Human Molecular Genetics Advance Access originally published online on March 9, 2005
Human Molecular Genetics 2005 14(8):1069-1076; doi:10.1093/hmg/ddi119
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Abnormal Ca2+ release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy
1Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden, 2Department of Medical Nutrition and Laboratory Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden and 3Department of Physiology and Biocenter Oulu, University of Oulu, FIN-90014 Oulu, Finland
* To whom correspondence should be addressed. Tel: +46 852487253; Fax: +46 8327026; Email: hakan.westerblad{at}fyfa.ki.se
Received January 3, 2005; Revised February 7, 2005; Accepted March 3, 2005
Mitochondrial dysfunction is implicated in numerous cardiac disorders. It has been assumed that the functional defects are directly related to a decreased rate of mitochondrial ATP production, but recent studies have challenged this idea. Here, we used mice with tissue-specific knockout of mitochondrial transcription factor A (Tfam) that leads to progressive cardiomyopathy. The role of changes in the excitation–contraction (E–C) coupling in cardiomyocytes of these mice was studied by measuring the free cytosolic Ca2+ concentration and by analyzing the expression of genes encoding E–C coupling proteins. Action potential-mediated Ca2+ transients, measured with the fluorescent indicator fluo-3 in isolated cardiomyocytes, were smaller and faster in Tfam knockout cardiomyocytes when compared with controls. The total sarcoplasmic reticulum (SR) Ca2+ content was decreased in Tfam knockout cells. The gene for the SR Ca2+ binding protein calsequestrin-2 (CASQ2), as well as other genes encoding proteins involved in SR Ca2+ handling, showed decreased expression in Tfam knockout hearts. Decreased CASQ2 levels have been linked to severe arrhythmias triggered by ß-adrenergic stimulation. In line with this, application of the ß-adrenergic agonist isoproterenol resulted in frequent doublet Ca2+ transients in Tfam knockout cardiomyocytes. In conclusion, our results show that mitochondrial dysfunction in the heart induces specific down-regulation of the expression of genes encoding proteins involved in E–C coupling. These changes predispose to cardiac arrhythmias and terminal heart failure and are thus important in the pathogenesis of mitochondrial cardiomyopathy.