AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival

Lactate is used as an energy source by producer cells or shuttled to neighboring cells and tissues. Both glucose and lactate fulfill the bioenergetic demand of neurons, the latter imported from astrocytes. The contribution of astrocytic lactate to neuronal bioenergetics and the mechanisms of astrocytic lactate production are incompletely understood. Through in vivo1H magnetic resonance spectroscopy, 13C glucose mass spectroscopy, and electroencephalographic and molecular studies, here we show that the energy sensor AMP activated protein kinase (AMPK) regulates neuronal survival in a non-cell-autonomous manner. Ampk-null mice are deficient in brain lactate and are seizure prone. Ampk deletion in astroglia, but not neurons, causes neuronal loss in both mammalian and fly brains. Mechanistically, astrocytic AMPK phosphorylated and destabilized thioredoxin-interacting protein (TXNIP), enabling expression and surface translocation of the glucose transporter GLUT1, glucose uptake, and lactate production. Ampk loss in astrocytes causes TXNIP hyperstability, GLUT1 misregulation, inadequate glucose metabolism, and neuronal loss. [Display omitted] •AMPK deletion reduces energy metabolites, including lactate, in the rodent brain•AMPK regulates astrocytic glycolysis and astrocyte-neuron lactate shuttle (ANLS)•Glia or neural stem cell AMPK deletion causes neuronal loss in rodent and fly brains•AMPK destabilizes TXNIP to enable GLUT1 localization, glucose import, and glycolysis Muraleedharan et al. demonstrate that AMPK is required for astrocytic glycolysis, lactate production, and lactate shuttle as an energy source to neurons such that AMPK loss in glia causes non-cell-autonomous neuronal loss in the mammalian and fly brain.