Poly(ADP‐ribose) mediates bioenergetic defects and redox imbalance in neurons following oxygen and glucose deprivation

• Published in: The FASEB journal 2024-03, Vol.38 (6), p.e23556-n/a
• Main Authors: Hossain, M. Iqbal, Lee, Jun Hee, Gagné, Jean‐Philippe, Khan, Junaid, Poirier, Guy G., King, Peter H., Dawson, Valina L., Dawson, Ted M., Andrabi, Shaida A.
• Format: Article
• Language: English
• Subjects: Animals; Brain Ischemia - metabolism; DPQ; Glucose - metabolism; Glycolysis; hexokinase; Hexokinase - genetics; Hexokinase - metabolism; ischemic stroke; Mice; mitochondria; Neurons - metabolism; Oxidation-Reduction; Oxygen - metabolism; PAR‐binding motif; pentose‐phosphate pathway; Poly Adenosine Diphosphate Ribose - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - metabolism; poly(ADP‐ribose)
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202302559R

PARP‐1 over‐activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP‐1 over‐activation can bind hexokinase‐1 (HK‐1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK‐1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose‐6‐phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK‐1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR‐mediated inhibition of HK‐1 results in bioenergetics defects and redox imbalance is not known. We used oxygen–glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP‐1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP‐1 and adenoviral‐mediated overexpression of wild‐type HK‐1 (wtHK‐1) and PAR‐binding mutant HK‐1 (pbmHK‐1). Our data show that PAR inhibition or overexpression of HK‐1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK‐1 during OGD drive bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function. Oxygen and glucose deprivation/ischemia–reperfusion leads to overactivation of PARP‐1, causing excessive generation PAR, which translocates to cytosol and binds proteins including HK‐1, resulting in its catalytic inhibition and dissociation from the mitochondria. These events lead to decreased glycolysis and subsequent mitochondrial dysfunction causing bioenergetic collapse. This process also results in redox imbalance via GSH/GSSG cycle by reduction of NADPH formation because of reduced pentose phosphate pathway function. Thus, targeting PAR/HK‐1 association posits a promising therapeutic approach in stroke.