Nitroxia: The pathological consequence of dysfunction in the nitric oxide–cytochrome c oxidase signaling pathway
Abstract
It is now recognized that mitochondria play an integral role in orchestrating the response of the cell to a wide variety of metabolic and environmental stressors. Of particular interest are the interactions of reactive oxygen and nitrogen species with the organelle and their potential regulatory function. The best understood example is the O(2) sensitive binding of NO (nitric oxide) to the heme group in cytochrome c oxidase. We have proposed that this reversible process serves the function of both regulating the formation of hydrogen peroxide from the respiratory chain for the purposes of signal transduction and controlling O(2) gradients in complex organs such as the liver or heart. It now appears that maladaptation in this pathway leads to a mitochondrial dysfunction which has some of the characteristics of hypoxia, such as a deficit in ATP, but occurs in the presence of normal or enhanced levels of O(2). These are the optimal conditions for the formation of reactive nitrogen species (RNS), such as peroxynitrite which lead to the irreversible modification of proteins. We term this unique pathological condition Nitroxia and describe how it may contribute to the pathology of chronic inflammatory diseases using ethanol-dependent hepatotoxicity as an example.
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NO is a better inhibitor of respiration in mitochondria that are actively respiring and at low oxygen tensions.
“NO is a better inhibitor of respiration in mitochondria that are actively respiring and at low oxygen tensions (13, 54).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [54]
Both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with increased hypoxia.
“Recently, we have shown that both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with increased sensitivity of the respiratory chain to inhibition by NO, increased hypoxia, and protein nitration (54, 68, 69).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [54]
Both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with protein nitration.
“Recently, we have shown that both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with increased sensitivity of the respiratory chain to inhibition by NO, increased hypoxia, and protein nitration (54, 68, 69).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [54]
Interaction of NO with CcOx is competitive with O2.
“However, unlike sGC, the interaction of NO with CcOx is competitive with O2 (13, 54).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [54]
Both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with increased sensitivity of the respiratory chain to inhibition by NO.
“Recently, we have shown that both alcoholic steatohepatitis and nonalcoholic steatohepatitis are associated with increased sensitivity of the respiratory chain to inhibition by NO, increased hypoxia, and protein nitration (54, 68, 69).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [54]
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References 79 · Cited by 112
- Authors
- Shiva, S., Oh, J.-Y., Landar, A. L., Ulasova, E., Venkatraman, A., Bailey, S. M., & Darley-Usmar, V. M.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Darley-Usmar, Victor M.
- ORCID
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 38
- Issue
- 3
- Pages
- 297-306
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2086251702
- Cited by
- 112
- References
- 79
- Citations by year
- 2024: 1 · 2022: 2 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 8
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r21aa013682-03)
- National Institute on Alcohol Abuse and Alcoholism (AA13682, R01AA013395, AA-13395)
- National Heart, Lung, and Blood Institute (P01HL070610, HL 070610)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide, cytochrome c oxidase, mitochondrial dysfunction, reactive nitrogen species, peroxynitrite, hydrogen peroxide, oxygen gradients, hypoxia, ATP deficiency, chronic inflammatory diseases, reactive oxygen species, protein nitration
- MeSH terms
- Ethanol, Animals, Electron Transport Complex IV, Hepatitis, Alcoholic, Liver, Mitochondria, Nitric Oxide, Oxidation-Reduction, Signal Transduction, Reactive Oxygen Species, Cell Respiration
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