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

Cabral-Costa JV, Vicente-Gutiérrez C, Agulla J, Lapresa R, Elrod JW, Almeida Á, Bolaños JP, Kowaltowski AJ. J Neurochem. 2022 Dec 23. doi: 10.1111/jnc.15745. Online ahead of print. PMID: 36563047
Abstract: Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mito c ho nd r ia l c a lc ium unip o rte r c o mp le x (M C Uc ), while e fflu x occurs ma in ly through the mito c ho nd r ia l Na+/Ca2+ exchanger (N C LX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared to neurons. To assess the role of NCLX in mo us e p rima ry c ulture astrocytes, we inhib ited its functio n both pharmacologically or genetically. This re s ulte d in re -shaping of c yto s o lic C a2+ signa ling and a me ta b o lic s hift that increased glycolyt ic flux and lactate secretion in a C a2+-dependent manner. Interestingly, in v iv o genetic deletion of N CLX in hippocampal astrocytes improved cognit ive performance in behavioral tasks, whereas hippocampal neuron-specific deletion of NCLX imp a ire d cognitive performance. These results unveil a role for N CLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.
Funding: Authors were supported by grant #2020/06970–5 from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Centro de Pesquisa, Inovação e Difusão de Processos Redox em Biomedicina (CEPID Redoxoma, FAPESP grant #2013/07937–8); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) line 001; Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033, PDC2021-121013-I00 and RED2018‐102576‐T to JPB); Plan Nacional de Drogas (2020I028 to JPB); Instituto de Salud Carlos III (PI21/00727 and RD21/0006/0005 co-funded by the European Union FEDER/FSE+ and NextGenerationEU to AA); and Junta de Castilla y León(CS/151P20 co-funded by P.O. FEDER to AA; Apoyo Regional a la Competitividad Empresarial, ICE 04/18/LE/0017 to JPB, and Escalera de Excelencia CLU-2017-03 to JPB and AA). JVCC was also supported by FAPESP fellowships #2017/14713-0 and #2019/22178-2.