Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK

Nature. 2017 Aug 3;548(7665):112-116. doi: 10.1038/nature23275. Epub 2017 Jul 19.

Abstract

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Diphosphate / metabolism
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Axin Protein / metabolism
  • Binding Sites
  • Enzyme Activation
  • Fibroblasts
  • Fructose-Bisphosphate Aldolase / genetics
  • Fructose-Bisphosphate Aldolase / metabolism*
  • Fructosediphosphates / metabolism*
  • Glucose / deficiency
  • Glucose / metabolism*
  • Humans
  • Male
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • Axin Protein
  • Fructosediphosphates
  • Adenosine Monophosphate
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Adenosine Triphosphatases
  • Fructose-Bisphosphate Aldolase
  • Glucose
  • fructose-1,6-diphosphate