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

Fecha de publicación: 01/05/2023 Fecha Ahead of Print: 01/01/2023

Autores de IBSAL

• Carlos Vicente Gutiérrez

  Autor

• Jesús Agulla Freire

  Autor

• Rebeca Lapresa Ruiz De Gauna

  Autor

• 

  Ángeles Almeida Parra

  Autor

• 

  Juan Pedro Bolaños Hernández

  Autor

Autores ajenos a IBSAL

• Cabral-Costa, JV
• Elrod, JW
• Kowaltowski, AJ

Grupos

• IIMD-14 - Neuroenergética y Metabolismo

  

  Investigador Principal

  Juan Pedro Bolaños Hernández

• NEUR-03 - Neurobiología Molecular

  

  Investigador Principal

  Ángeles Almeida Parra

Abstract

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.

Keywords

• astrocyte; brain metabolism; calcium transport; energy metabolism; glycolysis; lactate; metabolic regulation; mitochondrial metabolism; NCLX; sodium transport; sodium-calcium exchange