Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice.

Autor: Safdar A; 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., Khrapko K; Northeastern University, Boston, MA 02115 USA., Flynn JM; Buck Institute for Research on Aging, Novato, CA 94945 USA., Saleem A; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada., De Lisio M; Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada., Johnston AP; Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada., Kratysberg Y; Northeastern University, Boston, MA 02115 USA., Samjoo IA; Department of Medical Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada., Kitaoka Y; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada., Ogborn DI; Department of Medical Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada., Little JP; School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC V1V 1V7 Canada., Raha S; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada., Parise G; Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada., Akhtar M; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada., Hettinga BP; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada., Rowe GC; Division of Cardiovascular Disease, University of Alabama, Birmingham, AL 35294 USA., Arany Z; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA., Prolla TA; Departments of Genetics, University of Wisconsin, Madison, WI 53706 USA ; Departments of Medical Genetics, University of Wisconsin, Madison, WI 53706 USA., Tarnopolsky MA; Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.
Jazyk: angličtina
Zdroj: Skeletal muscle [Skelet Muscle] 2016 Jan 31; Vol. 6, pp. 7. Date of Electronic Publication: 2016 Jan 31 (Print Publication: 2016).
DOI: 10.1186/s13395-016-0075-9
Abstrakt: 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.
Databáze: MEDLINE
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