To add to the list of possible mechanisms by which exercise improves long-term health, researchers here offer evidence for exercise to enhance repair of damage to mitochondrial DNA. Note that they are using mice with a DNA repair deficiency that exhibit accelerated development of age-related disease, and this is often a path to results that have little bearing on normal aging, but in this case I don't think that greatly impacts the principal finding of a evidence for a novel mitochondrial DNA repair mechanism triggered by exercise. The herd of hundreds of mitochondria found in every cell are the remnants of symbiotic bacteria, with many important roles in cellular biochemistry. They still replicate like bacteria and carry their own DNA. Unfortunately that DNA is more prone to damage and less readily repaired than the DNA in the cell nucleus. Some forms of damage, such as deletions that impair the mitochondrial processes that produce the energy store molecule ATP, lead to mitochondria that are both dysfunctional and able to replicate more effectively than their peers. Cells become taken over by these broken mitochondria and fall into a state in which they export harmful, reactive molecules into the surrounding tissues. This process contributes to degenerative aging. Therefore any mechanism that improves mitochondrial DNA repair is likely to slow the impact of aging, and we might expect to find such mechanisms involved in at least some of the known methods of modestly slowing aging in laboratory species.
Molecular investigations of age-related pathologies implicate mitochondrial DNA (mtDNA) mutations as one of the primary instigators driving multisystem degeneration, stress intolerance, and energy deficits. It is intuitive to assume that the de novo mtDNA mutations observed during aging are due to accumulated, unrepaired oxidative damage, but some evidence actually suggests that mtDNA replication errors may be the more important culprit. The demonstration that multiple aspects of aging are accelerated in mutator mice harboring error-prone mitochondrial polymerase gamma (POLG1) provides support for the causal role of mtDNA replication errors in instigating mammalian aging.
The epidemic emergence of modern chronic diseases largely stems from the adoption of a sedentary lifestyle and excess energy intake. There is incontrovertible evidence that endurance exercise extends life expectancy and reduces the risk of chronic diseases in both rodents and humans. We have previously shown that endurance exercise effectively rescued progeroid aging in mutator mice concomitant with a reduction in mtDNA mutations, despite an inherent defect in POLG1 proofreading function. Exercise has also been shown to increase telomerase activity and reduce senescence markers. These findings suggest a link between exercise-mediated metabolic adaptations and genomic (nuclear and mitochondrial) stability; however, the identity of this metabolic link remains unknown. In this study, we have utilized PolG mice to investigate the mitochondrial-telomere dysfunction axis in the context of progeroid aging, and to elucidate how exercise counteracts mitochondrial dysfunction and mtDNA mutation burden through mitochondrial localization of the tumor suppressor protein p53.
Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient 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. Our 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.