Abnormal Ca(2+) release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy

Hum Mol Genet. 2005 Apr 15;14(8):1069-76. doi: 10.1093/hmg/ddi119. Epub 2005 Mar 9.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / metabolism
  • Calcium / metabolism*
  • Cardiomyopathies / metabolism*
  • Catecholamines / pharmacology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / metabolism
  • Isoproterenol / pharmacology
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Sarcoplasmic Reticulum / metabolism

Substances

  • Adrenergic beta-Agonists
  • Catecholamines
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Tfam protein, mouse
  • Isoproterenol
  • Calcium