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Human Molecular Genetics Advance Access published online on March 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi119
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Abnormal Ca2+ release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy

Pasi Tavi 1, Anna Hansson 2, Shi-Jin Zhang 3, Nils-Göran Larsson 2, and Håkan Westerblad 3*

1 Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Physiology and Biocenter Oulu, FIN-90014 University of Oulu, Finland
2 Department of Medical Nutrition and Laboratory Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden
3 Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden

* To whom correspondence should be addressed.
Håkan Westerblad, E-mail: hakan.westerblad{at}fyfa.ki.se


  Abstract

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 in comparison 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 {beta}-adrenergic stimulation. In line with this, application of the {beta}-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 cardiomopathy.


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