Life after the birth of the mitochondrial Na+/Ca2+ exchanger, NCLX

Abstract

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

Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation

“…Powered by the steep electrical potential across the inner membrane of the mitochondria (∆Ψ m , −180 mV), cytosolic calcium flows rapidly into the matrix, primarily via the mitochondrial calcium uniporter (MCU) 18 – 21 . Calcium efflux is substantially slower (10-100 fold) and is mediated by the mitochondrial sodium/lithium/calcium exchanger (NCLX); 22 , 23 , which is the main calcium extruder from mitochondria of excitable cells 24 . Due to its slower rate of transport compared to the MCU, it is the rate limiting step in defining mitochondrial calcium transients 25 .…”

Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

“…Mitochondria also act as buffers and stores of Ca 2+ , via the action of a number of specific proteins. Thus, Ca 2+ uptake is mediated by the inner mitochondrial membrane-spanning mitochondrial Ca 2+ uniporter (MCU) (Hoppe 2010, Pendin et al, 2014, while the mitochondrial Na + /Ca 2+ exchanger extrudes Ca 2+ (Nita et al, 2015 (Lewis 2007, Wu et al, 2007. ER emptying is sensed by the ER membrane protein stromal interaction molecule 1 (STIM1), which responds by coming into close contact with the plasma membrane channel Orai1, activating it and thus causing Ca 2+ influx (Feske 2007, Lewis 2007, Wu et al, 2007.…”

The Mitochondrial Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and Their Regulation

“…Several recent reviews have discussed the basic principles that govern [Ca 2+ ] m homeostasis and maintenance of Ca 2+ dynamics within organelles (18–22). The OMM and IMM pathways allowing Ca 2+ entry into and exit from mitochondria are presented below.…”