RETRACTED ARTICLE:Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice

Abstract

BackgroundHuman 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0075-9) contains supplementary material, which is available to authorized users.

Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis

“…Increased oxidative stress in the mitochondria of the PolG mouse also induces nuclear DNA damage, as represented by telomere erosion [16••], which in turn facilitates translocation of the tumor suppressor protein, p53, into the nucleus from its cytoplasmic depots [17]. Indeed, we clearly observed elevated nuclear p53 levels in the sedentary PolG mouse, in tandem with nuclear DNA damage [16••].…”

“…Indeed, we clearly observed elevated nuclear p53 levels in the sedentary PolG mouse, in tandem with nuclear DNA damage [16••]. Nuclear p53 has been shown to activate senescence and apoptosis programs in both somatic and stem cells [17].…”

“…Furthermore, p53 represses the transcription of PGC-1α, the master regulator of mitochondrial biogenesis and cellular antioxidant response [19••]. We believe that this may add to the general downregulation of mitochondrial bioenergetic capacity, reduced mtDNA copy number, and overall decrease in mitochondrial electron transport chain complex assembly in the sedentary PolG mouse [3,15,9,4••,16••], which probably also depends o the high levels of mtDNA mutations. We believe that the nuclear relocalization of p53, reduces the availability of p53 for the mitochondria, which subsequently attenuates p53/TFAM, and p53/POLG1 complex formation in the mitochondria of PolG mice [20•,16••].…”

“…Recent work by our group showed that the systemic mitochondrial dysfunction and multisystem pathology in PolG mice is efficiently mitigated by endurance exercise [4••,16••]. Not surprisingly, the hunt for molecular mechanism(s) underlying the systemic rescue of pathology in PolG mice as executed by endurance exercise has garnered much attention.…”

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

“…In the mtDNA mutator mouse, endurance exercise improves oxidative capacity, prevents or repairs mtDNA depletion and mutations through tumor suppressor protein p53 and increases lifespan (Safdar et al, 2011; Safdar et al, 2015). However, others have reported that although oxidative capacity is improved, there are no changes in the mtDNA mutation load (Jeppesen et al, 2009; Taivassalo et al, 2006).…”