Format

Send to

Choose Destination
Skelet Muscle. 2016 Jan 31;6:7. doi: 10.1186/s13395-016-0075-9. eCollection 2016.

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

Author information

1
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.
2
Northeastern University, Boston, MA 02115 USA.
3
Buck Institute for Research on Aging, Novato, CA 94945 USA.
4
Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada.
5
Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada.
6
Department of Medical Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada.
7
School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC V1V 1V7 Canada.
8
Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, ON L8N 3Z5 Canada.
9
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.
10
Division of Cardiovascular Disease, University of Alabama, Birmingham, AL 35294 USA.
11
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
12
Departments of Genetics, University of Wisconsin, Madison, WI 53706 USA ; Departments of Medical Genetics, University of Wisconsin, Madison, WI 53706 USA.
13
Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5 Canada ; Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5 Canada.

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.

KEYWORDS:

Apoptosis; Endurance exercise; Mitochondrial DNA mutations; Mutator mouse; Oxidative stress; Satellite cells; Senescence; Skeletal muscle; Telomere; p53

PMID:
26834962
PMCID:
PMC4733510
DOI:
10.1186/s13395-016-0075-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center