The mitochondrial Na+-Ca 2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes

Abstract

Mitochondrial Ca 2+ is known to change dynamically, regulating mitochondrial as well as cellular functions such as energy metabolism and apoptosis. The NCLX gene encodes the mitochondrial Na +-Ca 2+ exchanger (NCX mit), a Ca 2+ extrusion system in mitochondria. Here we report that the NCLX regulates automaticity of the HL-1 cardiomyocytes. NCLX knockdown using siRNA resulted in the marked prolongation of the cycle length of spontaneous Ca 2+ oscillation and action potential generation. The upstrokes of action potential and Ca 2+ transient were markedly slower, and sarcoplasmic reticulum (SR) Ca 2+ handling were compromised in the NCLX knockdown cells. Analyses using a mathematical model of HL-1 cardiomyocytes demonstrated that blocking NCX mit reduced the SR Ca 2+ content to slow spontaneous SR Ca 2+ leak, which is a trigger of automaticity. We propose that NCLX is a novel molecule to regulate automaticity of cardiomyocytes via modulating SR Ca 2+ handling.