Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

摘要

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. Author summary The energy needs of an animal cell are supplied by tiny organelles known as mitochondria. Each of the many mitochondria in a cell has a set of blueprints for making more mitochondria, known as mitochondrial DNA (mtDNA). As animals age, their mtDNA acquires irreversible defects called mutations, which accumulate and may cause aging. Cells can selectively destroy malfunctioning mitochondria, so we hypothesized that mitochondria with harmful mutations would be selectively destroyed. To test our theory, we created a fruit fly strain with a high mtDNA mutation rate. Our hypothesis predicts that, because mitochondria bearing harmful mtDNA mutations would be destroyed, we should detect primarily less harmful mutations in our strain. However, the mtDNA mutations we detected were more harmful than expected by chance. We suggest two possible explanations: First, mitochondria with harmful mtDNA mutations may be degraded less often because they generate little energy and are not damaged by toxic byproducts of energy production. Second, cells may compensate for harmful mtDNA mutations by stimulating mitochondria to multiply, creating more healthy mitochondria but also more mitochondria with harmful mtDNA mutations. Future studies will distinguish between these models and further advance our understanding of aging and aging related disease.