Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis
Open accessAbstract
Significance: Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety of organ systems. It has long been thought that the cell death caused by excessive activation of PARP occurs through the catalytic consumption of NAD + followed by reduction of ATP and bioenergetic collapse. This study shows that the bioenergetic collapse is caused not by the consumption of NAD + but by PAR-dependent inhibition of hexokinase activity leading to defects in glycolysis. These results are consistent with the notion that cell death induced by excessive PARP activity (parthanatos) is an active cell-death program that is initiated by PAR signaling.
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HK1 binding to poly(ADP-ribose) polymers inhibits glycolysis to cause a bioenergetic collapse that precipitates RCD.
“hexokinase 1 (HK1), whose binding to poly(ADP-ribose) polymers inhibits glycolysis to cause a bioenergetic collapse that precipitates RCD [680, 681].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [680]
Excessive PARP1 activation induces ATP depletion via PAR-dependent inhibition of hexokinase, causing dysfunctional glycolysis, likely independently of NAD+ depletion.
“Notably, excessive PARP1 activation induces ATP depletion through PAR-dependent inhibition of hexokinase activity, resulting in dysfunctional glycolysis, a mechanism likely independent of NAD+ depletion (Andrabi et al., 2014; Fouquerel et al., 2014).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Andrabi et al., 2014
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- Authors
- Andrabi, S. A., Umanah, G. K. E., Chang, C., Stevens, D. A., Karuppagounder, S. S., Gagné, J.-P., Poirier, G. G., Dawson, V. L., & Dawson, T. M.
- Affiliations
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,
- Johns Hopkins University (US)
- Université Laval (CA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-07
- Volume
- 111
- Issue
- 28
- Pages
- 10209-10214
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4104885
- OpenAlex
- W2095061901
- Cited by
- 307
- References
- 40
- Citations by year
- 2026: 9 · 2025: 24 · 2024: 23 · 2023: 28 · 2022: 20 · 2021: 31 · 2020: 30 · 2019: 26 · 2018: 32 · 2017: 28 · 2016: 28 · 2015: 18 · 2014: 9 · 2013: 1
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute on Drug Abuse (P50DA000266, DA000266)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079637)
- National Institute of Neurological Disorders and Stroke (NS 38377, NS067525, R37NS067525, P50NS038377, R01NS067525)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- PARP1, parthanatos, hexokinase inhibition, glycolysis, NAD+ depletion, apoptosis-inducing factor, mitochondrial dysfunction, cortical neurons, visfatin, pyruvate, glutamine
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Acrylamides, Animals, Cells, Cultured, Cerebral Cortex, Enzyme Activation, Glucose, Glycolysis, Hexokinase, Methylnitronitrosoguanidine, Mitochondria, NAD, Nerve Tissue Proteins, Neurons, Piperidines, Poly(ADP-ribose) Polymerases, Glucose-6-Phosphate, Mice
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