NCLX: The mitochondrial sodium calcium exchanger

The free Ca2 + concentration within the mitochondrial matrix ([Ca2 +]m) regulates the rate of ATP production and other [Ca2 +]m sensitive processes. It is set by the balance between total Ca2 + influx (through the mitochondrial Ca2 + uniporter (MCU) and any other influx pathways) and the total Ca2 + efflux (by the mitochondrial Na+/Ca2 + exchanger and any other efflux pathways). Here we review and analyze the experimental evidence reported over the past 40 years which suggest that in the heart and many other mammalian tissues a putative Na+/Ca2 + exchanger is the major pathway for Ca2 + efflux from the mitochondrial matrix. We discuss those reports with respect to a recent discovery that the protein product of the human FLJ22233 gene mediates such Na+/Ca2 + exchange across the mitochondrial inner membrane. Among its many functional similarities to other Na+/Ca2 + exchanger proteins is a unique feature: it efficiently mediates Li+/Ca2 + exchange (as well as Na+/Ca2 + exchange) and was therefore named NCLX. The discovery of NCLX provides both the identity of a novel protein and new molecular means of studying various unresolved quantitative aspects of mitochondrial Ca2 + movement out of the matrix. Quantitative and qualitative features of NCLX are discussed as is the controversy regarding the stoichiometry of the NCLX Na+/Ca2 + exchange, the electrogenicity of NCLX, the [Na+]i dependency of NCLX and the magnitude of NCLX Ca2 + efflux. Metabolic features attributable to NCLX and the physiological implication of the Ca2 + efflux rate via NCLX during systole and diastole are also briefly discussed.