Cryptic Mitochondrial Ageing Coincides with Mid-Late Life and is Pathophysiologically Informative in Single Cells Across Tissues and Species

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA (mtDNA) mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mtDNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mtDNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mtDNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory, hits high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and ER stress. We identify mechanistic links to ER stress experimentally and further give evidence that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.### Competing Interest StatementThe authors have declared no competing interest.