Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway.
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.
Almeida
Angeles
A
Unidad de Investigación, Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
Moncada
Salvador
S
Bolaños
Juan P
JP
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D005333:Fetus; D006019:Glycolysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010732:Phosphofructokinase-1 / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D025481:Phosphofructokinase-2; D010732:Phosphofructokinase-1; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases