Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in mitochondrial DNA (mtDNA) are known to play a critical role in aging and a wide range of age-related diseases, but it has remained unclear when the mutations that drive physiological decline first arise.

To address this, the authors generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Using this model, they found that mutations arising during the first two months of life are sufficient to drive a wide variety of age-related pathologies. The severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age.

The study further shows that selection against deleterious variants can be modulated by manipulating mitochondrial fusion both in vitro and in vivo. These observations raise the possibility that in some tissues the pace of aging is pre-determined by events occurring early in life, and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of pathogenic variants.

The results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.