Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance

• Published in: Journal of neurochemistry Vol. 165; no. 4; pp. 521 - 535
• Main Authors: Cabral‐Costa, João Victor, Vicente‐Gutiérrez, Carlos, Agulla, Jesús, Lapresa, Rebeca, Elrod, John W., Almeida, Ángeles, Bolaños, Juan P., Kowaltowski, Alicia J.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2023
• Subjects: Animals; astrocyte; Astrocytes; Astrocytes - metabolism; brain metabolism; Calcium; Calcium (intracellular); Calcium (mitochondrial); Calcium - metabolism; Calcium influx; Calcium ions; Calcium Signaling - physiology; Calcium signalling; calcium transport; Cognition; Cognitive ability; Cognitive tasks; Deletion; Efflux; Endoplasmic reticulum; energy metabolism; Glucose metabolism; Glycolysis; Hippocampus; lactate; metabolic regulation; Mice; Mitochondria; Mitochondria - metabolism; mitochondrial metabolism; Na+/Ca2+ exchanger; NCLX; Sodium; Sodium - metabolism; sodium transport; Sodium-Calcium Exchanger - genetics; sodium‐calcium exchange; brain metabolism; NCLX; glycolysis; sodium transport; lactate; astrocyte; calcium transport; energy metabolism; metabolic regulation; mitochondrial metabolism; sodium-calcium exchange
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15745

Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUc), while efflux occurs mainly through the mitochondrial Na+/Ca2+ exchanger (NCLX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared with neurons. To assess the role of NCLX in mouse primary culture astrocytes, we inhibited its function both pharmacologically or genetically. This resulted in re‐shaping of cytosolic Ca2+ signaling and a metabolic shift that increased glycolytic flux and lactate secretion in a Ca2+‐dependent manner. Interestingly, in vivo genetic deletion of NCLX in hippocampal astrocytes improved cognitive performance in behavioral tasks, whereas hippocampal neuron‐specific deletion of NCLX impaired cognitive performance. These results unveil a role for NCLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.
Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUc), while efflux occurs mainly through the mitochondrial Na+/Ca2+ exchanger (NCLX). We inhibited NCLX function pharmacologically or genetically in mouse primary culture astrocytes. Our results unveil a role for NCLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition. The schematic illustrates that in astrocytes, (1) inhibition/deletion of mitochondrial Na+/Ca2+ exchanger (NCLX) activity leads to (2) augmented cytosolic Ca2+ clearance. This results in (3) increased glycolytic flux; and (4) slightly decreased mitochondrial oxidative phosphorylation, leading to (5) increased lactate dehydrogenase (LDH)‐mediated reduction of pyruvate to lactate. The resulting increased lactate in astrocytes (6) is secreted (7) and may contribute to enhanced behavioral performance in vivo. (ETC: electron transport chain).