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Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10209-14. doi: 10.1073/pnas.1405158111. Epub 2014 Jul 1.

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

Author information

1
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Departments of Neurology, sandrabi@jhmi.edu vdawson@jhmi.edu tdawson@jhmi.edu.
2
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Departments of Neurology.
3
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Biomedical Engineering.
4
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
5
Centre de Recherche du CHU de Québec, Université Laval, Québec, Canada G1V 4G2.
6
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Departments of Neurology,Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; andPhysiology, and sandrabi@jhmi.edu vdawson@jhmi.edu tdawson@jhmi.edu.
7
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,Departments of Neurology,Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; andPharmacology and Molecular Sciences, and sandrabi@jhmi.edu vdawson@jhmi.edu tdawson@jhmi.edu.

Abstract

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.

PMID:
24987120
PMCID:
PMC4104885
DOI:
10.1073/pnas.1405158111
[Indexed for MEDLINE]
Free PMC Article
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