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.