期刊
PLOS GENETICS
卷 14, 期 11, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1007805
关键词
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资金
- Mitochondrial Research Guild
- National Institute of Neurological Disorders and Stroke [R21NS090073]
- National Institute of General Medicine [R01GM104990]
- Intramural Research Program of the National Institute of Neurological Disorders and Stroke
- DOD/CDMRP grant [W81XWH-16-1-0579]
- Genetic Approaches to Aging Training Grant [T32AG000057]
- University of Washington Genome Training Grant [T32HG000035]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [T32HG000035] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM104990] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003123] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [T32AG000057] Funding Source: NIH RePORTER
Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.
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