Germline mitochondrial DNA mutations aggravate ageing and can impair brain development

Mutations in mitochondrial DNA (mtDNA) accumulate at a higher rate than mutations in nuclear DNA, and although somatic mtDNA mutations are known to be involved in mammalian ageing, the role of germline mutations in this process is unclear: here germline-transmitted mtDNA mutations are shown to be associated with ageing and brain malformations, and maternally transmitted mtDNA mutations may thus influence both development and ageing. Variant mtDNA linked to ageing Mutations in mitochondrial DNA (mtDNA) accumulate at a higher rate than mutations in nuclear DNA. But whereas somatic mtDNA mutations are firmly associated with mammalian ageing, the extent to which such mutations contribute to ageing when inherited via the mother is not clear. Here it is shown that germline-transmitted mtDNA mutations can induce ageing phenotypes in offspring, aggravate ageing induced by somatic mitochondrial mutations and cause brain malformations in the presence of somatic mtDNA mutations. These findings suggest that inherited human mtDNA sequence variants may have a key influence on the rate of human ageing. Ageing is due to an accumulation of various types of damage 1 , 2 , and mitochondrial dysfunction has long been considered to be important in this process 3 , 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 mtDNA 10 , 11 , 12 , 13 . Despite these protective mechanisms 14 , it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans 15 , 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 ( PolgA wt/mut ) and aggravate premature ageing phenotypes in mtDNA mutator mice ( PolgA mut/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 expan