title: Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice.
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.
authors.affiliation: Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Adeel
authors.initials: A
authors.lastname: Safdar
authors.affiliation: Northeastern University, Boston, MA 02115 USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khrapko
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945 USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Flynn
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Saleem
authors.affiliation: Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: De Lisio
authors.affiliation: Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Adam P W
authors.initials: AP
authors.lastname: Johnston
authors.affiliation: Northeastern University, Boston, MA 02115 USA.
authors.forename: Yevgenya
authors.initials: Y
authors.lastname: Kratysberg
authors.affiliation: Department of Medical Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Imtiaz A
authors.initials: IA
authors.lastname: Samjoo
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kitaoka
authors.affiliation: Department of Medical Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Ogborn
authors.affiliation: School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC V1V 1V7 Canada.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Little
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Raha
authors.affiliation: Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Gianni
authors.initials: G
authors.lastname: Parise
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Akhtar
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Hettinga
authors.affiliation: Division of Cardiovascular Disease, University of Alabama, Birmingham, AL 35294 USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
authors.affiliation: Departments of Genetics, University of Wisconsin, Madison, WI 53706 USA ; Departments of Medical Genetics, University of Wisconsin, Madison, WI 53706 USA.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005838:Genotype; D008017:Life Expectancy; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D010641:Phenotype; D021381:Protein Transport; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D016159:Tumor Suppressor Protein p53; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse
keywords: Apoptosis; Endurance exercise; Mitochondrial DNA mutations; Mutator mouse; Oxidative stress; Satellite cells; Senescence; Skeletal muscle; Telomere; p53
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