Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission.

Autor:	Zhang H; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Esposito M; EPSRC Centre for the Mathematics of Precision Healthcare, Department of Mathematics, Imperial College, London, UK.; Leverhulme Centre for Cellular Bionics, Imperial College, London, UK., Pezet MG; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Aryaman J; EPSRC Centre for the Mathematics of Precision Healthcare, Department of Mathematics, Imperial College, London, UK., Wei W; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Klimm F; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; EPSRC Centre for the Mathematics of Precision Healthcare, Department of Mathematics, Imperial College, London, UK., Calabrese C; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Burr SP; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Macabelli CH; Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos 13565-905, Brazil., Viscomi C; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK., Saitou M; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan., Chiaratti MR; Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos 13565-905, Brazil., Stewart JB; Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.; Biosciences Institute, Faculty of Medical Sciences, Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Jones N; EPSRC Centre for the Mathematics of Precision Healthcare, Department of Mathematics, Imperial College, London, UK.; Leverhulme Centre for Cellular Bionics, Imperial College, London, UK., Chinnery PF; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2021 Dec 10; Vol. 7 (50), pp. eabi5657. Date of Electronic Publication: 2021 Dec 08.
DOI:	10.1126/sciadv.abi5657
Abstrakt:	Heteroplasmic mitochondrial DNA (mtDNA) mutations are a common cause of inherited disease, but a few recurrent mutations account for the vast majority of new families. The reasons for this are not known. We studied heteroplasmic mice transmitting m.5024C>T corresponding to a human pathogenic mutation. Analyzing 1167 mother-pup pairs, we show that m.5024C>T is preferentially transmitted from low to higher levels but does not reach homoplasmy. Single-cell analysis of the developing mouse oocytes showed the preferential increase in mutant over wild-type mtDNA in the absence of cell division. A similar inheritance pattern is seen in human pedigrees transmitting several pathogenic mtDNA mutations. In m.5024C>T mice, this can be explained by the preferential propagation of mtDNA during oocyte maturation, counterbalanced by purifying selection against high heteroplasmy levels. This could explain how a disadvantageous mutation in a carrier increases to levels that cause disease but fails to fixate, causing multigenerational heteroplasmic mtDNA disorders.
Databáze:	MEDLINE
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