triggered by defects in protein synthesis quality control. Life Science Alliance. 2:e201800219.
Mancini, C., E. Hoxha, L. Iommarini, A. Brussino, U. Richter, F. Montarolo, C. Cagnoli, R. Parolisi, D.I.G. Morosini, V. Nicolò, F. Maltecca, L. Muratori, G. Ronchi, S. Geuna, F. Arnaboldi, E. Donetti, E. Giorgio, S. Cavalieri, E. Di Gregorio, E. Pozzi, M. Ferrero, E. Riberi, G. Casari, F. Altruda, E. Turco, G. Gasparre, B.J. BATTERSBY, A.M. Porcelli, E. Ferrero, A. Brusco, F. Tempia. 2019. Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity. Neurobiology of Disease. 124:14-28.
Jackson, C.B., M. Huemer, R. Bolognini, F. Martin, G. Szinnai, B.C. Donner, U. Richter, B.J. BATTERSBY, J.M. Nuoffer, A. Suomalainen, A. Schaller. 2019. Mutations in MRPS14 (uS14m) cause perinatal hypertrophic cardiomyopathy with neonatal lactic acidosis, growth retardation, dysmorphic features and neurological involvement. Human Molecular Genetics. 28:639-649.
Richter, U., M.E. Evans, W.C. Clark, P. Marttinen, E.A. Shoubridge, A. Suomalainen, A. Wredenberg, A. Wedell, T. Pan, and B.J. BATTERSBY***. 2018. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nature Communications. 9:3966.
Suomalainen, A. and B.J. BATTERSBY***. 2018. Mitochondrial diseases: contribution of organelle stress responses to pathology. Nature Reviews Molecular Cell Biology. 19: 77-92.
Thompson, K., N. Mai, M. Oláhová, F. Scialó, L.E. Formosa, D.A. Stroud, M. Garrett, N.Z. Lax, F.M. Robertson, C. Jou, A. Nascimento, C. Ortez, C. Jimenez-Mallebrera, S.A. Hardy, L. He, G.K. Brown, P. Marttinen, R. McFarland, A. Sanz, B.J. BATTERSBY, P.E. Bonnen, M.T. Ryan, Z.M.A. Chrzanowska-Lightowlers, R.N. Lightowlers, and R.W. Taylor. 2018. OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. EMBO Molecular Medicine. 10:e9060
mtDNA maintenance and expression
The role of mitochondrial RNA polymerase in mtDNA replication priming
University of Eastern Finland, Finland
mtDNA maintenance and expression
Mitochondrial content is significantly reduced during the early stages of human pluripotent stem cell differentiation
University of Helsinki, Finland
# DÖHLA J & KUULUVAINEN E, GEBERT N, AMARAL A, ENGLUND JI, GOPALAKRISHNAN S, KONOVALOVA S, NIEMINEN AI, SALMINEN ES, TORREGROSA-MUÑUMER R, AHLQVIST K, YANG Y, BUI H, OTONKOSKI T, KÄKELÄ R, HIETAKANGAS V, TYYNISMAA H, ORI A & KATAJISTO P. (2022). Metabolic determination of cell fate through selective inheritance of mitochondria. Nature Cell Biol.
# TORREGROSA-MUÑUMER R & KENVIN S, REIDELBACH M, PENNONEN P, TURKIA JJ, RANNILA E, KVIST J, SAINIO MT, HUBER N, HERUKKA SK, HAAPASALO A, AURANEN M, TROKOVIC R, SHARMA V, YLIKALLIO E, TYYNISMAA H. (2021). Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism. Human Molecular Genetics.
# TORREGROSA-MUÑUMER R, HANGAS A, GOFFART S, BLEI D, ZSURKA G, GRIFFITH J, KUNZ WS &POHJOISMÄKI J. (2019). Replication fork rescue in mammalian mitochondria. Scientific Reports.
# TORREGROSA-MUÑUMER R, FORSLUND J, GOFFART S, STOJKOVIC G, PFEIFFER A, CARVALHO G,BLANCO L, WANROOIJ S & POHJOISMÄKI J. (2017). PrimPol is required for replication re-initiation aftermitochondrial DNA damage. PNAS.
# TORREGROSA-MUÑUMER R, GOFFART S, HAIKONEN J, AND POHJOISMÄKI J. (2015). Low doses of UV and oxidative damage induce dramatic accumulation of mitochondrial DNA replication intermediates, forkregression and replication initiation shift. Mol Biol Cell.
mtDNA maintenance and expression
Loss of RNase H1 in early B cell development induces mitochondrial-based dysfunction
1DIR Eunice Kennedy Shriver National Institute of Child Health and Human Devlopment; 2Department of Molecular and Cellular Biology, University of Califofnia, Davis
Cerritelli SM, Sakhuja K, Crouch RJ. RNase H1, the Gold Standard for R-Loop Detection. Methods Mol Biol. 2022;2528:91-114. doi: 10.1007/978-1-0716-2477-7_7. PMID: 35704187.
mtDNA maintenance and expression
New insights into late-maturation steps of the human mitochondrial small ribosomal subunit
1Department of Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany; 2Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Goettingen, Goettingen, Germany
mtDNA maintenance and expression
Early-stages during large mitoribosomal subunit assembly
1University Medical Center Göttingen, Germany; 2Cluster of Excellence (MBExC), University of Göttingen, Germany
mtDNA maintenance and expression
Effect of post-transcriptional modifications of tRNAMet on mitochondrial codon recognition
Max Planck Institute of Multidisciplinary Sciences, Göttingen, Germany
mtDNA maintenance and expression
Establishing the OPA1 role in the mtDNA maintenance in cell models of Dominant Optic Atrophy (DOA)
1IRCCS, Istituto delle Scienze Neurologiche di Bologna, Italy - Programma di Neurogenetica; 2DIBINEM, Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Italy; 3Vall d'Hebron Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Raras-CIBERER, Autonomous University of Barcelona, Barcelona, Spain
mtDNA maintenance and expression
Mutations affecting the relation between mtDNA synthesis and proofreading by POLγ
Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden
mtDNA maintenance and expression
Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation
1Genetics Section, Molecular and Clinical Sciences, St George’s, University of London, London, United Kingdom; 2Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 3Research Programs Unit, Molecular Neurology, Biomedicum, University of Helsinki, • Helsinki, Finland; 4Department of Immunology, Institute of Clinical Medicine, University of Oslo and Oslo, University Hospital, Oslo, Norway; 5Core Facilities, St George’s, University of London, London, United Kingdom.; 6Wellcome Centre for Mitochondrial Research, Translational and Clinical Research • Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 7NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 8Department of Genetics, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem. 9112001 Jerusalem Israel.; 9Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; 10Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain; 11Institute of Biotechnology, University of Helsinki, Helsinki, Finland
mtDNA maintenance and expression
The role of mL45 N-terminus in mitochondrial translation under standard and stress conditions
Department of Neurology, University of Miami, Miller School of Medicine, FL, USA
mtDNA maintenance and expression
Characterization of human mitochondrial translation elongation and ribosome recycling factors mtEFG1 and mtEFG2
Max-Planck Institute for Multidisciplinary Sciences, Germany
mtDNA maintenance and expression
Knock-out of OGG1 in HEK293 cells does not alter the formation of single strand breaks in mitochondrial DNA upon H2O2 treatment
1Institute of Experimental Epileptology and Cognition Research, University of Bonn, Germany; 2Department of Epileptology, University Hospital Bonn, Germany
mtDNA maintenance and expression
Ligase 3 is indispensable for repair of oxidative lesions of mtDNA but dispensable for circular genome end ligation
University Bonn, Department of Epileptology, Germany
1. Zsurka G, Trombly G, Schöler S, Blei D, Kunz WS. Functional Assessment of Mitochondrial DNA Maintenance by Depletion and Repopulation Using 2',3'-Dideoxycytidine in Cultured Cells. Methods Mol Biol. 2023;2615:229-240
2. Mikhailova AG, Mikhailova AA, Ushakova K, Tretiakov EO, Iliushchenko D, Shamansky V, Lobanova V, Kozenkov I, Efimenko B, Yurchenko AA, Kozenkova E, Zdobnov EM, Makeev V, Yurov V, Tanaka M, Gostimskaya I, Fleischmann Z, Annis S, Franco M, Wasko K, Denisov S, Kunz WS, Knorre D, Mazunin I, Nikolaev S, Fellay J, Reymond A, Khrapko K, Gunbin K, Popadin K. A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand. Nucleic Acids Res. 2022 Oct 14;50(18):10264-10277
3. Hippen M, Zsurka G, Peeva V, Machts J, Schwiecker K, Debska-Vielhaber G, Wiesner RJ, Vielhaber S, Kunz WS. Novel Pathogenic Sequence Variation m.5789T>C Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome. Neurol Genet. 2021 Mar 3;8(2):e660.
4. Birtel J, von Landenberg C, Gliem M, Gliem C, Reimann J, Kunz WS, Herrmann P, Betz C, Caswell R, Nesbitt V, Kornblum C, Charbel Issa P. Mitochondrial Retinopathy. Ophthalmol Retina. 2022 Jan;6(1):65-79.
5. Rotko D, Kudin AP, Zsurka G, Kulawiak B, Szewczyk A, Kunz WS. Molecular and Functional Effects of Loss of Cytochrome c Oxidase Subunit 8A. Biochemistry (Mosc). 2021 Jan;86(1):33-43.
6. Torregrosa-Muñumer R, Hangas A, Goffart S, Blei D, Zsurka G, Griffith J, Kunz WS, Pohjoismäki JLO. Replication fork rescue in mammalian mitochondria. Sci Rep. 2019 Jun 19;9(1):8785.
7. Peeva V, Blei D, Trombly G, Corsi S, Szukszto MJ, Rebelo-Guiomar P, Gammage PA, Kudin AP, Becker C, Altmüller J, Minczuk M, Zsurka G, Kunz WS. Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. Nat Commun. 2018 Apr 30;9(1):1727.
mtDNA maintenance and expression
Modulation of mtDNA heteroplasmy through endosomal-mitophagy
1Institute of Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; 2Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; 3Institute of Genetics, University of Cologne, Germany
1. Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination. Autophagy. 2023 Jan 29;1-2. doi: 10.1080/15548627.2023.2170959
2. Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA. Nat Commun. 2022 Nov 7;13(1):6704. doi: 10.1038/s41467-022-34205-9.
3. Combined fibre atrophy and decreased muscle regeneration capacity driven by mitochondrial DNA alterations underlie the development of sarcopenia. Journal Cachexia Sarcopenia Muscle. 2022 Aug;13(4):2132-2145. doi: 10.1002/jcsm.13026. Epub 2022 Jun 28.
mtDNA maintenance and expression
The role of mitoSAM in mitochondrial gene expression
1Division of Molecular Metabolism, Karolinska Institutet, Stockholm, Sweden; 2Max Planck Institute of Biochemistry, Munich, Germany; 3Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden; 4Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; 5Proteomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
mtDNA maintenance and expression
The slumbering mitochondrion awakes: monitoring mitochondrial gene expression during oocyte and early embryo development
1Newcastle Fertility Centre, International Centre for Life, Newcastle upon Tyne, NE1 3BZ, United Kingdom; 2Wellcome Centre for Mitochondrial Research, Newcastle University Biosciences Institute, Newcastle upon Tyne, NE2 4HH, United Kingdom
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.
Van Blerkom J. Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion. 2011 Sep;11(5):797-813.
De La Fuente R, Eppig JJ. Transcriptional activity of the mouse oocyte genome: companion granulosa cells modulate transcription and chromatin remodeling. Dev Biol. 2001;229(1):224-36.
Heyn P, Kircher M, Dahl A, Kelso J, Tomancak P, Kalinka AT, Neugebauer KM. The earliest transcribed zygotic genes are short, newly evolved, and different across species. Cell Rep. 2014 Jan 30;6(2):285-92.
Cheng S, Altmeppen G, So C, Welp LM, Penir S, Ruhwedel T, Menelaou K, Harasimov K, Stützer A, Blayney M, Elder K, Möbius W, Urlaub H, Schuh M. Mammalian oocytes store mRNAs in a mitochondria-associated membraneless compartment. Science. 2022 Oct 21;378(6617):eabq4835.
Garcia-Alonso, L., Lorenzi, V., Mazzeo, C.I. et al. Single-cell roadmap of human gonadal development. Nature 607, 540–547 (2022).
mtDNA maintenance and expression
How mitochondrial DNA metabolism shapes cellular senescence
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå 90736, Sweden
L'Hôte V, Mann C, Thuret JY. From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biol. 2022 Sep;12(9):220171. doi: 10.1098/rsob.220171
L'Hôte V, Courbeyrette R, Pinna G, Cintrat JC, Le Pavec G, Delaunay-Moisan A, Mann C, Thuret JY. Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy. Aging Cell. 2021 Sep;20(9):e13447. doi: 10.1111/acel.13447
Doimo M., Abrahamsson S., L'Hôte V., Ndi M., Nath Das R., Aasumets K., Berner A., Goffart S., Pohjoismäki J.L.O., Dávila López M., Chorell E., Wanrooij S. Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells. bioRxiv. 2022 Jun. doi: 10.1101/2022.06.08.495283
mtDNA maintenance and expression
Processing of stalled replication forks in mitochondria
University of Eastern Finland, Finland
mtDNA maintenance and expression
Stochastic survival of the densest accounts for the expansion of mitochondrial mutations in the ageing of skeletal muscle fibres
1Department of Mathematics, Imperial College London, United Kingdom; 2EPSRC Centre for the Mathematics of Precision Healthcare, Imperial College London, United Kingdom
https://www.pnas.org/doi/10.1073/pnas.2122073119
F. Insalata, H. Hoitzing, J. Aryaman, N. S. Jones. Stochastic survival of the densest and mitochondrial DNA clonal expansion in ageing. Proceedings of the National Academy of Sciences of the United States of America, doi: 10.1073/pnas.2122073119.
mtDNA maintenance and expression
Top3α is the replicative topoisomerase in mitochondrial DNA replication
1University of Eastern Finland, Finland; 2Radboud Center for Mitochondrial Medicine, Department of Paediatrics, Radboudumc, Nijmegen, The Netherlands
mtDNA maintenance and expression
Mitochondrial-nuclear compatibility in hare cybrids
1University of Eastern Finland, Finland; 2Tampere University, Finland
mtDNA maintenance and expression
Identification of drugs for the treatment of POLG-related diseases by means of a high throughput drug repurposing approach performed in Saccharomyces cerevisiae
1Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy; 2Department of Biology, University of Padova, Padova, Italy
Magistrati M., Gilea A.I., Ceccatelli Berti C., Baruffini E., Dallabona C. (2023) Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models. Int J Mol Sci. 24:2178. doi: 10.3390/ijms24032178. (Corresponding author)
Gilea A.I., Ceccatelli Berti C., Magistrati M., di Punzio G., Goffrini P., Baruffini E., Dallabona C. (2021) Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability. Genes (Basel). 12:1866. doi: 10.3390/genes12121866. (Corresponding author)
di Punzio G., Gilberti M., Baruffini E., Lodi T., Donnini C., Dallabona C. (2021) A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool. Int. J. Mol. Sci. 22:12223. doi: 10.3390/ijms222212223.
Cappuccio G., Ceccatelli Berti C., Baruffini E., Sullivan J, Shashi V., Jewett T, Stamper T., Maitz S., Canonico F., Revah-Politi A., Kupchik G.S., Anyane-Yeboa K., Aggarwal V., Benneche A., Bratland E., Berland S., D'Arco F., Alves C.A., Vanderver A., Longo D., Bertini E., Torella A., Nigro V.; D'Amico A., van der Knaap M.S., Goffrini P., Brunetti-Pierri N. (2021) Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease. Hum. Mutat. 42:745-761. doi: 10.1002/humu.24210. (Co-first author)
Figuccia S., Degiorgi A., Ceccatelli Berti C., Baruffini E., Dallabona C., Goffrini P. (2021) Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants. Int. J. Mol. Sci. 22:4524. doi: 10.3390/ijms22094524.
Hytönen M.K., Sarviaho R., Jackson C.B., Syrjä P., Jokinen T., Matiasek K., Rosati M., Dallabona C., Baruffini E., Quintero I., Arumilli M., Monteuuis G., Donner J., Anttila M., Suomalainen A., Bindoff LA., Lohi H. (2021) In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum. Genet. 140:1593-1609. doi: 10.1007/s00439-021-02279-y.
Ceccatelli Berti C., di Punzio G., Dallabona C., Baruffini E., Goffrini P., Lodi T., Donnini C. (2021) The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases. Genes (Basel). 12:300. doi: 10.3390/genes12020300.
Facchinello N., Laquatra C., Locatello L., Beffagna G., Brañas Casas R., Fornetto C., Dinarello A., Martorano L., Vettori A., Risato G., Celeghin R., Meneghetti G., Santoro M.M., Delahodde A., Vanzi F., Rasola A., Dalla Valle L., Rasotto M.B., Lodi T., Baruffini E., Argenton F., Tiso N. (2021) Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish. Cell. Death Dis. 12:100. doi: 10.1038/s41419-020-03359-z. (Co-corresponding author)
Aleo S.J., Del Dotto V., Fogazza M., Maresca A., Lodi T., Goffrini P., Ghelli A., Rugolo M., Carelli V., Baruffini E., Zanna C. (2021) Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations. Hum. Mol. Genet. 29:3631-3645. doi: 10.1093/hmg/ddaa244. (Co-senior author)
Benincá C., Zanette V., Brischigliaro M., Johnson M., Reyes A., Valle D.A.D., J Robinson A., Degiorgi A., Yeates A., Telles B.A., Prudent J., Baruffini E., S. F. Santos M.L., R. de Souza R.L., Fernandez-Vizarra .E, Whitworth A.J., Zeviani M. (2021) Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. J. Med. Genet. 58:155-167. doi: 10.1136/jmedgenet-2020-106861.
Hoyos-Gonzalez N., Trasviña-Arenas C.H., Degiorgi A., Castro-Lara A.Y., Peralta-Castro A., Jimenez-Sandoval P., Diaz-Quezada C., Lodi T., Baruffini E., Brieba LG. (2020) Modeling of pathogenic variants of mitochondrial DNA polymerase: insight into the replication defects and implication for human disease. Biochim. Biophys. Acta Gen. Subj. 1864:129608. doi: 10.1016/j.bbagen.2020.129608. (Co-corresponding author)
Trasviña-Arenas C.H., Hoyos-Gonzalez N., Castro-Lara A.I., Rodriguez-Hernandez A., Sanchez-Sandoval M.E., Jimenez-Sandoval P., Ayala-García V.M., Díaz-Quezada C., Lodi T., Baruffini E., Brieba L.G. (2019) Amino and carboxy-terminal extensions of yeast mitochondrial DNA polymerase assemble both the polymerization and exonuclease active sites. Mitochondrion, 49:166-177. doi: 10.1016/j.mito.2019.08.005. ISSN: 1567-7249
Chin H., Goh D.L., Wang F.S, Hong Tay S.K., Heng C.K., Donnini C., Baruffini E., Pines O. (2019) A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension. J. Mol. Med. (Berl). 97:1557-1566. doi: 10.1007/s00109-019-01834-5. (Co-corresponding author)
Verrigni D., Di Nottia M., Ardissone A., Baruffini E., Nasca A., Legati A., Bellacchio E., Fagiolari G., Martinelli D., Fusco L., Battaglia D., Trani G., Versienti G., Marchet S., Torraco A., Rizza T., Verardo M., D'Amico A., Diodato D., Moroni I., Lamperti C., Petrini S., Moggio M., Goffrini P., Ghezzi D., Carrozzo R., Bertini E. (2019) Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy. Hum. Mutat. 40, 601-618. doi: 10.1002/humu.23729. (Co-first author)
Therapy 1: preclinical developments
Mitochondrial genome replacement can rejuvenate aging cells
Kyoto prefectural University of Medicine, Japan
1: Suzuki Y, Kami D, Taya T, Sano A, Ogata T, Matoba S, Gojo S. ZLN005 improves
the survival of polymicrobial sepsis by increasing the bacterial killing
via inducing lysosomal acidification and biogenesis in phagocytes. Front
Immunol. 2023 Feb 3;14:1089905. doi: 10.3389/fimmu.2023.1089905.
2: Kami D, Ishizaki T, Taya T, Katoh A, Kouji H, Gojo S. A novel mRNA decay
inhibitor abolishes pathophysiological cellular transition. Cell Death Discov.
2022 Jun 7;8(1):278. doi: 10.1038/s41420-022-01076-4.
3: Shikuma A, Kami D, Maeda R, Suzuki Y, Sano A, Taya T, Ogata T, Konkel A,
Matoba S, Schunck WH, Gojo S. Amelioration of Endotoxemia by a Synthetic Analog
of Omega-3 Epoxyeicosanoids. Front Immunol. 2022 Feb 24;13:825171. doi:
10.3389/fimmu.2022.825171.
4: Maeda R, Kami D, Shikuma A, Suzuki Y, Taya T, Matoba S, Gojo S. RNA decay in
processing bodies is indispensable for adipogenesis. Cell Death Dis. 2021 Mar
17;12(4):285. doi: 10.1038/s41419-021-03537-7.
Therapy 1: preclinical developments
Project pearl: raising the profile of mitochondrial disease
Wellcome Centre for Mitochondrial Research, Newcastle University, United Kingdom
Rhys H. Thomas, Amy Hunter, Lyndsey Butterworth, Catherine Feeney, Tracey D. Graves, Sarah Holmes, Pushpa Hossain, Jo Lowndes, Jenny Sharpe, Sheela Upadhyaya, Kristin N. Varhaug, Marcela Votruba, Russell Wheeler, Kristina Staley, Shamima Rahman. Research priorities for mitochondrial disorders: Current landscape and patient and professional views. J Inherit Metab Dis. 2022 Jul;45(4):796-803. doi: 10.1002/jimd.12521.
Craven L, Murphy JL, Turnbull DM. Mitochondrial donation - hope for families with mitochondrial DNA disease. Emerg Top Life Sci. 2020 Sep 8;4(2):151-154. doi: 10.1042/ETLS20190196.
Ahmed ST, Craven L, Russell OM, Turnbull DM, Vincent AE. Diagnosis and Treatment of Mitochondrial Myopathies. Neurotherapeutics. 2018 Oct;15(4):943-953. doi: 10.1007/s13311-018-00674-4.
Rai PK, Craven L, Hoogewijs K, Russell OM, Lightowlers RN. Advances in methods for reducing mitochondrial DNA disease by replacing or manipulating the mitochondrial genome. Essays Biochem. 2018 Jul 20;62(3):455-465. doi: 10.1042/EBC20170113.
Craven L, Murphy J, Turnbull DM, Taylor RW, Gorman GS McFarland R. Scientific and Ethical Issues in Mitochondrial Donation. The New Bioethics. In publication.
Craven L*, Tang MX*, Gorman GS, De Sutter P, Heindryckx B. Novel reproductive technologies to prevent mitochondrial disease. Hum Reprod Update. 2017 23:1-19. doi: 10.1093/humupd/dmx018.
Craven L, Alston CL, Taylor RW, Turnbull DM. Recent Advances in Mitochondrial Disease. Annu Rev Genomics Hum Genet. 2017 Aug 31;18:257-275. doi: 10.1146/annurev-genom-091416-035426.
Hyslop LA, Blakeley P, Craven L, et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature. 2016 16;534 (7607):383-6. doi: 10.1038/nature18303.
Craven L, Herbert M, Murdoch A, Murphy J, Lawford Davies J, Turnbull DM. Research into Policy: A Brief History of Mitochondrial Donation. Stem Cells. 2016 Feb;34(2):265-7. doi: 10.1002/stem.2221.
Chinnery PF, Craven L, Mitalipov S, Stewart JB, Herbert M, Turnbull DM. The challenges of mitochondrial replacement. PLoS Genet. 2014 Apr 24;10(4):e1004315. doi: 10.1371/journal.pgen.1004315.
Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010 6;465 (7294):82-5. doi: 10.1038/nature08958.
Therapy 1: preclinical developments
Innovative technology for regulating mitochondrial function in host cells
1Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; 2FOREST Program, Japan Science and Technology Agency Japan, Saitama, Japan; 3Faculty of Engineering, Hokkaido University, Sapporo, Japan; 4Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
Yamada Y, Munechika R, Satrialdi, Kubota F, Sato Y, Sakurai Y, Harashima H, Mitochondrial delivery of an anticancer drug via systemic administration using a mitochondrial delivery system that inhibits the growth of drug-resistant cancer engrafted on mice. J. Pharm. Sci. ;109: 2493-2500 (2020).
Yamada Y, Somiya K, Miyauchi A, Osaka H, Harashima H, Validation of a mitochondrial RNA therapeutic strategy using fibroblasts from a Leigh syndrome patient with a mutation in the mitochondrial ND3 gene. Sci. Rep. 10: 7511 (2020).
Yamada Y, Maruyama M, Kita T, Usami S, Kitajiri S, Harashima H, The use of a MITO-Porter to deliver exogenous therapeutic RNA to a mitochondrial disease’s cell with a A1555G mutation in the mitochondrial 12S rRNA gene results in an increase in mitochondrial respiratory activity. Mitochondrion 55: 134-144 (2020).
Yamada Y, Satrialdi, Hibino M, Sasaki D, Jiro A, Harashima H. Power of mitochondrial drug delivery systems to produce innovative nanomedicines. Adv. Drug. Deliv. Rev. 154-155： 187-209 (2020).
Sasaki D, Abe J, Takeda A, Harashima H, Yamada Y, Transplantation of MITO cells, mitochondria activated cardiac progenitor cells, to the ischemic myocardium of mouse enhances the therapeutic effect. Sci. Rep. 12: 4344 (2022).
Yamada Y, Sato Y, Nakamura T, Harashima H. Innovative cancer nanomedicine based on immunology, gene editing, intracellular trafficking control J. Control. Release 348: 357-369 (2022).
Therapy 1: preclinical developments
CNS gene therapy in a mouse model of complex I encephalopathy
University of Miami, United States of America
Walker, BR, Moraes, CT. Nuclear-Mitochondrial Interactions. Biomolecules, 2022, 12, 427. https://doi.org/10.3390/biom12030427
Therapy 1: preclinical developments
Strategies for fighting mitochondrial diseases: AAV-based gene therapy
1Venetian Institute of Molecular Medicine, Padova; 2Department of Neuroscience, University of Padova; 3Department of Biomedical Sciences, University of Padova
Therapy 1: preclinical developments
Cannabidiol ameliorates mitochondrial disease via PPARgamma activation
1Neuroscience Institute, Autonomous University of Barcelona, Bellaterra, Spain; 2Minoryx Therapeutics SL, Barcelona, Spain; 3Celltec-UB, Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat de Barcelona, Barcelona, Spain; 4CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
Therapy 1: preclinical developments
Sonlicromanol improves phenotypic changes in models of Selenoprotein N-related myopathies
1Khondrion, Nijmegen, The Netherlands; 2Department of Pediatrics, RCMM, RadboudUMC, Nijmegen, The Netherlands; 3Radboud University, Radboud Institute for Biological and Environmental Sciences, Cluster Ecology & Physiology, Department of Animal Physiology, Nijmegen, The Netherlands; 4Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 5Department of Pediatric Neurology, Centre of neuromuscular disorders in children and adolescents, University Clinic Essen, University of Duisburg-Essen, Germany
Therapy 1: preclinical developments
Therapeutic interventions to regulate the Q-junction, 1C metabolism and the neuroinflammatory response.
1Physiology Department, Biomedical Research Center, University of Granada, Spain; 2Ibs. Granada, Granada, Spain
1.Nikkanen, J., et al., Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism. Cell Metab, 2016. 23(4): p. 635-48.
2.Bao, X.R., et al., Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife, 2016. 5: p. e10575.
3.Forsström, S., et al., Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions. Cell Metabolism, 2019. 30(6): p. 1040-1054.e7.
4.Krug, A.K., et al., Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis, 2014. 5(5): p. e1222.
5.González-García, P., et al., Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism. Human molecular genetics, 2020. 29(19): p. 3296-3311.
6.Hidalgo-Gutierrez, A., et al., beta-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9 (R239X) mice. EMBO Mol Med, 2019. 11(1).
7.Gonzalez-Garcia, P., et al., The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency. Redox Biol, 2022. 55: p. 102403.
Therapy 1: preclinical developments
Yeast as a model for searching drugs against pathologies caused by mutations in ACO2
1Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy; 2IRCCS Istituto delle Scienze Neurologiche di Bologna, Bellaria Hospital, Bologna, Italy; 3Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna
Magistrati M., Gilea A.I., Ceccatelli Berti C., Baruffini E., Dallabona C. (2023) Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models. Int J Mol Sci. 24:2178. doi: 10.3390/ijms24032178. (Co-first author)
Gilea A.I., Ceccatelli Berti C., Magistrati M., di Punzio G., Goffrini P., Baruffini E., Dallabona C. (2021) Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability.Genes (Basel). 12:1866. doi: 10.3390/genes12121866.
Ceccatelli Berti C., Gilea A.I., De Gregorio M.A., Goffrini P. (2020) Exploring Yeast as a Study Model of Pantothenate Kinase-Associated Neurodegeneration and for the Identification of Therapeutic Compounds.Int J Mol Sci. 22:293. doi: 10.3390/ijms22010293.
Therapy 1: preclinical developments
MiR-181a/b modulation as a potential therapeutic approach for Stargardt disease treatment
1Telethon Institute of Genetics and Medicine,Italy; 2Institute for Genetic and Biomedical Research, CNR, Italy; 3Department of Translational Medical Science Federico II University of Naples, Italy; 4University of Campania Luigi Vanvitelli, Italy; 5Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Italy
1) Jabri Y, Biber J, Diaz-Lezama N, Grosche A, Pauly D. Cell-Type-Specific Complement Profiling in the ABCA4-/- Mouse Model of Stargardt Disease. Int J Mol Sci. 2020 Nov 11;21(22):8468. doi: 10.3390/ijms21228468. PMID: 33187113; PMCID: PMC7697683.
2) Indrieri A, Carrella S, Romano A, Spaziano A, Marrocco E, Fernandez-Vizarra E, Barbato S, Pizzo M, Ezhova Y, Golia FM, Ciampi L, Tammaro R, Henao-Mejia J, Williams A, Flavell RA, De Leonibus E, Zeviani M, Surace EM, Banfi S, Franco B. miR-181a/b downregulation exerts a protective action on mitochondrial disease models. EMBO Mol Med. 2019 May;11(5):e8734. doi: 10.15252/emmm.201708734. PMID: 30979712; PMCID: PMC6505685.
3)Barbato A, Iuliano A, Volpe M, D'Alterio R, Brillante S, Massa F, De Cegli R, Carrella S, Salati M, Russo A, Russo G, Riccardo S, Cacchiarelli D, Capone M, Madonna G, Ascierto PA, Franco B, Indrieri A, Carotenuto P. Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. Int J Mol Sci. 2021 Feb 11;22(4):1801. doi: 10.3390/ijms22041801. PMID: 33670365; PMCID: PMC7918089.
4) Carrella S, Indrieri A, Franco B, Banfi S. Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches. Front Neurosci. 2020 Sep 24;14:588234. doi: 10.3389/fnins.2020.588234. PMID: 33071752; PMCID: PMC7541846.
Therapy 1: preclinical developments
MitoTALEN reduces mutant mtDNA load in the mouse CNS
1Department of Neurology, University of Miami Miller School of Medicine, Miami USA; 2Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle UK
MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. Bacman SR, Kauppila JHK, Pereira CV, Nissanka N, Miranda M, Pinto M, Williams SL, Larsson NG, Stewart JB, Moraes CT. Nat Med. 2018 Nov;24(11):1696-1700.
Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo.
Zekonyte U, Bacman SR, Smith J, Shoop W, Pereira CV, Tomberlin G, Stewart J, Jantz D, Moraes CT. Nat Commun. 2021 May 28;12(1):3210.
Precise and simultaneous quantification of mitochondrial DNA heteroplasmy and copy number by digital PCR. Shoop WK, Gorsuch CL, Bacman SR, Moraes CT. J Biol Chem. 2022 Nov;298(11):102574.
Therapy 1: preclinical developments
Phosphodiesterase 5 inhibitors (PDE5i) as a promising treatment for MT-ATP6 associated mater-nally inherited Leigh Syndrome (MILS)
1Charité-Universitätsmedizin Berlin, Department of Neuropediatrics, Berlin, Germany; 2Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich Heine Universi-ty, Düsseldorf, Germany; 3Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, ScreeningPort, Hamburg, Germany; 4University of Verona, Italy; 5Fondazione IRCCS Instituto Neurologico "C. Besta", Milano, Italy; 6Ludwig Maximilians University (LMU), München, Germany; 7University of Bologna, Italy; 8Freie Universität Berlin, Germany
[1]D. Leigh, “Subacute necrotizing encephalomyelopathy in a neonatal infant,” J. Neurol. Neurosurg. Psychiat., vol. 14, pp. 216–221, 1951, doi: 10.1097/00005072-197703000-00010.
[2]S. Rahman, “Leigh syndrome,” in Handbook ofClinical Neurology, Mitochondrial Diseases, 3rd ed., vol. 194, R. Horvath, M. Hirano, and P. F. Chinnery, Eds. Elsevier B.V., 2023, pp. 43–63.
[3]C. Lorenz et al., “Generation of four iPSC lines from four patients with Leigh syndrome carrying homoplasmic mutations m.8993T > G or m.8993T > C in the mitochondrial gene MT-ATP6,” Stem Cell Res., vol. 61, p. 102742, 2022, doi: 10.1016/j.scr.2022.102742.
[4]M.-T. Henke, A. Zink, S. Diecke, A. Prigione, and M. Schuelke, “Generation of two mother – child pairs of iPSCs from maternally inherited Leigh syndrome patients with m . 8993 T > G and m . 9176 T > G MT-ATP6 mutations,” Stem Cell Res., vol. 67, no. December 2022, pp. 1–5, 2023, doi: 10.1016/j.scr.2023.103030.
[5]C. Lorenz et al., “Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders,” Cell Stem Cell, vol. 20, no. 5, pp. 659-674.e9, 2017, doi: 10.1016/j.stem.2016.12.013.
Therapy 1: preclinical developments
The effect of mitochondrial NMNAT3 overexpression on Alzheimer’s related proteinopathies
University of Miami, United States of America
1.Zhu, Y., et al., Human Nmnat1 Promotes Autophagic Clearance of Amyloid Plaques in a Drosophila Model of Alzheimer's Disease. Front Aging Neurosci, 2022. 14: p. 852972.
2.Huang, C., et al., The mouse nicotinamide mononucleotide adenylyltransferase chaperones diverse pathological amyloid client proteins. J Biol Chem, 2022. 298(5): p. 101912.
Therapy 1: preclinical developments
In vitro models to test modulators of cellular NAD+ levels
1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; 2UCL School of Pharmacy, UCL, London, UK; 3NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK
Therapy 1: preclinical developments
Novel small molecule improves mitochondrial function and mitophagy in a complex III deficiency model.
1Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, Los Angeles, USA.; 2Capacity Bio, Los Angeles, USA; 3Department of Pharmacology, Center for Innovations in Brain Science, University of Arizona, USA; 4Institut de Biologia Molecular De Barcelona (IBMB-CSIC), Spain.; 5Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, USA
Fernandez-del-Rio L, Benincá C, Villalobos F, Shu C, Liesa-Roig M, Stiles L, Acín-Perez R, Shirihai OS. A Novel Approach to Measure Complex V ATP Hydrolysis in Frozen Cell Lysates and Tissue Homogenates (in press; Life Science Alliance Journal)
Acín-Perez R, Benincá C, Shabane B, Shirihai OS, Stiles L. Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives. Life (Basel). 2021 Sep 10;11(9):949. doi: 10.3390/life11090949. PMID: 34575097; PMCID: PMC8467772.
Zanette V, Valle DD, Telles BA, Robinson AJ, Monteiro V, Santos MLSF, Souza RLR, Benincá C. NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms. Genet Mol Biol. 2021 Nov 19;44(4):e20210149. doi: 10.1590/1678-4685-GMB-2021-0149. PMID: 34807224; PMCID: PMC8607527.
Gaddale Devanna KK , Gawel JM , Prime TA , Cvetko F , Benincá C , Caldwell ST , Negoda A , Harrison A , James AM , Pavlov EV , Murphy MP , Hartley RC . Tetra-arylborate lipophilic anions as targeting groups. Chem Commun (Camb). 2021 Mar 28;57(25):3147-3150. doi: 10.1039/d0cc07924c. Epub 2021 Feb 26. PMID: 33634803; PMCID: PMC8062962.
Peruzzotti-Jametti L, Bernstock JD, Willis CM, Manferrari G, Rogall R, Fernandez-Vizarra E, Williamson JC, Braga A, van den Bosch A, Leonardi T, Krzak G, Kittel Á, Benincá C, Vicario N, Tan S, Bastos C, Bicci I, Iraci N, Smith JA, Peacock B, Muller KH, Lehner PJ, Buzas EI, Faria N, Zeviani M, Frezza C, Brisson A, Matheson NJ, Viscomi C, Pluchino S. Neural stem cells traffic functional mitochondria via extracellular vesicles. PLoS Biol. 2021 Apr;19(4):e3001166. doi: 10.1371/journal.pbio.3001166. eCollection 2021 Apr. PubMed PMID: 33826607; PubMed Central PMCID: PMC8055036.
Benincá C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, J Robinson A, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, S F Santos ML, R de Souza RL, Fernandez-Vizarra E, J Whitworth A, Zeviani M. Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. J Med Genet. 2021 Mar;58(3):155-167. doi: 10.1136/jmedgenet-2020-106861. Epub 2020 May 21. PMID: 32439808; PMCID: PMC7116790.
Zanette V, Reyes A, Johnson M, do Valle D, Robinson AJ, Monteiro V, Telles BA, L R Souza R, S F Santos ML, Benincá C, Zeviani M. Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations. Neurol Genet. 2020 Oct 7;6(6):e521. doi: 10.1212/NXG.0000000000000521. PMID: 33134517; PMCID: PMC7577545.
Luna-Sanchez M, Benincá C, Cerutti R, Brea-Calvo G, Yeates A, Scorrano L, Zeviani M, Viscomi C. Opa1 Overexpression Protects from Early-Onset Mpv17-/--Related Mouse Kidney Disease. Mol Ther. 2020 Aug 5;28(8):1918-1930. doi: 10.1016/j.ymthe.2020.06.010. Epub 2020 Jun 12. PMID: 32562616; PMCID: PMC7403474.
Therapy 1: preclinical developments
Preservation of bioenergetics and inhibition of ferroptosis with the novel compound SBT-588 in Friedreich’s Ataxia cell models
Stealth BioTherapeutics, Needham, MA, United States of America
1.McNeil, B., Beck, L., Sullivan, A., Kropp, LE., Abbruscato, A., Bergheanu, SC. Interventions with Potential to Mitigate Injection Site Reactions Following Subcutaneous Elamipretide Administration: Phase 1, Crossover Study in Healthy Subjects (In preparation).
2.Kropp, LE., Thomas, LM, Jackson-Thompson, B., Gable, K., McDaniels, D., Mitre, E., Chronic infection with a tissue invasive helminth causes mast cell granule depletion and protects against systemic anaphylaxis Clinical & Experimental Allergy. 2019 Dec 13. doi: 10.1111/cea.13549. Epub 2020 Jan 15.
3.Abdeladhim, M., Zhang, AH., Kropp, LE., Lindrose, AR., Venkatesha, SH., Mitre, E., Scott, DW. Engineered ovalbumin-expressing regulatory T cells protect against anaphylaxis in ovalbumin-sensitized mice. Clinical Immunology. 2019 Oct;207:49-54. doi: 10.1016/j.clim.2019.07.009. Epub 2019 Jul 17.
4.Killoran, K.*, Kropp, LE.*, Lindrose, A., Curtis, H., Cook, D., Mitre, E., Rush desensitization with a single antigen induces subclinical activation of mast cells and protects against bystander challenge in dually sensitized mice. Clinical & Experimental Allergy. 2019 Apr;49(4):484-494. doi: 10.1111/cea.13323. Epub 2019 Jan 16.
a.*contributed equally to the manuscript
Therapy 1: preclinical developments
The use of a coenzyme Q10 encapsulated mitochondrial targeting lipid nanoparticle formulation has therapeutic effects on a drug-induced liver injury.
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan; 2Faculty of Engineering, Hokkaido University, Japan; 3Fusion Oriented REsearch for disruptive Science and Technology (FOREST) Program, Japan Science and Technology Agency (JST) Japan, Saitama, Japan
1)Yuma Yamada, Satrialdi, Mitsue Hibino, Daisuke Sasaki, Jiro Abe, Hideyoshi Harashima, Power of mitochondrial drug delivery systems to produce innovative nanomedicines, Adv Drug Deliv Rev,154-155:187-209 (2020).
2)Yuma Yamada, Momo Ito, Manae Arai, Mitsue Hibino, Takao Tsujioka, Hideyoshi Harashima, Challenges in Promoting Mitochondrial Transplantation Therapy, Int J Mol Sci, 21(17):6365 (2020).
3)Yuma Yamada, Yuta Takano, Satrialdi, Jiro Abe, Mitsue Hibino, Hideyoshi Harashima, Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress, Biomolecules, 10(1):83 (2020).
4)Eriko Kawamura, Mitsue Hibino, Hideyoshi Harashima, Yuma Yamada, Targeted mitochondrial delivery of antisense RNA-containing nanoparticles by a MITO-Porter for safe and efficient mitochondrial gene silencing, Mitochondrion, 49, 178-188 (2019).
5)Takashi Katayama, Shintaro Kinugawa, Shingo Takada, Takaaki Furihata, Arata Fukushima, Takashi Yokota, Toshihisa Anzai, Mitsue Hibino, Hideyoshi Harashima, Yuma Yamada, A mitochondrial delivery system using liposome-based nanocarriers that target myoblast cells, Mitochondrion, 49, 66-72 (2019).
6)Mitsue Hibino, Yuma Yamada, Naoki Fujishita, Yusuke Sato, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima, The use of a microfluidic device to encapsulate a poorly water-soluble drug CoQ10 in lipid nanoparticles and an attempt to regulate intracellular trafficking to reach mitochondria, J Pharm Sci, 108 (8), 1668-2676 (2019).
Therapy 1: preclinical developments
In vitro 3D model of mitochondrial myopathy human skeletal muscle
1Wellcome Centre for Mitochondrial Research, Medical School, Newcastle University, United Kingdom; 2Translational and Clinical Research Institute, Newcastle University, United Kingdom; 3Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain; 4NHS Highly Specialised Service for Rare Mitochondrial Disorders, Royal Victoria Infirmary
1Di Leo V, Lawless C, Newman J, Robertson F, Chun C, Pickett S, Hudson G, Gorman GS, Tuppen HA, Vincent AE & Russell OM. Resistance exercise training induces molecular changes in mitochondrial myopathy patients. Manuscript in preparation.
2Fernández-Costa JM, Fernández-Garibay X, Velasco-Mallorquí F, Ramón-Azcón J. Bioengineered in vitro skeletal muscles as new tools for muscular dystrophies preclinical studies. J Tissue Eng. 2021 Feb 10;12:2041731420981339.
3Rocha MC, Grady JP, Grünewald A, Vincent A, Dobson PF, Taylor RW, Turnbull DM, Rygiel KA. A novel immunofluorescent assay to investigate oxidative phosphorylation deficiency in mitochondrial myopathy: understanding mechanisms and improving diagnosis. Sci Rep. 2015 Oct 15;5:15037.
413Fernández-Costa JM, Fernández-Garibay X, Velasco-Mallorquí F, Ramón-Azcón J. Bioengineered in vitro skeletal muscles as new tools for muscular dystrophies preclinical studies. J Tissue Eng. 2021 Feb 10;12:2041731420981339.
5Trevelyan AJ, Kirby DM, Smulders-Srinivasan TK, Nooteboom M, Acin-Perez R, Enriquez JA, Whittington MA, Lightowlers RN, Turnbull DM. Mitochondrial DNA mutations affect calcium handling in differentiated neurons. Brain. 2010 Mar;133(Pt 3):787-96.
6He L, Chinnery PF, Durham SE, Blakely EL, Wardell TM, Borthwick GM, Taylor RW, Turnbull DM. Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res. 2002 Jul 15;30(14):e68.
7Lehmann D, Tuppen HAL, Campbell GE, Alston CL, Lawless C, Rosa HS, Rocha MC, Reeve AK, Nicholls TJ, Deschauer M, Zierz S, Taylor RW, Turnbull DM, Vincent AE. Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level. Nucleic Acids Res. 2019 Aug 22;47(14):7430-7443.
8Fernández-Garibay X, Ortega MA, Cerro-Herreros E, Comelles J, Martínez E, Artero R, Fernández-Costa JM, Ramón-Azcón J. Bioengineeredin vitro3D model of myotonic dystrophy type 1 human skeletal muscle. Biofabrication. 2021 Apr 26;13(3).
Therapy 1: preclinical developments
Metabolic consequences for NAD+ and N- Acetyl cysteine treatment on Mitochondrial myopathy
1STEMM, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; 2Diabetes and Obesity Research Unit, Research Programs Unit, University of Helsinki, FIN-00290 Helsinki, Finland; 3Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne, Lausanne, Switzerland; 4Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; 5Helsinki University Hospital Diagnostic Centre, Helsinki 00260, Finland
Therapy 1: preclinical developments
Silencing the aberrant Coq9 mRNA in the Coq9R239X model normalizes complex Q and restores the mitochondrial phenotype.
1Physiology Department, Biomedical Research Center, University of Granada, Granada, Spain; 2Ibs.Granada, Spain; 3Biofisika Institute (CSIC,UPV-EHU) and Department of Biochemistry and Molecular Biology, University of Basque Country, Leioa, Spain
1.Luna‐Sánchez M, Díaz‐Casado E, Barca E, et al. The clinical heterogeneity of coenzyme Q 10 deficiency results from genotypic differences in the Coq9 gene. EMBO Mol Med. 2015;7(5):670-687. doi:10.15252/emmm.201404632
2.Wu H, Lima WF, Zhang H, Fan A, Sun H, Crooke ST. Determination of the Role of the Human RNase H1 in the Pharmacology of DNA-like Antisense Drugs. J Biol Chem. 2004;279(17):17181-17189. doi:10.1074/jbc.M311683200
Therapy 1: preclinical developments
A high-content in vitro screening to identify new mitophagy-activating compounds
1Department of Biomedical Sciences, University of Padova, Italy; 2Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, USA; 3Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, USA
Therapy 1: preclinical developments
B-RA targets mitochondria in white adipose tissue and reverses diet-induced obesity
1Physiology Department, Biomedical Research Center, University of Granada, Granada, Spain; 2Ibs. Granada, Granada, Spain
1. Fazakerley DJ, et al. Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance. Elife. 2018 Feb 6;7:e32111. doi: 10.7554/eLife.32111.
2.Hidalgo-Gutiérrez A, et al. β-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight. Biomedicines. 2021 Oct 13;9(10):1457. doi: 10.3390/biomedicines9101457.
Therapy 1: preclinical developments
HIF1α is a potentially druggable target for MNGIE disease
Alma Mater Studiorum University of Bologna, Italy
Therapy 1: preclinical developments
Mitochondrial modulation with Leriglitazone as a potential treatment for Rett syndrome
Institut de Recerca Sant Joan de Déu, Spain
Therapy 1: preclinical developments
New nutritional therapies for mitochondrial diseases
1Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), Madrid, Spain; 2Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Spain; 3Servicio de Genética, Hospital Universitario ‘12 de Octubre’, Madrid, Spain.; 4Unidad Pediátrica de Enfermedades Raras, Hospital Universitario ‘12 de Octubre’, Madrid, Spain.; 5Servicio de Medicina Interna, Hospital Universitario ‘12 de Octubre’, Madrid, Spain; 6Servicio de Neurología, Hospital Universitario ‘12 de Octubre’, Madrid, Spain; 7Centro Nacional de Referencia para Errores Congénitos del Metabolismo (CSUR) y Centro Europeo de Referencia para Enfermedades Metabólica Hereditarias (MetabERN), Madrid, Spain
Therapy 1: preclinical developments
Pyrroloquinoline quinone exerts neuroprotective effects on retinal ganglion cell degeneration
1Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden; 2Department of Biology, University of Pisa, Pisa, Italy
1.Canovai A. Experimental model of photo-oxidative damage. Ann Eye Sci 2022. (doi: 10.21037/aes-21-50)
2.Canovai A. Experimental models of retinopathy of prematurity. Ann Eye Sci 2022. (doi: 10.21037/aes-21-49)
3.Canovai A., Amato R., Melecchi A., Dal Monte M., Rusciano D., Bagnoli P., Cammalleri M. Preventive Efficacy of an Antioxidant Compound on Blood Retinal Barrier Breakdown and Visual Dysfunction in Streptozotocin-Induced Diabetic Rats. Front. Pharmacol 2022;12:811818. (doi: 10.3389/fphar.2021.811818)
4.Pesce N.A.*, Canovai A.*, Plastino F., Lardner E., Kvanta A., Cammalleri M., André H., Dal Monte M. An imbalance in autophagy contributes to retinal damage in a rat model of oxygen-induced retinopathy. J Cell Mol Med 2021;25(22):10480-10493. (doi:10.1111/jcmm.16977)
5.Amato R.*, Canovai A.*, Melecchi A., Pezzino S., Corsaro R., Dal Monte M., Rusciano D., Bagnoli P., Cammalleri M. Dietary Supplementation of Antioxidant Compounds Prevents Light-Induced Retinal Damage in a Rat Model. Biomedicines 2021; 9(9):1177. (doi: 10.3390/biomedicines9091177)
6.Pesce N.A., Canovai A., Lardner E., Cammalleri M., Kvanta A., André H., Dal Monte M. Autophagy Involvement in the Postnatal Development of the Rat Retina. Cells 2021;10(1):177. (doi: 10.3390/cells10010177)
*Equal author contribution
Therapy 1: preclinical developments
Quinone compounds in primary mitochondrial disease: acute metabolic effects in human-derived cells in vitro
1Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; 2Department of Anesthesiology, Tokyo Medical University, Tokyo 160-0023, Japan; 3Abliva AB, Lund, Sweden
Therapy 1: preclinical developments
A novel therapeutic strategy for mitochondrial Leigh Syndrome
1Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.; 2Luca Science Inc., Tokyo, Japan.; 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.; 4Department of Hematology, Osaka International Cancer Institute, Osaka, Japan.
1) Special AT-Rich Sequence-Binding Protein 1 Supports Survival and Maturation of Naive B Cells Stimulated by B Cell Receptors.
Ozawa T, Fujii K, Sudo T, Doi Y, Nakai R, Shingai Y, Ueda T, Baba Y, Hosen N, Yokota T. J Immunol. 2022 Apr 15;208(8):1937-1946.
2) Inotuzumab ozogamicin and blinatumomab sequential therapy for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Ueda T, Fukushima K, Kusakabe S, Yoshida K, Suga M, Nakai R, Koike M, Hino A, Akuta K, Toda J, Nagate Y, Doi Y, Fujita J, Yokota T, Hosen N.
Leuk Res Rep. 2022 Feb 15;17:100294.
3) Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia. Shingai Y, Yokota T, Okuzaki D, Sudo T, Ishibashi T, Doi Y, Ueda T, Ozawa T, Nakai R, Tanimura A, Ichii M, Shibayama H, Kanakura Y, Hosen N. Stem Cells. 2021 Jun;39(6):723-736.
4) Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, as a bridge to allogeneic stem cell transplantation in a patient with ALK-positive anaplastic large-cell lymphoma refractory to chemotherapy and brentuximab vedotin.
Nakai R, Fukuhara S, Maeshima AM, Kim SW, Ito Y, Hatta S, Suzuki T, Yuda S, Makita S, Munakata W, Suzuki T, Maruyama D, Izutsu K. Clin Case Rep. 2019 Nov 15;7(12):2500-2504.
5) Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver. Ueda T, Yokota T, Okuzaki D, Uno Y, Mashimo T, Kubota Y, Sudo T, Ishibashi T, Shingai Y, Doi Y, Ozawa T, Nakai R, Tanimura A, Ichii M, Ezoe S, Shibayama H, Oritani K, Kanakura Y. Stem Cell Reports. 2019 Dec 10;13(6):992-1005.
Therapy 1: preclinical developments
Generation of a new neuronal model of Friedreich’s Ataxia and establishment of a drug screening strategy
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR7104, Université de Strasbourg, France; 2Institut NeuroMyoGene, UMR5261, INSERM U1315, Université Claude Bernard Lyon I Faculté de médecine, Lyon, France
Therapy 1: preclinical developments
Downregulation of miR-181a/b ameliorates the Leigh syndrome phenotype in Ndufs4 KO mice
1Telethon Institute of Genetics and Medicine, Telethon Foundation, Pozzuoli (NA), Italy; 2European School of Molecular Medicine (SEMM); 3Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy; 4Ecosustainable Marine Biotechnology Department, Stazione Zoologica Anton Dohrn, Naples, Italy; 5Institute of Biochemistry and Cellular Biology (IBBC), National Research Council (CNR), Monterotondo (RM), Italy; 6Dep. of Precision Medicine, University of Campania "L. Vanvitelli", Caserta, Italy; 7Dep. of Translational Medicine, University of Naples "Federico II", Naples, Italy
1) Indrieri A, Carrella S, Romano A, Spaziano A, Marrocco E, Fernandez-Vizarra E, Barbato S, Pizzo M, Ezhova Y, Golia FM, Ciampi L, Tammaro R, Henao-Mejia J, Williams A, Flavell RA, De Leonibus E, Zeviani M, Surace EM, Banfi S, Franco B. miR-181a/b downregulation exerts a protective action on mitochondrial disease models. EMBO Mol Med. 2019 May;11(5):e8734. doi: 10.15252/emmm.201708734. PMID: 30979712; PMCID: PMC6505685.
2) Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008 Apr;7(4):312-20. doi: 10.1016/j.cmet.2008.02.004. PMID: 18396137; PMCID: PMC2593686.
3) Barbato A, Iuliano A, Volpe M, D'Alterio R, Brillante S, Massa F, De Cegli R, Carrella S, Salati M, Russo A, Russo G, Riccardo S, Cacchiarelli D, Capone M, Madonna G, Ascierto PA, Franco B, Indrieri A, Carotenuto P. Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. Int J Mol Sci. 2021 Feb 11;22(4):1801. doi: 10.3390/ijms22041801. PMID: 33670365; PMCID: PMC7918089.
4) Carrella S, Indrieri A, Franco B, Banfi S. Mutation-Independent Therapies for Retinal Diseases: Focus on Gene-Based Approaches. Front Neurosci. 2020 Sep 24;14:588234. doi: 10.3389/fnins.2020.588234. PMID: 33071752; PMCID: PMC7541846.
Therapy 1: preclinical developments
Succinate does not increase reactive oxygen species generation in phosphorylating human mitochondria
1Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; 2Department of Anesthesiology, Tokyo Medical University, Tokyo, Japan; 3Abliva, AB, Lund, Sweden; 4Otorhinolaryngology Head and Neck Surgery, Department of Clinical Sciences, Lund University, Skåne University Hospital, Lund, Sweden
Ganetzky RD, Markhard AL, Yee I, Clever S, Cahill A, Shah H, Grabarek Z, To TL, Mootha VK. Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation. N Engl J Med. 2022;387(15):1395-403.
Therapy 1: preclinical developments
Disease modeling and drug screening of mitochondrial complex I disorders: From Podospora anserina to Human
1MITOVASC Institute, CNRS UMR 6015 INSERM U1083, Angers University - Angers (France); 2Pharmacology laboratory UR7296, Strasbourg University - Strasbourg (France); 3Côte d'Azur University, CNRS, Institute of Chemistry- Nice (France); 4IRCAN, UMR 7284 INSERM U1081/UCA - Nice (France); 5IBGC Institute, CNRS UMR 5095 - Bordeaux (France); 6Institute for Integrative Biology of the Cell I2BC, UMR9198, University of Paris-Saclay - Paris (France)
Therapy 1: preclinical developments
Nifuroxazide rescues deleterious effects of MICOS disassembly in disease models
1IRCAN, UMR 7284/INSERM U1081/UCA, Nice, France; 2Université Côte d’Azur, Centre Commun de Microscopie Appliquée, Nice, France; 3Université Côte d’Azur, Inserm U1065, C3M, Nice, France; 4Université Paris Saclay, CEA, CNRS, I2BC, Gif-sur-Yvette, France; 5Université Côte d’Azur, CNRS UMR 7272, ICN, Nice, France; 6Université Paris Descartes-Sorbonne Paris Cité, Inserm U1163, Imagine Institute, Paris, France; 7IBGC, UMR5095 CNRS, Bordeaux, France; 8CRBS, UR7296, Strasbourg, France; 9Université d'Angers, UMR CNRS 6015 – INSERM U1083, Angers, France
1.Genin* EC, Bannwarth* S, Ropert B, Lespinasse F, Mauri-Crouzet A, Augé G, Fragaki K, Cochaud C, Donnarumma E, Lacas-Gervais S, Wai T, Paquis-Flucklinger V. CHCHD10 and SLP2 control the stability of the PHB complex: a key factor for motor neuron viability. Brain. 2022 Jun 3:awac197. (*co-first authors). doi: 10.1093/brain/awac197. Epub ahead of print. PMID: 35656794.
2.Baek M, Choe Y-J, Bannwarth S, Kim J, Maitra S, Dorn II GW, Taylor JP, Paquis-Flucklinger V, Kim NC. Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1. Nat Com, 2021; 74 :20-38.
3. Genin EC, Madji Hounoum B, Bannwarth S, Fragaki K, Lacas-Gervais S, Mauri-Crouzet A, Lespinasse F, Neveu J, Ropert B, Augé G, Cochaud C, Lefebvre-Omar C, Bigou S, Chiot A, Mochel F, Boillée S, Lobsiger CS, Bohl D, Ricci JE, Paquis-Flucklinger. Mitochondrial defect in muscle precedes neuromuscular junction degradation and motor neuron death in CHCHD10S59L/+ mouse. Acta Neuropathol, 2019; 138:123-145.
Therapy 1: preclinical developments
Lithospermum erythrorhizon complexs extract prevents dexamethasone-induced muscle atrophy in mice
Korea Food Research Institute, Korea, Republic of (South Korea)
Fuzhuan brick tea extract prevents diet-induced obesity via stimulation of fat browning in mice. Food Chem. 2022 May 30;377:132006
Therapy 1: preclinical developments
Myocardial regeneration therapy using human cardiosphere-derived cells with activated mitochondria
1Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 2Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; 3Faculty of Engineering, Hokkaido University, Sapporo, Japan; 4Fusion Oriented REsearch for disruptive Science and Technology (FOREST) Program, Japan Science and Technology Agency (JST) Japan, Saitama, Japan
Therapy 1: preclinical developments
Quinone compounds in primary mitochondrial disease: in vitro characterization of NQO1-mediated NAD+/NADH modulation
1Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; 2Isomerase Therapeutics Ltd, Chesterford Research Park, Cambridge, UK; 3Abliva AB, Lund, Sweden
Åsander Frostner E, Simón Serrano S, Chamkha I, Donnelly E, Elmér E, Hansson MJ (2022) Towards a treatment for mitochondrial disease: current compounds in clinical development. https://doi.org/10.26124/mitofit:2022-0014 — 2022-06-28 published in Bioenerg Commun 2022.4.
Therapy 1: preclinical developments
Metformin in mitochondrial disease patients cardiac cells
University of Eastern Finland, Finland
Ryytty S, Modi SR, Naumenko N, et al. Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes. Cells. 2022;11(16):2593. Published 2022 Aug 19. doi:10.3390/cells11162593
Therapy 2: clinical trials
Mavodelpar clinical development program in adult patients with primary mitochondrial myopathy (PMM): results from Phase 1b study and design of ongoing pivotal study (STRIDE).
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; 3Wellcome Centre for Mitochondrial Research, Newcastle University, UK; 4NIHR Newcastle Biomedical Research Centre, Newcastle University, UK; 5Paramstat Ltd., UK; 6Reneo Pharma Ltd., UK; 7Reneo Pharmaceuticals Inc., USA; 8Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy; 9Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Therapy 2: clinical trials
Rationale and design of a clinical phase 2a study to evaluate the safety and efficiency of OMT-28 in primary mitochondrial disease
1OMEICOS Therapeutics GmbH, Germany; 2University of Alberta, Canada; 3Max-Delbrueck Center for Molecular Medicine, Germany
Therapy 2: clinical trials
Treatment with lenadogene nolparvovec gene therapy results in sustained visual improvement in m.11778G>A MT-ND4-LHON patients: the RESTORE study
1Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 2Departments of Ophthalmology, Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, GA, USA; 3IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 4Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA; 5Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France; 6Department of Neurology, Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; 7Doheny Eye Institute, UCLA School of Medicine, Los Angeles, CA, USA; 8GenSight Biologics, Paris, France; 9Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
Newman NJ, Yu-Wai-Man P, Subramanian PS, Moster ML, Wang AG, Donahue SP, Leroy BP, Carelli V, Biousse V, Vignal-Clermont C, Sergott RC, Sadun AA, Fernández GR, Chwalisz BK, Banik R, Bazin F, Roux M, Cox ED, Taiel M, Sahel JA; LHON REFLECT Study Group. Randomized trial of bilateral gene therapy injection for m.11778G > A MT-ND4 Leber optic neuropathy. Brain. 2022 Nov 9:awac421. doi: 10.1093/brain/awac421. Epub ahead of print. PMID: 36350566.
Chen BS, Holzinger E, Taiel M, Yu-Wai-Man P. The Impact of Leber Hereditary Optic Neuropathy on the Quality of Life of Patients and Their Relatives: A Qualitative Study. J Neuroophthalmol. 2022 Sep 1;42(3):316-322. doi: 10.1097/WNO.0000000000001564. Epub 2022 Apr 27. PMID: 35483081.
Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, Sahel JA; LHON Study Group. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study. J Neuroophthalmol. 2021 Sep 1;41(3):309-315. doi: 10.1097/WNO.0000000000001367. PMID: 34415265; PMCID: PMC8366761.
Therapy 2: clinical trials
Current status of the phase 3 trial of dichloroacetate (DCA) for pyruvate dehydrogenase complex deficiency (PDCD)
1University of Florida, United States of America; 2Saol Therapeutics, United States of America
Therapy 2: clinical trials
Efficacy and safety of elamipretide in subjects with primary mitochondrial disease resulting from pathogenic nuclear DNA mutations (nPMD): phase 3 study design
1Massachusetts General Hospital, Harvard Medical School Boston, MA, United States of America; 2Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy
Therapy 2: clinical trials
Long-term efficacy of idebenone in patients with LHON in the LEROS study: Analyzing change in visual acuity categories according to mitochondrial DNA mutation and disease phase
1John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; 2Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 3Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; 4Institute of Ophthalmology, University College London, London, United Kingdom; 5IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 6Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 7Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; 8The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom; 9Chiesi Farmaceutici S.p.A., Parma, Italy; 10German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 11Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 12Department of Neurology, Friedrich‑Baur Institute, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany
Therapy 2: clinical trials
Long-term efficacy of idebenone in patients with LHON in the LEROS study: Analyzing change in visual acuity over time according to mitochondrial DNA mutation and disease phase
1Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; 2John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; 3Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 4Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; 5Institute of Ophthalmology, University College London, London, United Kingdom; 6IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 7Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 8The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom; 9Chiesi Farmaceutici S.p.A., Parma, Italy; 10German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 11Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 12Department of Neurology, Friedrich‑Baur Institute, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany
Therapy 2: clinical trials
Long-term efficacy of idebenone in patients with LHON in the LEROS study: Analyzing the impact of idebenone on rates of recovery and worsening of vision according to primary mitochondrial DNA mutation
1Moorfields Eye Hospital NHS Foundation Trust, United Kingdom; 2Institute of Ophthalmology, University College London, London, United Kingdom; 3The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom; 4John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; 5Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 6Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; 7IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 8Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 9Chiesi Farmaceutici S.p.A., Parma, Italy; 10German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 11Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 12Department of Neurology, Friedrich‑Baur Institute, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany
Therapy 2: clinical trials
Enzyme replacement strategy by transplantation in MNGIE: lessons from the updated Bologna case series
1IRCCS Istituto Scienze Neurologiche di Bologna, Italy; 2IRCCS Policlinico Sant’Orsola-Malpighi di Bologna, Bologna, Italy; 3Department of Clinical and experimental Medicine, University of Messina, Messina, Italy; 4Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena; 5Institute of Neurology, University of Verona, Verona, Italy; 6Center for Neuromuscular Diseases, Unit of Neurology, ASST "Spedali Civili", Brescia, Italy; 7Department of Medico-Surgical Sciences and Biotechnologies, University ‘La Sapienza’, Roma, Italy; 8Department of Morphology, Surgery and Experimental Medicine, St. Anna Hospital, University of Ferrara, Ferrara, Italy
•D'Angelo R, Rinaldi R, Carelli V, et al. ITA-MNGIE: an Italian regional and national survey for mitochondrial neuro-gastro-intestinal encephalomyopathy. Neurol Sci. 2016; 37:1149-1151
•De Giorgio R, Pironi L, Rinaldi R, Boschetti E, Caporali L, Capristo M, Casali C, Cenacchi G, Contin M, D'Angelo R, et al. Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Ann Neurol. 2016;80:448-455
•D'Angelo R, Rinaldi R, Pironi L, et al. Liver transplant reverses biochemical imbalance in mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrion. 2017;34:101-102
•Gramegna LL, Pisano A, Testa C, Manners DN, D'Angelo R, et al. Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy. AJNR Am J Neuroradiol. 2018; 39:427-434
•D'Angelo R, Boschetti E, Amore G et al. Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications. J Neurol. 2020;267:3702-3710
•Hirano M, Carelli V, De Giorgio R, Pironi L, Accarino A, Cenacchi G, D'Alessandro R, Filosto M, Martí R, Nonino F, Pinna AD, Baldin E, Bax BE, Bolletta A, Bolletta R, Boschetti E, Cescon M, D'Angelo R, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.J Inherit Metab Dis. 2021; 44:376-387
•Boschetti E, D'Angelo R, Tardio ML, et al. Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy. Am J Physiol Gastrointest Liver Physiol. 2021; 320:G768-G779
•Boschetti E, Caporali L, D'Angelo R, et al. Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant. Int J Mol Sci. 2022; 23:8792
mtDNA maintenance and expression
Developing mouse models to investigate the molecular mechanisms of POLG-related diseases
1Venetian Institute of Molecular Medicine, Padova; 2Department of Neuroscience, University of Padova; 3Department of Biomedical Sciences, University of Padova; 4Dept. Medical Chemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg; 5Mitochondrial Biology Unit, MRC/University of Cambridge, Cambridge, UK
Therapy 2: clinical trials
Long-term efficacy of idebenone in patients with LHON in the LEROS study: Analyzing the impact of idebenone on rates of recovery and worsening of vision according to disease phase
1Chiesi Farmaceutici S.p.A., Parma, Italy; 2John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; 3Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 4Moorfields Eye Hospital NHS Foundation Trust, United Kingdom; 5Institute of Ophthalmology, University College London, London, United Kingdom; 6IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 7Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 8Department of Ophthalmology, Medical University of Vienna, Vienna, Austria; 9The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom; 10German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; 11Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 12Department of Neurology, Friedrich Baur Institute, University Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany
Therapy 1: preclinical developments
Validation of drug delivery and functional activation to mitochondria in skeletal muscle cell
1Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; 2Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; 3Faculty of Engineering, Hokkaido University, Sapporo, Japan; 4Fusion Oriented research for disruptive Science and Technology (FOREST) Program, Japan Science and Technology Agency (JST) Japan, Saitama, Japan
mtDNA maintenance and expression
Novel approaches to modulate mutant mitochondrial DNA in patient-derived induced-pluripotent stem cells
1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; 2Department of Molecular Genetics, University of Toronto, Toronto, Canada; 3Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Bodenstein DF, Kim HK, Brown NC, Navaid B, Young LT, Andreazza AC. Mitochondrial DNA content and oxidation in bipolar disorder and its role across brain regions. NPJ Schizophr. 2019 Dec 4;5(1):21. doi: 10.1038/s41537-019-0089-5. PMID: 31797868; PMCID: PMC6892804.
Choi J, Bodenstein DF, Geraci J, Andreazza AC. Evaluation of postmortem microarray data in bipolar disorder using traditional data comparison and artificial intelligence reveals novel gene targets. J Psychiatr Res. 2021 Oct;142:328-336. doi: 10.1016/j.jpsychires.2021.08.011. Epub 2021 Aug 15. PMID: 34419753.
Cadoná FC, de Souza DV, Fontana T, Bodenstein DF, Ramos AP, Sagrillo MR, Salvador M, Mota K, Davidson CB, Ribeiro EE, Andreazza AC, Machado AK. Açaí (Euterpe oleracea Mart.) as a Potential Anti-neuroinflammatory Agent: NLRP3 Priming and Activating Signal Pathway Modulation. Mol Neurobiol. 2021 Sep;58(9):4460-4476. doi: 10.1007/s12035-021-02394-x. Epub 2021 May 22. PMID: 34021869.
de Souza DV, Pappis L, Bandeira TT, Sangoi GG, Fontana T, Rissi VB, Sagrillo MR, Duarte MM, Duarte T, Bodenstein DF, Andreazza AC, Cruz IBMD, Ribeiro EE, Antoniazzi A, Ourique AF, Machado AK. Açaí (Euterpe oleracea Mart.) presents anti-neuroinflammatory capacity in LPS-activated microglia cells. Nutr Neurosci. 2022 Jun;25(6):1188-1199. doi: 10.1080/1028415X.2020.1842044. Epub 2020 Nov 10. PMID: 33170113.
mtDNA maintenance and expression
Evaluation of mtDNA copy number assessment in patients with suspected mitochondrial disease
1NHS Highly Specialised Services for Rare Mitochondrial Disorders, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 2Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 3Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 4Department of Neurology, Gregorio Marañón University Hospital, Madrid, Spain; 5Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK
PMID: 36513735
PMID: 35141356
PMID: 35024855
Therapy 1: preclinical developments
Hepatoencephalopathy due to GFM1 mutations: generation of a mouse model and preclinical study of an AAV-based gene therapy for the disease
1Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona - Barcelona (Spain); 2Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III - Madrid (Spain); 3Pathology Department, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona - Barcelona (Spain); 4Programa de Terapia Génica y Regulación de la Expresión Génica, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra - Pamplona (Spain); 5Instituto de Investigación Sanitaria de Navarra, IdiSNA - Pamplona (Spain)
Molina-Berenguer M, Vila-Julià F, Pérez-Ramos S, Salcedo-Allende MT, Cámara Y, Torres-Torronteras J, Martí R. Dysfunctional mitochondrial translation and combined oxidative phosphorylation deficiency in a mouse model of hepatoencephalopathy due to Gfm1 mutations. FASEB J. 2022 Jan;36(1):e22091. doi: 10.1096/fj.202100819RRR. PMID: 34919756.
Therapy 1: preclinical developments
Neuroglobin overexpression in cerebellar neurons of Harlequin mice improves mitochondrial homeostasis and reduces ataxic behavior
1Université Paris Cité, NeuroDiderot, Inserm, F-75019 Paris, France; 2Neonatal Research Group, Health Research Institute La Fe, 46026 Valencia, Spain; 3Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain; 4Université Paris Cité, Platform of Cellular and Molecular Imaging, US25 Inserm, UAR3612 CNRS, 75006 Paris, France; 5Université de Paris, UMR-S 1144 Inserm, 75006 Paris, France
1.Hélène Cwerman-Thibault, Christophe Lechauve, Vassilissa Malko-Baverel, Sébastien Augustin, Gwendoline Le Guilloux, Élodie Reboussin, Julie Degardin-Chicaud, Manuel Simonutti, Thomas Debeir, Marisol Corral-Debrinski. Neuroglobin effectively halts vision loss in Harlequin mice at an advanced stage of optic nerve degeneration. Neurobiology of Disease, 2021. doi.org/10.1016/j.nbd.2021.105483.
2.Hélène Cwerman-Thibault, Vassilissa Malko-Baverel, Gwendoline Le Guilloux, Isabel Torres-Cuevas, Bruno Saubaméa, Edward Ratcliffe, Djmila Mouri, Virginie Mignon, Odile Boespflug-Tanguy, Pierre Gressens, Marisol Corral-Debrinski. Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor. Brain Pathology (In submission).
3.Hélène Cwerman-Thibault, Vassilissa Malko-Baverel, Gwendoline Le Guilloux, Edward Ratcliffe, Djmila Mouri, Isabel Torres-Cuevas, Ivan Millán, Virginie Mignon, Bruno Saubaméa, Odile Boespflug-Tanguy, Pierre Gressens, Marisol Corral-Debrinski. Neuroglobin overexpression in cerebellar neurons of Harlequin mice improves mitochondrial homeostasis and reduces ataxic behavior. (In submission)
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.
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).
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
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
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.
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
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.
Late breaking news
Host-microbiome co-adaptation to severe nutritional challenge
1Department of Biomolecular Sciences, Weizmann Institute of Science, Israel; 2Life Sciences Core Facilities, Weizmann Institute of Science, Israel
Late breaking news
The heme exporter FLVCR1a regulates ER-mitochondria membranes tethering and mitochondrial calcium handling
1University of Turin, Department of Molecular Biotechnology and Health Sciences; 2Department of Pediatrics, University of California San Francisco, San Francisco, United States; 3Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy; 4Université de Paris, NeuroDiderot, Inserm, 75019 Paris, France; 5Instituto de Ciencias de la Salud, Universidad de O'Higgins, Rancagua, Chile; 6Leibniz Institute of Analytical Sciences, ISAS, Dortmund, Germany; 7Department of Oncology, University of Torino, Italy; 8Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics, Center for Neuromuscular Disorders in Children and Adolescents, University of Duisburg-Essen, Essen, Germany
Therapy 1: preclinical developments
Genetic variants impact on NQO1 expression and activity driving efficacy of idebenone treatment in Leber’s hereditary optic neuropathy cell models
1Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 2IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy.; 3Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; 4Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Therapy 1: preclinical developments
Peptide mimetic molecules as potential therapeutic agents against diseases related to mt-tRNA point mutations.
1Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Italy; 2Department of Biochemical Sciences "A. Rossi Fanelli, Sapienza University of Rome, Italy; 3Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR) of Italy
Perli E, Pisano A, Pignataro MG, Campese AF, Pelullo M, Genovese I, de Turris V, Ghelli AM, Cerbelli B, Giordano C, Colotti G, Morea V, d'Amati G. Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects. FASEB J. 2020 Jun;34(6):7675-7686. doi: 10.1096/fj.201903270R
Italian Patent n.102021000032930 THERAPEUTICAL PEPTIDOMIMETIC
Inventors: Giulia d’Amati, Veronica Morea, Annalinda Pisano, Elena Perli, Maria Gemma Pignataro
International application No. PCT/IB2022/062354
Therapy 1: preclinical developments
The mitoDdCBE system as a mitochondrial gene therapy approach
1University of Miami, United States of America; 2Max Planck Institute of Biochemistry, Germany; 3Broad Institute, Harvard University, and HHMI, United States of America
Mitochondrial genome engineering coming-of-age. Barrera-Paez et al. Trends Genet. 2022, May 19. PMID: 35599021.
Mitochondrial gene editing. Shoop et al (Barrera-Paez as third author). Nat Rev Methods Primers. 2023, in press (March 16).
Therapy 2: clinical trials
Niacin treatment improves metabolic changes in early-stage mitochondrial myopathy
1Research Program for Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 3Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland; 4Department of Clinical Physiology and Nuclear Medicine, Laboratory of Clinical Physiology, Helsinki University Hospital, Helsinki, Finland; 5HUS Diagnostic Center, Radiology, Helsinki University and Helsinki University Hospital, Helsinki, Finland; 6Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; 7Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 8Healthy Weight Hub, Abdominal Center, Endocrinology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 9Helsinki University Hospital Diagnostic Centre, Helsinki, Finland
Eija Pirinen, Mari Auranen, Nahid A. Khan, Virginia Brilhante, Niina Urho, Alberto Pessia, Antti Hakkarainen, Juho Kuula, Ulla Heinonen, Mark S. Schmidt, Kimmo Haimilahti, Päivi Piirilä, Nina Lundbom, Marja-Riitta Taskinen, Charles Brenner, Vidya Velagapudi, Kirsi H. Pietiläinen, Anu Suomalainen. Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metab 2020;31(6):1078-1090.e5.
Therapy 2: clinical trials
PHEMI: Phenylbutyrate Therapy in Mitochondrial Diseases with lactic acidosis: an open label clinical trial in MELAS and PDH deficiency patients.
1Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Experimental Neuroscience, Unit of Medical Genetics and Neurogenetics, Milan, Italy; 2Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Pediatric Neurosciences, Milan, Italy; 3Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis.
Ferriero R, Manco G, Lamantea E, Nusco E, Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, Brunetti-Pierri N.
Sci Transl Med. 2013 Mar 6;5(175):175ra31. doi: 10.1126/scitranslmed.3004986.
PMID: 23467562
Therapy 2: clinical trials
Use of lenadogene nolparvovec gene therapy for Leber hereditary optic neuropathy in early access programs
1IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; 2Department of Neuro Ophthalmology and Emergencies, Rothschild Foundation Hospital, Paris, France; 3Centre Hospitalier National d’Ophtalmologie des Quinze Vingts, Paris, France; 4Departments of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, USA; 5Department of Ophthalmology, Neurology, and Pediatrics, Vanderbilt University, and Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, USA; 6Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; 7Institut de Génétique Médicale d’Alsace, CHU de Strasbourg, Strasbourg, France; 8Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilians-University, Munich, Germany; 9University Hospital, Ludwig-Maximilians-University, Munich, Germany; 10Service Explorations de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France; 11Service d'Ophtalmologie, CHU de Rennes, Rennes, France; 12Service d'Ophtalmologie, CHU de Bordeaux, Groupe Hospitalier Pellegrin, Bordeaux, France; 13Service d'Ophtalmologie, CHU de Nantes, Nantes, France; 14Service de Neuro-Cognition et Neuro-Ophtalmologie, CHU de Lyon, Lyon, France; 15Service d'Ophtalmologie, Centre Hospitalier de Valence, Valence, France; 16Service d'Ophtalmologie, CHU de Caen, Caen, France; 17Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas, USA; 18Retina Consultants, P.C, Hartford, Connecticut, USA; 19Service d'Ophtalmologie, Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland; 20Centre Hospitalier de Wallonie Picarde, Tournai, Belgium; 21GenSight Biologics, Paris, France; 22Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; 23Department of Biomedical and Neuromotor Sciences, DIBINEM, Bologna, Italy
Yu-Wai-Man P, Newman NJ, Carelli V, Moster ML, Biousse V, Sadun AA, Klopstock T, Vignal-Clermont C, Sergott RC, Rudolph G, La Morgia C, Karanjia R, Taiel M, Blouin L, Burguière P, Smits G, Chevalier C, Masonson H, Salermo Y, Katz B, Picaud S, Calkins DJ, Sahel JA. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. 2020 Dec 9;12(573):eaaz7423. doi: 10.1126/scitranslmed.aaz7423. PMID: 33298565.
Newman NJ, Yu-Wai-Man P, Carelli V, Biousse V, Moster ML, Vignal-Clermont C, Sergott RC, Klopstock T, Sadun AA, Girmens JF, La Morgia C, DeBusk AA, Jurkute N, Priglinger C, Karanjia R, Josse C, Salzmann J, Montestruc F, Roux M, Taiel M, Sahel JA. Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison. Front Neurol. 2021 May 24;12:662838. doi: 10.3389/fneur.2021.662838. PMID: 34108929; PMCID: PMC8181419.
Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, Sahel JA; LHON Study Group. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study. J Neuroophthalmol. 2021 Sep 1;41(3):309-315. doi: 10.1097/WNO.0000000000001367. PMID: 34415265; PMCID: PMC8366761.
Therapy 3: reproductive options and mtDNA editing
MitoCRISPR/Cas9 shifts mtDNA heteroplasmy not as effective as other site-specific nucleases.
1Novosibirsk State University, Novosibirsk, Russia; 2Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; 3Skolkovo Institute of Science and Technology, Moscow, Russia
1.Tanaka, M.; Borgeld, H.-J.; Zhang, J.; Muramatsu, S.; Gong, J.-S.; Yoneda, M.; Maruyama, W.; Naoi, M.; Ibi, T.; Sahashi, K.; et al. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J. Biomed. Sci. 2002, 9, 534–41. https://doi.org/10.1159/000064726.
2. Zakirova, E.G.; Vyatkin, Y.V.; Verechshagina, N.A.; Muzyka, V.V.; Mazunin, I.O.; Orishchenko, K.E. Study of the effect of the introduction of mitochondrial import determinants into the gRNA structure on the activity of the gRNA/SpCas9 complex in vitro.Vavilov Journal of Genetics and Breeding 2020, 24(5):512-518. https://doi.org/10.18699/VJ20.643.
3.Silva-Pinheiro, P., Minczuk, M. The potential of mitochondrial genome engineering. Nat Rev Genet 23, 199–214 (2022). https://doi.org/10.1038/s41576-021-00432-x.
4. Zakirova, E.G.; Muzyka, V.V.; Mazunin, I.O.; Orishchenko, K.E. Natural and Artificial Mechanisms of Mitochondrial Genome Elimination. Life 2021, 11, 76. https://doi.org/10.3390/life11020076.
Therapy 3: reproductive options and mtDNA editing
Prenatal diagnostics for a family with 13513G>A mtDNA mutation associated with Leigh Syndrome
1Center for Embryonic Cell and Gene Therapy, Oregon Health and Science University, United States of America; 2Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Oregon Health and Science University, United States of America
Therapy 3: reproductive options and mtDNA editing
Specific elimination of m.3243A>G mutant mitochondria DNA using mitoARCUS
1Precision BioSciences - Durham, NC, United States of America; 2University of Miami - Miami, FL, United States of America
Shoop WK, Gorsuch CL, Bacman SR, Moraes CT. Precise and simultaneous quantification of mitochondrial DNA heteroplasmy and copy number by digital PCR. J Biol Chem. 2022;298(11):102574. doi:10.1016/j.jbc.2022.102574
Mitochondrial mechanisms in neurodegeneration and neurodevelopment
Identification of autophagy as a functional target suitable for the pharmacological treatment of MPAN in vitro
1Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; 2Protein Expression and Purification Facility, Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; 3Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy; 4Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; 5Bavarian NMR Centre, Department of Bioscience, School of Natural Sciences, Technical University of Munich, 85747 Garching, Germany; 6Molecular Cell Biology Section, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands; 7Expertise Center Movement Disorders Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands; 8Department of Neurology and Epileptology, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland; 9Alembic, Experimental Imaging Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy; 10Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-University (LMU), 80336 Munich, Germany; 11Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; 12German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; 13Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany
Therapy 1: preclinical developments
PPAR Gamma Agonist Pioglitazone restores Mitochondrial Quality Control in fibroblasts of PITRM1 deficient patients
1Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy; 2Department of Biology, University of Padua, Italy; 3Department of Clinical Medicine, University of Bergen, Norway; 4Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel; 5Molecular Medicine, IRCCS Fondazione Stella Maris, Italy; 6Department of Biomedical Sciences, University of Padova, Italy; 7Department of Neurosciences, University of Padova, Italy
Therapy 1: preclinical developments
Mitochondrial derived vesicles retain membrane potential and contain a functional ATP synthase
1Hebrew university, Israel; 2Technion, Haifa, Israel; 3Weizmann Institute of Science, Rehovot, Israel; 4Kimron Veterinary Institute, Bet Dagan, Israel; 5Hadassah Medical Center and Faculty of Medicine, Hebrew University, Jerusalem Israel
Weill U1, Yofe I1, Sass E2, Stynen B3, Davidi D4, Natarajan J5, Ben-Menachem R6, Avihou Z1, Goldman O1, Harpaz N1, Chuartzman S1, Kniazev K1, Knoblach B7, Laborenz J8, Boos F8, Kowarzyk J3, Ben-Dor S9, Zalckvar E1, Herrmann JM8, Rachubinski RA7, Pines O6, Rapaport D5, Michnick SW3, Levy ED2, Schuldiner M10. Genome-wide SWAp-Tag yeast libraries for proteome exploration. Nat Methods. 2018 Jul 9. doi: 10.1038/s41592-018-0044-9
Ben-Menachem R, Wang K, Marcu O, Yu Z, Lim TK, Lin Q, Schueler-Furman O, Pines O. Yeast aconitase mitochondrial import is modulated by interactions of its C and N terminal domains and Ssa1/2 (Hsp70). Scientific Reports volume 8, Article number: 5903(2018)
Ben-Menachem R, Pines O. 2017. Detection of Dual Targeting and Dual Function of Mitochondrial Proteins in Yeast. Methods Mol Biol. 2017;1567:179-195
Ben-Menachem R, Tal M, Shadur T and Pines O. 2011. A third of the yeast mitochondrial proteome is dual localized: a question of evolution. Proteomics. 11(23):4468-76. Impact Factor-4.815.
Ben-Menachem R, Regev-rudzki N and Pines O. 2011. The aconitase C-terminal domain is an independent dual targeting element. J Mol Biol. 409(2):113-23. Impact Factor-4.0.
mtDNA maintenance and expression
Metabolic modulation of mitochondrial DNA release in cellular models of Parkin-associated Parkinson’s disease
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; 2Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
1. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.
Wasner, Kobi; Smajic, Semra; Ghelfi, Jenny; Delcambre, Sylvie; Prada-Medina, Cesar A.; Knappe, Evelyn; Arena, Giuseppe; Mulica, Patrycja; Agyeah, Gideon; Rakovic, Aleksandar; Boussaad, Ibrahim; Badanjak, Katja; Ohnmacht, Jochen; Gerardy, Jean-Jacques; Takanashi, Masashi; Trinh, Joanne; Mittelbronn, Michel; Hattori, Nobutaka; Klein, Christine; Antony, Paul; Seibler, Philip; Spielmann, Malte; Pereira, Sandro L.; Grünewald, Anne
in Movement disorders : official journal of the Movement Disorder Society (2022)
2. Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop
Arena, Giuseppe; Sharma, K.; Agyeah, Gideon; Krüger, Rejko; Grünewald, Anne; Fitzgerald, J. C.
in Current Neurology and Neuroscience Reports (2022), 22(8), 427440
Mitochondrial mechanisms in neurodegeneration and neurodevelopment
ATP synthase c-subunit leak metabolism associated with abnormal mitophagic clearance
1University College London, United Kingdom; 2Yale University , USA
Metabolic stress responses in mitochondrial diseases, ageing and cancer
Investigating the role of mitochondrial regulators in sorafenib and lenvatinib resistance in HCC cell line
1Department of Pharmacological and Biomolecular Sciences - DiSFeB, University of Milan, Italy; 2Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
Mitochondrial mechanisms in neurodegeneration and neurodevelopment
Glucose-derived glutamate drives neuronal differentiation
1Department of Pharmacological and Biomolecular Sciences -DiSFeB, Università degli Studi di Milano, Milan, Italy; 2Department of Medical Biotechnology and Translational Medicine - BIOMETRA, Università degli Studi di Milano, Milan, Italy; 3Institute of Neuroscience, IN-CNR, Milan, Italy; 4Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland; 5Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.