title: Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A-->G.
abstract: Mitochondrial DNA (mtDNA) mutations are a common cause of human disease and accumulate as part of normal ageing and in common neurodegenerative disorders. Cells express a biochemical defect only when the proportion of mutated mtDNA exceeds a critical threshold, but it is not clear whether the actual cause of this defect is a loss of wild-type mtDNA, an excess of mutated mtDNA, or a combination of the two. Here, we show that segments of human skeletal muscle fibers harboring two pathogenic mtDNA mutations retain normal cytochrome c oxidase (COX) activity by maintaining a minimum amount of wild-type mtDNA. For these mutations, direct measurements of mutated and wild-type mtDNA molecules within the same skeletal muscle fiber are consistent with the "maintenance of wild type" hypothesis, which predicts that there is nonselective proliferation of mutated and wild-type mtDNA in response to the molecular defect. However, for the m.3243A-->G mutation, a superabundance of wild-type mtDNA was found in many muscle-fiber sections with negligible COX activity, indicating that the pathogenic mechanism for this particular mutation involves interference with the function of the wild-type mtDNA or wild-type gene products.
authors.affiliation: Mitochondrial Research Group, Newcastle University, Newcastle, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Durham
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Cree
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000648:ultrastructure; D017354:Point Mutation
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV