Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology
Abstract
Nitric oxide (NO) is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron ( a 3) and copper (Cu B) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a 3) and oxygen-independent (at Cu B) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct “metabolic” effects on oxygen consumption or via indirect “signaling” effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited.
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The high affinity and rapid binding of NO to ferrous heme are important biologically for activation of sGC to generate cGMP.
“The high affinity and rapid binding to ferrous heme are important biologically for the activation of sGC to generate the second messenger cGMP and the regulation of mitochondrial respiration at CcOx (9–16).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [13]
The high affinity and rapid binding of NO to ferrous heme are important biologically for regulation of mitochondrial respiration at CcOx.
“The high affinity and rapid binding to ferrous heme are important biologically for the activation of sGC to generate the second messenger cGMP and the regulation of mitochondrial respiration at CcOx (9–16).”
From What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology (2010) · cites this paper as [13]
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 [13]
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 [13]
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What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology
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- Authors
- Cooper, C. E., & Giulivi, C.
- Affiliations
- University of Essex (GB)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2007-06
- Volume
- 292
- Issue
- 6
- Pages
- C1993-C2003
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2142137775
- Cited by
- 176
- References
- 96
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 15 · 2014: 12 · 2013: 16 · 2012: 11
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (069769)
- Biotechnology and Biological Sciences Research Council (BB/D017858/1)
- National Institute of Environmental Health Sciences (ES-005707)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- nitric oxide, cytochrome c oxidase, mitochondrial oxygen consumption, heme a3, mitochondrial redox signaling, free radical generation, soluble guanylate cyclase, NO synthase inhibition, tissue physiology
- MeSH terms
- Animals, Mitochondria, Models, Biological, Nitric Oxide, Oxygen
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