TY - JOUR
T1 - Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A
AU - Mott, J. L.
AU - Zhang, D.
AU - Freeman, J. C.
AU - Mikolajczak, P.
AU - Chang, S. W.
AU - Zassenhaus, H. P.
N1 - Funding Information:
We are grateful for grant support from the National Institutes on Aging, Heart, Lung, and Blood, Neurological Disorders and Stroke, and the American Heart Association to H.P.Z., and from the American Diabetes Association to J.L.M.
PY - 2004/7/9
Y1 - 2004/7/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bbrc.2004.05.104
DO - 10.1016/j.bbrc.2004.05.104
M3 - Article
C2 - 15194495
AN - SCOPUS:2942576595
SN - 0006-291X
VL - 319
SP - 1210
EP - 1215
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -