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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ranjithmenon Muraleedharan - (Author)
  • Mruniya V. Gawali - (Author)
  • Durgesh Tiwari - (Author)
  • Abitha Sukumaran - (Author)
  • Nicole Oatman - (Author)
  • Jane Anderson - (Author)
  • Diana Nardini - (Author)
  • Mohammad Alfrad Nobel Bhuiyan - (Author)
  • Ivan Tkáč - (Author)
  • Amber Lynne Ward - (Author)
  • Mondira Kundu - (Author)
  • Ronald Waclaw - (Author)
  • Lionel M. Chow - (Author)
  • Christina Gross - (Author)
  • Raghavendra Rao - (Author)
  • Stefanie Schirmeier - , Chair of Zoology and Animal Physiology (Author)
  • Biplab Dasgupta - (Author)

Abstract

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.

Details

Original languageEnglish
JournalCell reports
Volume32
Issue number9
Publication statusPublished - 1 Sept 2020
Peer-reviewedYes

External IDs

PubMed 32877674
Scopus 85090019766

Keywords

Keywords

  • AMP kinase, GLUT1, TXNIP, astrocyte-neuron lactate shuttle, brain metabolism, glucose flux, glycolysis, proton spectroscopy