Sigma-1 receptor promotes glycolysis in neuronal systems by suppressing GRIM19.

Sigma-1 receptor (S1R) is a Ca2+ sensitive, ligand-operated receptor chaperone protein present at the mitochondria-associated ER membrane. The relevance of S1R to glycolysis in neurons is not known. This study examines the impact of S1R on glycolysis, mitochondrial activity, and NAD+/NADH metabolism in wild-type and S1R knockout (S1R KO) Neuro2a (N2a) cells and mice. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 (NDUFA13). Furthermore, we noted an increased NAD+/NADH ratio in S1R KO condition. PET-imaging revealed decreased [18F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking-down GRIM19 rescued the glycolysis deficit in S1R KO condition. Altogether, these data show that S1R modulates glycolysis and NAD metabolism in neuronal systems. This insight into S1R function may expand the therapeutic potential of S1R ligands in conditions associated with impaired glycolysis and altered cellular NAD+/NADH ratios, such as aging and neurodegenerative diseases.