c-Src Is Responsible for Mitochondria-Mediated Arrhythmic Risk in Ischemic Cardiomyopathy.

BACKGROUND: Increased mitochondrial Ca²⁺ uptake has been implicated in the QT prolongation and lethal arrhythmias associated with nonischemic cardiomyopathy. We attempted to define the role of mitochondria in ischemic arrhythmic risk and to identify upstream regulators. METHODS: Myocardial infarction (MI) was induced in wild-type FVB/NJ mice by ligation of the left anterior descending coronary artery. Western blot, immunoprecipitation, ECG telemetry, and patch-clamp techniques were used. RESULTS: After MI, c-Src (proto-oncogene tyrosine-protein kinase Src) and its active form (phosphorylated Src, p-Src) were increased. The activation of c-Src was associated with increased diastolic Ca²⁺ sparks, action potential duration prolongation, and arrhythmia in MI mice. c-Src upregulation and arrhythmia could be reversed by treatment of mice with the Src inhibitor PP1 but not with the inactive analogue PP3. Tyrosine phosphorylated mitochondrial Ca²⁺ uniporter (MCU) was upregulated in the heart tissues of MI mice and patients with ischemic cardiomyopathy. In a heterologous expression system, c-Src could bind MCU and phosphorylate MCU tyrosines. Overexpression of wild-type c-Src significantly increased the mitochondrial Ca²⁺ transient while overexpression of dominant-negative c-Src significantly decreased the mitochondrial Ca²⁺ transient. c-Src inhibition by PP1, MCU inhibition by Ru360, or MCU knockdown could reduce the action potential duration, Ca²⁺ sparks, and arrhythmia after MI. The human heart tissue showed that patients with ischemic cardiomyopathy had significantly increased c-Src active form associated with increased MCU tyrosine phosphorylation and ventricular arrhythmia. CONCLUSIONS: MI leads to increased c-Src active form that results in MCU tyrosine phosphorylation, increased mitochondrial Ca²⁺ uptake, QT prolongation, and arrhythmia, suggesting c-Src or MCU may represent novel antiarrhythmic targets. GRAPHIC ABSTRACT: A graphic abstract is available for this article. [ABSTRACT FROM AUTHOR]