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 vivo 1H 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.
Bibliographical noteFunding Information:
We would like to thank Shabnam Pooya and Janvi Gandhi for assisting with western blots, Oluwadamilola Omojola for performing genotyping PCR, and Ashwini Hinge for assistance with fluorescence-activated cell sorting (FACS) analysis. We thank Matthew Kofron of CCHMC Microscopy Core for assistance with imaging. This work was supported by National Institutes of Health (NIH) grants R01 NS075291 and R01 NS099162 (to B.D.), R01 MH115058 (to M.K.), and R01 NS092705 (to C.G.). The Center for Magnetic Resonance Research at the University of Minnesota is supported by NIH grants P41 EB015894 and P30 NS076408 .
© 2020 The Author(s)
- AMP kinase
- astrocyte-neuron lactate shuttle
- brain metabolism
- glucose flux
- proton spectroscopy