A genetic view of the mitochondrial role in ageing: killing us softly

In contrast to the nuclear genome, the mitochondrial DNA (mtDNA) is maternally inherited and resides in multiple cellular copies that may vary in sequence (heteroplasmy). Although the interaction between mtDNA and nuclear DNA-encoded factors (mito-nuclear interaction) is vital, the mtDNA accumulates mutations an order of magnitude faster than the nuclear genome both during evolution and during the lifetime of the individual, thus requiring tight mito-nuclear co-evolution. These unique features drew the attention of many to suggest a role for the mitochondria in ageing. Although an excess of mtDNA mutations has been found in aged humans and animal models, most of these mutations had minor functional potential. Moreover, there are mtDNA mutations that recur in aged humans, but do not have any clear functionality. Nevertheless, accumulation of recurrent private mutations with minor functionality in the fast-ageing, mtDNA polymerase mutated mice (Pol-gamma), suggested that these very mtDNA alterations participate in ageing. This introduces a paradox: how would either single or recurrent mutations with negligible functionality play a role in a major chronic phenotype such as ageing?Here, we propose a hypothesis to partially resolve this paradox: accumulation of mitochondrial mutations with subtle functionality, which was overlooked by the mechanisms of selection, supplemented by slightly affected fusion-fission cycles, will hamper mitochondrial functional complementation within cells, disrupt mito-nuclear interactions and lead to ageing. Since certain mito-nuclear genotypes are less functionally compatible than others, and since the mtDNA and the nuclear genome segregate independently among generations, mild functionality of mutations will have differential effect on individuals in the population thus explaining the large variability in the ageing phenotype even within ethnic groups. We emphasize the role of recurrent mtDNA mutations with functional potential during evolution and during the lifetime of the individual.