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

J. L. Mott, D. Zhang, J. C. Freeman, P. Mikolajczak, S. W. Chang, H. P. Zassenhaus

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1210-1215
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume319
Issue number4
DOIs
StatePublished - Jul 9 2004

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Mitochondrial DNA
Cyclosporine
Heart Diseases
Transgenes
Mutation
Up-Regulation
Apoptosis
Drug therapy
Connexin 43
Apoptosis Regulatory Proteins
Calcineurin
Dilated Cardiomyopathy
Tacrolimus
Mutation Rate
DNA-Directed DNA Polymerase
Cardiac Myocytes
Dilatation
Permeability
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A. / Mott, J. L.; Zhang, D.; Freeman, J. C.; Mikolajczak, P.; Chang, S. W.; Zassenhaus, H. P.

In: Biochemical and Biophysical Research Communications, Vol. 319, No. 4, 09.07.2004, p. 1210-1215.

Research output: Contribution to journalArticle

Mott, J. L. ; Zhang, D. ; Freeman, J. C. ; Mikolajczak, P. ; Chang, S. W. ; Zassenhaus, H. P. / Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A. In: Biochemical and Biophysical Research Communications. 2004 ; Vol. 319, No. 4. pp. 1210-1215.
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