Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial m...Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ 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+/Ca2+ 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 Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ 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 Ca2+ 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.展开更多
文摘Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ 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+/Ca2+ 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 Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ 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 Ca2+ 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.
