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

• Published in: The Journal of neuroscience Vol. 33; no. 17; pp. 7206 - 7219
• Main Authors: Parnis, Julia, Montana, Vedrana, Delgado-Martinez, Ignacio, Matyash, Vitali, Parpura, Vladimir, Kettenmann, Helmut, Sekler, Israel, Nolte, Christiane
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 24.04.2013
• Subjects: Animals; Animals, Newborn; Astrocytes - physiology; Calcium Signaling - physiology; Cell Proliferation; Cells, Cultured; Female; Intracellular Fluid - physiology; Male; Mice; Mice, Inbred C57BL; Mitochondria - physiology; Neuroglia - physiology; Sodium-Calcium Exchanger - physiology; Synaptic Transmission - physiology
• ISSN: 1529-2401; 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.5721-12.2013

Mitochondria not only provide cells with energy, but are central to Ca(2+) signaling. Powered by the mitochondrial membrane potential, Ca(2+) enters the mitochondria and is released into the cytosol through a mitochondrial Na(+)/Ca(2+) exchanger. We established that NCLX, a newly discovered mitochondrial Na(+)/Ca(2+) 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 Ca(2+) imaging and NCLX inhibition either by siRNA or by the pharmacological blocker CGP37157, we demonstrated that NCLX is responsible for mitochondrial Ca(2+) extrusion. Suppression of NCLX function altered cytosolic Ca(2+) dynamics in astrocytes and this was mediated by a strong effect of NCLX activity on Ca(2+) influx via store-operated entry. Furthermore, Ca(2+) influx through the store-operated Ca(2+) entry triggered strong, whereas ER Ca(2+) release triggered only modest mitochondrial Ca(2+) 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 Ca(2+)-dependent processes in astrocytes (i.e., exocytotic glutamate release, in vitro wound closure, and proliferation), whereas Ca(2+) wave propagation was not affected. Therefore, NCLX, by meditating astrocytic mitochondrial Na(+)/Ca(2+) exchange, links between mitochondria and plasma membrane Ca(2+) signaling, thereby modulating cytoplasmic Ca(2+) transients required to control a diverse array of astrocyte functions.