title: Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes.
abstract: 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.
authors.affiliation: Cellular Neurosciences, Max Delbrück Centre for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Parnis
authors.forename: Vedrana
authors.initials: V
authors.lastname: Montana
authors.forename: Ignacio
authors.initials: I
authors.lastname: Delgado-Martinez
authors.forename: Vitali
authors.initials: V
authors.lastname: Matyash
authors.forename: Vladimir
authors.initials: V
authors.lastname: Parpura
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.forename: Israel
authors.initials: I
authors.lastname: Sekler
authors.forename: Christiane
authors.initials: C
authors.lastname: Nolte
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D007424:Intracellular Fluid / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins; D009457:Neuroglia / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D024101:Mitochondrial Proteins; C483046:SLC8B1 protein, human; D019831:Sodium-Calcium Exchanger