Inactivation of nitric oxide by cytochrome c oxidase under steady-state oxygen conditions
Open accessAbstract
We have developed a respiration chamber that allows intact cells to be studied under controlled oxygen (O(2)) conditions. The system measures the concentrations of O(2) and nitric oxide (NO) in the cell suspension, while the redox state of cytochrome c oxidase is continuously monitored optically. Using human embryonic kidney cells transfected with a tetracycline-inducible NO synthase we show that the inactivation of NO by cytochrome c oxidase is dependent on both O(2) concentration and electron turnover of the enzyme. At a high O(2) concentration (70 microM), and while the enzyme is in turnover, NO generated by the NO synthase upon addition of a given concentration of l-arginine is partially inactivated by cytochrome c oxidase and does not affect the redox state of the enzyme or consumption of O(2). At low O(2) (15 microM), when the cytochrome c oxidase is more reduced, inactivation of NO is decreased. In addition, the NO that is not inactivated inhibits the cytochrome c oxidase, further reducing the enzyme and lowering O(2) consumption. At both high and low O(2) concentrations the inactivation of NO is decreased when sodium azide is used to inhibit cytochrome c oxidase and decrease electron turnover.
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Recent data suggest that many biologic effects of nitrite involve interaction with mitochondria.
“Recent data suggest that many of the biologic effects of nitrite involve interaction with mitochondria.124,125”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [125]
This mechanism also prevents mitochondrial permeability transition pore opening and cytochrome c release, which are mechanisms involved in apoptosis.
“This mechanism also prevents mitochondrial permeability transition pore opening and cytochrome c release, which are mechanisms involved in apoptosis.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [125]
Nitrite-mediated protection occurs through reversible inhibition of mitochondrial complex I, which dampens electron transfer to the respiratory chain, thereby decreasing production of oxygen radicals.
“They show that nitrite-mediated protection occurs through reversible inhibition of mitochondrial complex I, which dampens electron transfer to the respiratory chain, thereby decreasing the production of oxygen radicals.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [125]
Shiva et al. identified mitochondria as targets for nitrite-mediated protection.
“Although the mechanism of nitrate-nitrite-mediated cytoprotection is not fully elucidated, Shiva et al. have identified the mitochondria as targets for protection.125”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [125]
Nitric oxide is a mediator of the ischemic preconditioning cell survival program, and nitrate administered as long as 24 h before injury was also protective.
“It has been shown that nitric oxide is a mediator of the ischemic preconditioning cell survival program, 154 and it is worth noting that Shiva et al. found that nitrate administered as long as 24 h before injury was also protective.125”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [125]
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“This is in contrast with studies in which an increase in [NO] at low [O2]was also observed, butwas attributed to the conversion of NO2 − to NO by either cytochrome c oxidase itself [37,38], cytochrome bc1 (mitochondrial complex III) [39,40] or other cytosolic enzymes [41-43] under hypoxic conditions.”
ResultNitric Oxide and Mitochondrial Signaling: From Physiology to Pathophysiology
Erusalimsky, J. D., & Moncada, S. (2007) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.107.151167 · Cited by 336 · see citing works
Self-citationCharacterization of the Magnitude and Kinetics of Xanthine Oxidase-catalyzed Nitrite Reduction
Li, H., Samouilov, A., Liu, X., & Zweier, J. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011648200 · Cited by 280 · see citing works
Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia
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On the Biologic Role of the Reaction of NO with Oxidized Cytochrome <i>c</i> Oxidase
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Roles of dietary inorganic nitrate in cardiovascular health and disease
Lundberg, J. O., Carlström, M., Larsen, F. J., & Weitzberg, E. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq325 · Cited by 355 · see citing works
Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care
Weitzberg, E., Hezel, M., Lundberg, J. O., & Warner, D. S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181fcf3cc · Cited by 145 · see citing works
- Authors
- Unitt, D. C., Hollis, V. S., Palacios-Callender, M., Frakich, N., & Moncada, S.
- Affiliations
- University College London (GB)
- Corresponding author
- Moncada, Salvador
- ORCID
- Moncada, Salvador
- Venue
- Biochimica et Biophysica Acta (BBA) - Bioenergetics
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 1797
- Issue
- 3
- Pages
- 371-377
- ISSN
- 0005-2728 (ISSN-L)
- OpenAlex
- W2133438264
- Cited by
- 21
- References
- 7
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 1
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- nitric oxide inactivation, cytochrome c oxidase, oxygen concentration, nitric oxide synthase, human embryonic kidney cells, respiration chambers, oxygen consumption, sodium azide, L-arginine
- MeSH terms
- Arginine, Cells, Cultured, Electron Transport Complex IV, Humans, Kidney, Nitric Oxide, Oxidation-Reduction, Oxygen, Oxygen Consumption, Cell Respiration, Nitric Oxide Synthase Type II
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