Ageing is due to an accumulation of various types of damage1, 2, and mitochondrial dysfunction has long been considered to be important in this process3, 4, 5, 6, 7, 8. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA)9, and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA10, 11, 12, 13. Despite these protective mechanisms14, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans15, 16. We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgAwt/mut) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgAmut/mut). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations17 to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues18, 19. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.
参考文献：Jaime M. Ross et. al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature (2013)