Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway

Nat Cell Biol. 2004 Jan;6(1):45-51. doi: 10.1038/ncb1080. Epub 2003 Dec 14.


After inhibition of cytochrome c oxidase by nitric oxide, astrocytes maintain energy production by upregulating glycolysis--a response which does not seem to be available to neurons. Here, we show that in astrocytes, after inhibition of respiration by nitric oxide, there is a rapid, cyclic GMP-independent increase in the activity of 6-phosphofructo-1-kinase (PFK1), a master regulator of glycolysis, and an increase in the concentration of its most powerful positive allosteric activator, fructose-2,6-bisphosphate (F2,6P(2)). In neurons, nitric oxide failed to alter F2,6P(2) concentration or PFK1 activity. This failure could be accounted for by the much lower amount of 6-phosphofructo-2-kinase (PFK2, the enzyme responsible for F2,6P(2) biosynthesis) in neurons. Indeed, full activation of neuronal PFK1 was achieved by adding cytosol from nitric oxide-treated astrocytes. Furthermore, using the small interfering RNA (siRNA) strategy, we demonstrated that the rapid activation of glycolysis by nitric oxide is dependent on phosphorylation of the energy charge-sensitive AMP-activated protein kinase, resulting in activation of PFK2 and protection of cells from apoptosis. Thus the virtual absence of PFK2 in neurons may explain their extreme sensitivity to energy depletion and degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Animals, Newborn
  • Astrocytes / metabolism*
  • Brain Chemistry / physiology
  • Cell Survival / physiology
  • Cells, Cultured
  • Energy Metabolism / physiology
  • Fetus
  • Glycolysis / physiology*
  • Mice
  • Mice, Knockout
  • Multienzyme Complexes / metabolism*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Neurons / metabolism*
  • Nitric Oxide / metabolism*
  • Phosphofructokinase-1 / metabolism
  • Phosphofructokinase-2 / deficiency
  • Phosphofructokinase-2 / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering
  • Rats
  • Rats, Wistar
  • Signal Transduction / physiology


  • Multienzyme Complexes
  • RNA, Small Interfering
  • Nitric Oxide
  • Phosphofructokinase-2
  • Phosphofructokinase-1
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases