ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD + Depletion

Abstract

Summary ARTD1 (PARP1) is a key enzyme involved in DNA repair by synthesizing poly(ADP-ribose) (PAR) in response to strand breaks and plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD+ depletion and ATP loss, however the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we directly compared the effects of ARTD1 activation and direct NAD+ depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD+ depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics based PAR-interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing new insight on the importance of nucleus to mitochondria communication via ARTD1 activation.

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.…”

NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects

“…These results indicated that impaired mitochondrial respiration was the consequence of lower pyruvate availability in response to glycolysis inhibition [160,161].…”

“…First, the hypothesis that pyruvate is diverted away from mitochondrial respiration towards lactate dehydrogenase will have to be tested. Failure of mitochondrial respiration resulting from PARP1 activation is rescued by addition of pyruvate [160,161].…”

FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration

“…11 Overactivation of PARP1 by extensive DNA damage quickly depletes intracellular NAD + and inhibits glycolysis through the PAR-dependent inhibition of hexokinase 1, leading to bioenergetic collapse and regulated necrosis. [12][13][14] In addition, excess PAR polymers generated by PARP1 result in the depolarization of the mitochondrial membrane potential and the translocation of apoptosisinducing factor (AIF) from the mitochondria to the nucleus, leading to chromatin condensation and large-scale DNA fragmentation. 15,16 Such biochemical events lead to PARP1-mediated necrosis, specifically named parthanatos.…”