Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Summary Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic MPC-ablation in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify a novel pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation. Highlights • Quiescent NSPCs have high levels of MPC and an active mitochondrial network • The import of pyruvate into mitochondria is necessary to maintain quiescence of NSPCs • MPC inhibition increases intracellular aspartate levels and triggers the activation of quiescent NSPCs • MPC-knockout NSPCs generate mature newborn neurons, leading to overall increased neurogenesis in adult and advanced age mice Graphical abstract