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Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A→G

Lookup NU author(s): Dr Steve Durham, Dr David Samuels, Dr Lynsey Cree, Professor Patrick Chinnery


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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. © 2007 by The American Society of Human Genetics. All rights reserved.

Publication metadata

Author(s): Durham SE, Samuels DC, Cree LM, Chinnery PF

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2007

Volume: 81

Issue: 1

Pages: 189-195

Print publication date: 01/07/2007

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1086/518901

PubMed id: 17564976


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