期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 48, 页码 19408-19413出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1303046110
关键词
recombination; mtDNA mutations; repair
资金
- European Molecular Biology Organization, Academy of Finland
- Jane and Aatos Erkko Foundation
- James and Esther King Biomedical Research Program [3KN09]
- Max Planck Society
- Excellence Cluster Cardiopulmonary System
- Deutsche Forschungsgemeinschaft [SFB TRR81]
Mitochondrial DNA (mtDNA) in adult human heart is characterized by complex molecular forms held together by junctional molecules of unknown biological significance. These junctions are not present in mouse hearts and emerge in humans during postnatal development, concomitant with increased demand for oxidative metabolism. To analyze the role of mtDNA organization during oxidative stress in cardiomyocytes, we used a mouse model, which recapitulates the complex mtDNA organization of human hearts by overexpression of the mitochondrial helicase, TWINKLE. Overexpression of TWINKLE rescued the oxidative damage induced replication stalling of mtDNA, reduced mtDNA point mutation load, and modified mtDNA rearrangements in heterozygous mitochondrial superoxide dismutase knockout hearts, as well as ameliorated cardiomyopathy in mice superoxide dismutase knockout in a p21-dependent manner. We conclude that mtDNA integrity influences cell survival and reason that tissue specific modes of mtDNA maintenance represent an adaptation to oxidative stress.
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