AbstractBackgroundHuman genetic disorders and transgenic mouse models have shown that
mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging
process. Epidemiologically, exercise is associated with greater life expectancy
and reduced risk of chronic diseases. While the beneficial effects of exercise are
well established, the molecular mechanisms instigating these observations remain
unclear.ResultsEndurance exercise reduces mtDNA mutation burden, alleviates
multisystem pathology, and increases lifespan of the mutator mice, with
proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence
for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising
notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme.
Here, we show that the tumor suppressor protein p53 translocates to mitochondria
and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to
endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53,
exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis,
preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature
mortality.ConclusionsOur data establish a new role for p53 in exercise-mediated
maintenance of the mtDNA genome and present mitochondrially targeted p53 as a
novel therapeutic modality for diseases of mitochondrial etiology.
