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

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After inhibition of cytochrome c oxidase by nitric oxide1,2,3, astrocytes maintain energy production by upregulating glycolysis4,5 — 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 glycolysis6, and an increase in the concentration of its most powerful positive allosteric activator7, fructose-2,6-bisphosphate (F2,6P2). In neurons, nitric oxide failed to alter F2,6P2 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 F2,6P2 biosynthesis8) 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) strategy9, 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 degeneration4,5,10.

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Figure 1: Nitric oxide activates glycolysis through PFK1.
Figure 2: Nitric oxide triggers allosteric PFK1 activation through PFK2.
Figure 3: Activation of glycolysis by nitric oxide is cyclic GMP-independent and may involve AMPK phosphorylation.
Figure 4: AMPK mediates nitric oxide-dependent glycolytic activation and prevents apoptotic cell death.

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This work was funded by FIS (A.A.), Fundación CNIC (S.M.) and Ministerio de Ciencia y Tecnología (SAF2001/1961; J.P.B.). S.M. is partially funded by the Medical Research Council (U.K.). Technical assistance from M. Delgado-Esteban and M. Resch (CNIC, Spain) and M. C. Alguero (Hospital Universitario de Salamanca, Spain) are greatly appreciated. We are grateful to A. Higgs for critical evaluation of this paper.

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Correspondence to Salvador Moncada.

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