Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A

Biochem Biophys Res Commun. 2004 Jul 9;319(4):1210-5. doi: 10.1016/j.bbrc.2004.05.104.


Mice expressing an error-prone mitochondrial DNA polymerase rapidly accumulate random mutations in mitochondrial DNA. Expression of the transgene in the heart leads to dilated cardiomyopathy accompanied by a wave of apoptosis in cardiomyocytes, and a vigorous and persistent protective response, including upregulation of the anti-apoptotic protein, Bcl-2. To investigate the role of the mitochondrial permeability transition pore in the development of disease, we treated mice with cyclosporin A (CsA), an inhibitor of pore opening. Drug treatment prevented cardiac dilatation, transgene-specific apoptosis, and upregulation of Bcl-2. It also rescued hearts from the profound decrease in connexin 43, which characterizes the dilatated heart. Treatment with FK506, which like CsA inhibits cytoplasmic calcineurin but not the mitochondrial pore, did not affect disease development, suggesting that the relevant target of CsA was the mitochondrial pore. These data implicate breakdowns in the mitochondrial permeability barrier in pathogenesis of elevated frequencies of mtDNA mutations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Death
  • Connexin 43 / metabolism
  • Cyclosporine / metabolism*
  • DNA, Mitochondrial / genetics*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Dilatation, Pathologic
  • Enzyme Inhibitors / metabolism
  • Heart Diseases / genetics*
  • Heart Diseases / metabolism
  • Immunosuppressive Agents / metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria / physiology
  • Mutation*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Tacrolimus / metabolism


  • Connexin 43
  • DNA, Mitochondrial
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Cyclosporine
  • DNA-Directed DNA Polymerase
  • Tacrolimus