Overexpression of Twinkle-helicase protects cardiomyocytes from genotoxic stress caused by reactive oxygen species

Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19408-13. doi: 10.1073/pnas.1303046110. Epub 2013 Nov 11.


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.

Keywords: mtDNA mutations; recombination; repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Biological / physiology*
  • Animals
  • Base Sequence
  • Blotting, Southwestern
  • Blotting, Western
  • DNA Helicases / metabolism*
  • DNA Helicases / pharmacology
  • DNA Replication / drug effects
  • DNA, Mitochondrial / metabolism*
  • DNA, Mitochondrial / physiology
  • Electrophoresis, Gel, Two-Dimensional
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proteins / pharmacology
  • Molecular Sequence Data
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / physiology
  • Oxidative Stress / physiology*
  • Reactive Oxygen Species / metabolism*
  • Superoxide Dismutase / genetics


  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Twnk protein, mouse
  • DNA Helicases