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

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.

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Along the same lines, HK is crucial for coupling glycolysis and mitochondrial oxidation [26]. HK dissociates from the mitochondrial surface upon Iduna-mediated PAR efflux from the nucleus [23][24][25], suggesting that PARP activation can in fact uncouple glycolysis and mitochondrial anabolism. Furthermore, HIF activation, that suppresses mitochondria and induces glycolysis (Warburgtype metabolism) and neoplastic transformation, is supported by PARP activation [60][61][62]64,66].…”

“…An acceptor of PAR on the mitochondrial surface is hexokinase (HK) [24,25]. HK binds to the mitochondrial surface, where it interacts with voltage-dependent anion channels and regulates ADP/ATP exchange between the cytosol and mitochondria.…”

Poly(ADP-Ribose) Polymerases in Aging - Friend or Foe?

“…HIFs) [44,45], 3) inhibiting mitochondrial membrane and membrane-associated enzymes (e.g. ANT, the hexokinase-ANT complex) by cytosolic PAR polymers [8,46,47], 4) impairs mitophagy and nuclear-mitochondrial protein balance [40,48].…”

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

“…Stimulated by DNA strand breaks, Parp1 consumes NAD + to form PAR chains on various nuclear proteins, including histones, polymerases, transcription factors, and Parp1 itself. Hyperactivation of Parp1 leads to defective glycolysis or cellular NAD + depletion, which consequently results in diminished cellular ATP, mitochondrial depolarization, and a bioenergetics collapse that ensures cell death (16,19,20). We assayed total NAD and ATP in hepatic tissue 24 h after I/R; total NAD and ATP were significantly decreased in WT mice 24 h after I/R, consistent with Parp1 hyperactivation, whereas Aag −/− mice only showed moderately decreased NAD and ATP levels that were not statistically significant (P > 0.05; Fig.…”