Abnormal Ca(2+) release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy.
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 Ca(2+) concentration and by analyzing the expression of genes encoding E-C coupling proteins. Action potential-mediated Ca(2+) 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) Ca(2+) content was decreased in Tfam knockout cells. The gene for the SR Ca(2+) binding protein calsequestrin-2 (CASQ2), as well as other genes encoding proteins involved in SR Ca(2+) 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-adrenergic agonist isoproterenol resulted in frequent doublet Ca(2+) 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.
Tavi
Pasi
P
Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Hansson
Anna
A
Zhang
Shi-Jin
SJ
Larsson
Nils-Göran
NG
Westerblad
Håkan
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism*; D002395:Catecholamines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse; D007545:Isoproterenol; D002118:Calcium