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

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...

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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:	eng
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
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Summary:	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.
ISSN:	0027-8424 1091-6490