Powered by the mitochondrial membrane potential, Ca 2+ permeates the mitochondria via a Ca 2+ channel termed Ca 2+ uniporter and is pumped out by a Na + /Ca 2+ exchanger, both of which are located on the inner mitochondrial membrane. Mitochondrial Ca 2+ transients are critical for metabolic activity and regulating global Ca 2+ responses. On the other hand, failure to control mitochondrial Ca 2+ is a hallmark of ischemic and neurodegenerative diseases. Despite their importance, identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific. This review will focus on the mitochondrial exchanger, initially describing how it was molecularly identified and linked to a novel member of the Na + /Ca 2+ exchanger superfamily termed NCLX. Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types. In lymphocytes, NCLX is essential for refilling the endoplasmic reticulum Ca 2+ stores required for antigen-dependent signaling. Communication of NCLX with the store-operated channel in astroglia controls Ca 2+ influx and thereby neuro-transmitter release and cell proliferation. The refilling of the Ca 2+ stores in the sarcoplasmic reticulum, which is controlled by NCLX, determines the frequency of action potential and Ca 2+ transients in cardiomyocytes. NCLX is emerging as a hub for integrating glucose-dependent Na + and Ca 2+ signaling in pancreatic β cells, and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells. Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca 2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes. Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria. NCLX, MCU, mitochondrial
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