Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-07, Vol.111 (28), p.10209-10214
• Main Authors: Andrabi, Shaida A., Umanah, George K. E., Chang, Calvin, Stevens, Daniel A., Karuppagounder, Senthilkumar S., Gagné, Jean-Philippe, Poirier, Guy G., Dawson, Valina L., Dawson, Ted M.
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Animals; Antibodies; Apoptosis; Biological Sciences; Cell death; Cells; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - enzymology; Cultured cells; Energy metabolism; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzymes; Glucose - metabolism; Glucose-6-Phosphate - metabolism; Glycolysis; Glycolysis - drug effects; Glycolysis - physiology; Hexokinase - metabolism; Kinases; Lactates; Metabolism; Methylnitronitrosoguanidine - pharmacology; Mice; Mitochondria; Mitochondria - enzymology; NAD - metabolism; Nerve Tissue Proteins - metabolism; Neurons; Neurons - cytology; Neurons - enzymology; Oligomycins; Piperidines - pharmacology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Respiration
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405158111

Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated “parthanatos” in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD ⁺ and energetic collapse, which have been thought to be caused by the consumption of cellular NAD ⁺ by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD ⁺ depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD ⁺ depletion in N -methyl- N -nitroso- N -nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1–mediated mitochondrial dysfunction. Depleting neurons of NAD ⁺ with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.