MPC Inhibition Activates Neural Stem Cells to Increase Neurogenesis
Stem cells spend much of their time quiescent, only intermittently activating to produce daughter somatic cells. Some well studied populations of stem cells are known to become increasingly quiescent with age, a response to some mix of internal damage and altered signaling environment that arises due to chronic inflammation and other age-related issues. Researchers here report on a way to force neural stem cells back into greater activity, increasing the pace at which new neurons are generated. Since this process of neurogenesis declines with age, contributing to loss of cognitive function, there is considerable interest in finding ways to increase neurogenesis in the aged brain.
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 and oxidative phosphorylation. 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 Mpc1 ablation in vitro and 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 an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.