Mitochondrial exchanger NCLX plays a major role in the intracellular Ca²⁺ signaling, gliotransmission, and proliferation of astrocytes

Mitochondria not only provide cells with energy, but are central to Ca²⁺signaling. Powered by the mitochondrial membrane potential, Ca²⁺enters the mitochondria and is released into the cytosol through a mitochondrial Na⁺/Ca²⁺exchanger. Weestablished that NCLX, a newly discovered mitochondrial Na⁺/Ca²⁺exchanger, is expressed in astrocytes isolated from mice of either sex. Immunoblot analysis of organellar fractions showed that the location of NCLX is confined to mitochondria. Using pericam-based mitochondrial Ca²⁺imaging and NCLX inhibition either by siRNA or by the pharmacological blocker CGP37157, we demonstrated that NCLX is responsible for mitochondrial Ca²⁺ extrusion. Suppression of NCLX function altered cytosolic Ca²⁺ dynamics in astrocytes and this was mediated by a strong effect of NCLX activity on Ca²⁺ influx via store-operated entry. Furthermore, Ca²⁺ influx through the store-operated Ca²⁺ entry triggered strong, whereas ER Ca²⁺release triggered only modest mitochondrial Ca²⁺transients, indicating that the functional cross talk between the plasma membrane and mitochondrial domains is particularly strong in astrocytes. Finally, silencing of NCLX expression significantly reduced Ca²⁺-dependent processes in astrocytes (i.e., exocytotic glutamate release, in vitro wound closure, and proliferation), whereas Ca²⁺ wave propagation was not affected. Therefore, NCLX, by meditating astrocytic mitochondrial Na⁺/Ca²⁺ exchange, links between mitochondria and plasma membrane Ca²⁺signaling, thereby modulating cytoplasmic Ca²⁺transients required to control a diverse array of astrocyte functions.