Mitochondria are known as ATP-producing factories as well as Ca²⁺ stores. Mitochondrial Ca²⁺ (Ca²⁺_m) changes dynamically, and this change is mainly balanced by an influx via a Ca²⁺ uniporter (MCU) and an efflux via a Na⁺-Ca²⁺ exchanger (NCLX). It has been suggested that Ca²⁺_m is involved in regulating mitochondrial energy metabolism. However, little is known about the roles of NCLX in cardiomyocytes, where repetitive Ca²⁺ transients occur and where a huge amount of ATP is generated and utilized. To clarify its roles, we carried out a study combining NCLX knockdown in the spontaneously beating atrial myocyte-derived cell line HL-1 and mathematical simulations. NCLX knockdown using siRNA resulted in -50% reduction of its mRNA and protein expressions, attenuating Ca²⁺_m efflux and increasing Ca²⁺_m content. Cycle length of spontaneous Ca²⁺ oscillation and action potential generation were markedly prolonged. The upstrokes of action potential and Ca²⁺ transient were slower, and sarcoplasmic reticulum (SR) Ca²⁺ content and reuptake were reduced by knocking down NCLX. Analysis of a mathematical model of HL-1 demonstrated that a substantial amount of Ca²⁺ is transferred either directly or indirectly via NCLX from mitochondria to SR and that blocking NCLX reduces the SR Ca²⁺ content to slow SR Ca²⁺ leak, which triggers automaticity. We propose that Ca²⁺_m dynamics via NCLX is involved in the generation of abnormal automaticity and arrhythmia.

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