Functional properties and mode of regulation of the mitochondrial Na⁺/Ca²⁺ exchanger, NCLX

Mitochondrial Ca²⁺ transient is the earliest discovered organellar Ca²⁺ signaling pathway. It consist of a Ca²⁺ influx, mediated by mitochondrial Ca²⁺ uniporter (MCU), and mitochondrial Ca²⁺ efflux mediated by a Na⁺/Ca²⁺ exchanger (NCLX). Mitochondrial Ca²⁺ signaling machinery plays a fundamental role in linking metabolic activity to cellular Ca²⁺ signaling, and in controlling local Ca²⁺ concertation in distinct cellular compartments. Impaired balance between mitochondrial Ca²⁺ influx and efflux leads to mitochondrial Ca²⁺ overload, an early and key event in ischemic or neurodegenerative syndromes. Molecular identification of NCLX and MCU happened only recently. Surprisingly, MCU knockout yielded a relatively mild phenotype while conditional knockout of NCLX led to a rapid fatal heart failure. Here we will focus on recent functional and molecular studies on NCLX structure and its mode of regulation. We will describe the unique crosstalk of this exchanger with Na⁺ and Ca²⁺ signaling pathways in the cell membrane and the endoplasmic reticulum, and with protein kinases that posttranslationally modulate NCLX activity. We will critically compare selectivity of pharmacological blockers versus molecular control of NCLX expression and activity. Finally we will discuss why this exchanger is essential for survival and can serve as an attractive therapeutic target.