Persistent S-Nitrosation of Complex I and Other Mitochondrial Membrane Proteins by S-Nitrosothiols but Not Nitric Oxide or Peroxynitrite
Open accessAbstract
S-nitrosation of mitochondrial proteins has been proposed to contribute to the pathophysiological interactions of nitric oxide (NO) and its derivatives with mitochondria but has not been shown directly. Furthermore, little is known about the mechanism of formation or the fate of these putative S-nitrosothiols. Here we have determined whether mitochondrial membrane protein thiols can be S-nitrosated on exposure to free NO from 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene (DETA-NONOate) by interaction with S-nitrosoglutathione or S-nitroso-N-acetylpenicillamine (SNAP) and by the NO derivative peroxynitrite. S-Nitrosation of protein thiols was measured directly by chemiluminescence detection. S-Nitrosoglutathione and S-nitroso-N-acetylpenicillamine led to extensive protein thiol oxidation, with about 30% of the modified protein thiols persistently S-nitrosated. In contrast, there was no protein thiol oxidation or S-nitrosation on exposure to 3,3-bis (aminoethyl)-1-hydroxy-2-oxo-1-triazene. Peroxynitrite extensively oxidized protein thiols but produced negligible amounts of S-nitrosothiols. Therefore, mitochondrial membrane protein thiols are S-nitrosated by preformed S-nitrosothiols but not by NO or by peroxynitrite. These S-nitrosated protein thiols were readily reduced by glutathione, so S-nitrosation will only persist when the mitochondrial glutathione pool is oxidized. Respiratory chain complex I was S-nitrosated by S-nitrosothiols, consistent with it being an important target for S-nitrosation during nitrosative stress. The S-nitrosation of complex I correlated with a significant loss of activity that was reversed by thiol reductants. S-Nitrosation was also associated with increased superoxide production from complex I. These findings point to a significant role for complex I S-nitrosation and consequent dysfunction during nitrosative stress in disorders such as Parkinson disease and sepsis.
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Prior work showed that complex I is inhibited by various nitric oxide donors in vitro and that this inhibition is associated with S-nitrosation.
“previous work has shown that complex I is inhibited by various nitric oxide donors in vitro and that this inhibition is associated with S-nitrosation2,10,11,21–24.”
From Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I (2013) · cites this paper as [23]
Mitochondria-selective S-nitrosating agent studies show that Complex I nitrosation protects during ischemia/reperfusion by reducing oxidative damage and tissue necrosis.
“Murphy and coworkers used a mitochondria-selective S-nitrosating agent to demonstrate that nitrosation of Complex I serves a protective role during ischemia/reperfusion by reducing oxidative damage and tissue necrosis [212, 213].”
From Signaling and stress: The redox landscape in NOS2 biology (2015) · cites this paper as [212]
S-nitrosothiols such as GSNO are better donors of NO· for transfer to redox-active thiols than other forms of NO· donors.
“Other studies of isolated mitochondria suggest that S-nitrosothiols such as GSNO are better donors of NO· for transfer to redox-active thiols than other forms of NO· donors (108).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [108]
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References 78 · Cited by 194
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- Authors
- Dahm, C. C., Moore, K., & Murphy, M. P.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- University College London (GB)
- Corresponding author
- Murphy, Michael P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 281
- Issue
- 15
- Pages
- 10056-10065
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2093935547
- Cited by
- 194
- References
- 78
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 15 · 2012: 13
- FWCI
- 8.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Mitochondrial Function and Pathology
- Keywords
- S-nitrosylation, S-nitrosothiols, respiratory chain complex I, mitochondrial membrane proteins, S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, nitric oxide, peroxynitrite, protein thiol oxidation, glutathione, nitrosative stress, superoxide production, Parkinson's disease, sepsis
- MeSH terms
- Animals, Disulfides, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Glutathione, Intracellular Membranes, Liver, Mitochondria, Mitochondria, Liver, Models, Chemical, Nitric Oxide, Nitroso Compounds, Oxygen Consumption, Parkinson Disease, Sulfhydryl Compounds, Superoxides, Time Factors, Immunoblotting, Nitrosation, Sepsis, S-Nitrosothiols, S-Nitroso-N-Acetylpenicillamine, Peroxynitrous Acid, Rats
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