Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany.
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany;
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9620-E9629. doi: 10.1073/pnas.1721683115. Epub 2018 Sep 24.
Mammals develop age-associated clonal expansion of somatic mtDNA mutations resulting in severe respiratory chain deficiency in a subset of cells in a variety of tissues. Both mathematical modeling based on descriptive data from humans and experimental data from mtDNA mutator mice suggest that the somatic mutations are formed early in life and then undergo mitotic segregation during adult life to reach very high levels in certain cells. To address whether mtDNA mutations have a universal effect on aging metazoans, we investigated their role in physiology and aging of fruit flies. To this end, we utilized genetically engineered flies expressing mutant versions of the catalytic subunit of mitochondrial DNA polymerase (DmPOLγA) as a means to introduce mtDNA mutations. We report here that lifespan and health in fruit flies are remarkably tolerant to mtDNA mutations. Our results show that the short lifespan and wide genetic bottleneck of fruit flies are limiting the extent of clonal expansion of mtDNA mutations both in individuals and between generations. However, an increase of mtDNA mutations to very high levels caused sensitivity to mechanical and starvation stress, intestinal stem cell dysfunction, and reduced lifespan under standard conditions. In addition, the effects of dietary restriction, widely considered beneficial for organismal health, were attenuated in flies with very high levels of mtDNA mutations.
哺乳动物随着年龄的增长会出现体细胞 mtDNA 突变的克隆性扩张，导致多种组织中部分细胞的呼吸链严重缺陷。基于人类描述性数据的数学建模和 mtDNA 突变体小鼠的实验数据都表明，体细胞突变是在生命早期形成的，然后在成年期经历有丝分裂分离，在某些细胞中达到非常高的水平。为了研究 mtDNA 突变是否对衰老的后生动物具有普遍影响，我们研究了它们在果蝇生理和衰老中的作用。为此，我们利用表达线粒体 DNA 聚合酶（DmPOLγA）催化亚基突变体的基因工程果蝇作为引入 mtDNA 突变的手段。我们在此报告称，果蝇的寿命和健康对 mtDNA 突变具有惊人的耐受性。我们的研究结果表明，果蝇寿命短且遗传瓶颈宽，限制了 mtDNA 突变在个体和代际之间的克隆性扩张程度。然而，mtDNA 突变增加到非常高的水平会导致对机械和饥饿应激的敏感性、肠干细胞功能障碍以及在标准条件下寿命缩短。此外，广泛认为对机体健康有益的饮食限制在 mtDNA 突变水平非常高的果蝇中效果减弱。
