Clonal expansion of mitochondrial DNA deletions is a private mechanism of ageing in long-lived animals

Abstract

Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of ageing (Lopez-Otin et al. 2013). Human ageing is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle ageing is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions co-localize with sites of fiber-breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age-dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans ageing. Here we report identification of 266 novel mtDNA deletions in ageing nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (1) mtDNA deletions in nematode is extremely rare, (2) there is no significant age-dependent increase in mtDNA deletions and (3) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age-dependent functional decline commonly observed in C. elegans. Computational modelling of mtDNA dynamics in C. elegans indicates that the lifespan of short-lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of ageing predominantly relevant in long-lived animals such as humans and rhesus monkey and possibly in rodents.