Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice

Adeel Safdar, Konstantin Khrapko, James M. Flynn, Ayesha Saleem, Michael De Lisio, Adam P.W. Johnston, Yevgenya Kratysberg, Imtiaz A. Samjoo, Yu Kitaoka, Daniel I. Ogborn, Jonathan P. Little, Sandeep Raha, Gianni Parise, Mahmood Akhtar, Bart P. Hettinga, Glenn C. Rowe, Zoltan Arany, Tomas A. Prolla, Mark A. Tarnopolsky

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Human 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. Results: Endurance 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. Conclusions: 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.

Original languageEnglish (US)
Article number7
JournalSkeletal Muscle
Volume6
Issue number1
DOIs
StatePublished - Jan 31 2016

Keywords

  • Apoptosis
  • Endurance exercise
  • Mitochondrial DNA mutations
  • Mutator mouse
  • Oxidative stress
  • P53
  • Satellite cells
  • Senescence
  • Skeletal muscle
  • Telomere

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology

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