AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival
Ranjithmenon Muraleedharan, Mruniya V. Gawali, Durgesh Tiwari, Abitha Sukumaran, Nicole Oatman, Jane L. Anderson, Diana Nardini, Mohammad Alfrad Nobel Bhuiyan, Ivan Tkáč, Amber L. Ward, Mondira Kundu, Ronald R. Waclaw, Lionel M.L. Chow, Christina Groß, Raghavendra Rao, Stefanie Schirmeier, Biplab Dasgupta
Abstract
C 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.