Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention
Abstract
Peroxynitrite is formed in biological systems when superoxide and nitric oxide are produced at near equimolar ratio. Although not a free radical by chemical nature (as it has no unpaired electron), peroxynitrite is a powerful oxidant exhibiting a wide array of tissue damaging effects ranging from lipid peroxidation, inactivation of enzymes and ion channels via protein oxidation and nitration to inhibition of mitochondrial respiration. Low concentrations of peroxynitrite trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as switch between the two modes of cell death. Peroxynitrite also damages DNA and thus triggers the activation of DNA repair systems. A DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) also becomes activated upon sensing DNA breakage. Activated PARP-1 cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced overactivation of PARP consumes NAD(+) and consequently ATP culminating in cell dysfunction, apoptosis or necrosis. This cellular suicide mechanism has been implicated among others in the pathomechanism of stroke, myocardial ischemia, diabetes and diabetes-associated cardiovascular dysfunction. Here, we review the cytotoxic effects (apoptosis and necrosis) of peroxynitrite focusing on the role of accelerated ADP-ribose turnover. Regulatory mechanisms of peroxynitrite-induced cytotoxicity such as antioxidant status, calcium signalling, NFkappaB activation, protein phosphorylation, cellular adaptation are also discussed.
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High concentrations of NO can react with superoxide anion to produce peroxynitrite, which is involved in several disorders including lipid peroxidation, membrane destabilization, oxidation, protein nitration, and DNA damage.
“In high concentrations NO can react with superoxide anion and produce potentially harmful peroxynitrite (Peluffo and Radi 2007), which is involved in the genesis of several disorders including induced lipid peroxidation, membrane destabilization (Virág et al. 2003), oxidation, protein nitration, and DNA damage (Ippoushi et al. 2009).”
From Evaluation of chemical constituents and antioxidant activity of coconut water (Cocus nucifera L.) and caffeic acid in cell culture (2013) · cites this paper as Virág et al. 2003
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- Authors
- Virág, L., Szabó, É., Gergely, P., & Szabó, C.
- Affiliations
- University of Debrecen (HU)
- Semmelweis University (HU)
- Corresponding author
- Virág, László
- Venue
- Toxicology Letters
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 140-141
- Pages
- 113-124
- ISSN
- 0378-4274 (ISSN-L)
- OpenAlex
- W1968130780
- Cited by
- 460
- References
- 88
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 14 · 2022: 18 · 2021: 10 · 2020: 25 · 2019: 19 · 2018: 23 · 2017: 14 · 2016: 19 · 2015: 16 · 2014: 14 · 2013: 18 · 2012: 21
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology Letters (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- Funders
- Hungarian Scientific Research Fund
- National Institute of General Medical Sciences (R01GM060915)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- peroxynitrite, cytotoxicity, apoptosis, necrosis, superoxide, nitric oxide, ADP-ribosylation, PARP1, NAD+ depletion, ATP depletion, DNA damage, DNA repair, lipid peroxidation, protein nitration, mitochondrial respiration, stroke, myocardial ischemia, diabetes mellitus, antioxidant status, calcium signaling, NF-κB, protein phosphorylation, cellular adaptation
- MeSH terms
- Animals, Humans, Poly(ADP-ribose) Polymerases, Apoptosis, Peroxynitrous Acid
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