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Cited by 121Mitochondrial Function and PathologyRedox biology and oxidative stressNitric Oxide and Endothelin Effects

Oxygen-regulated isoforms of cytochrome c oxidase have differential effects on its nitric oxide production and on hypoxic signaling

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Castello, Pablo R., Woo, Dong Kyun, Ball, Kerri, Wojcik, Jay, Liu, Laura, Poyton, Robert O.·2008·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0709461105PMC PMC2448815
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Abstract

Recently, it has been reported that mitochondria possess a novel pathway for nitric oxide (NO) synthesis. This pathway is induced when cells experience hypoxia, is nitrite (NO(2)(-))-dependent, is independent of NO synthases, and is catalyzed by cytochrome c oxidase (Cco). It has been proposed that this mitochondrially produced NO is a component of hypoxic signaling and the induction of nuclear hypoxic genes. In this study, we examine the NO(2)(-)-dependent NO production in yeast engineered to contain alternative isoforms, Va or Vb, of Cco subunit V. Previous studies have shown that these isoforms have differential effects on oxygen reduction by Cco, and that their genes (COX5a and COX5b, respectively) are inversely regulated by oxygen. Here, we find that the Vb isozyme has a higher turnover rate for NO production than the Va isozyme and that the Vb isozyme produces NO at much higher oxygen concentrations than the Va isozyme. We have also found that the hypoxic genes CYC7 and OLE1 are induced to higher levels in a strain carrying the Vb isozyme than in a strain carrying the Va isozyme. Together, these results demonstrate that the subunit V isoforms have differential effects on NO(2)(-)-dependent NO production by Cco and provide further support for a role of Cco in hypoxic signaling. These findings also suggest a positive feedback mechanism in which mitochondrially produced NO induces expression of COX5b, whose protein product then functions to enhance the ability of Cco to produce NO in hypoxic/anoxic cells.

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  • Cytochrome c oxidase has been proposed to reduce nitrite following a mechanism similar to Hb.

    “Cytochrome c oxidase has been proposed to reduce nitrite following a mechanism similar to Hb [78, 79].”

    From Mechanisms of nitrite bioactivation (2014) · cites this paper as [79]

  • Using maximum measured rates of NO production with 1 mM nitrite and assuming the rate of production is roughly linear down to a nitrite concentration of 10 μM, the rate of NO production from cytochrome c oxidase could be roughly estimated to be 1.5 nM/s in anoxia and less at higher oxygen concentrations.

    “Using maximum measured rates of NO production with 1 mM nitrite [79]and assuming the rate of production is roughly linear down to a nitrite concentration of 10 μM, the rate of NO production from cytochrome c oxidase could be roughly estimated to be 1.5 nM/s in anoxia and less at higher oxygen concentrations.”

    From Mechanisms of nitrite bioactivation (2014) · cites this paper as [79]

  • The rate of NO production by cytochrome c oxidase increases at lower oxygen concentration and depends on the subunit 5 isozyme.

    “The rate of NO production increases at lower oxygen concentration and depends on the subunit 5 isozyme [79].”

    From Mechanisms of nitrite bioactivation (2014) · cites this paper as [79]

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Research works printed but not linked: 7

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Authors
Castello, P. R., Woo, D. K., Ball, K., Wojcik, J., Liu, L., & Poyton, R. O.
Affiliations
  • University of Colorado Boulder (US)
  • University of California, Los Angeles (US)
  • Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2008-06-17
Volume
105
Issue
24
Pages
8203-8208
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0709461105
PMC
PMC2448815
OpenAlex
W2137992270
Cited by
121
References
84
Citations by year
2026: 3 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 12 · 2014: 9 · 2013: 12 · 2012: 10
FWCI
5.21
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (GM 30228, R01GM030228)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
cytochrome c oxidase, nitric oxide production, hypoxia signaling, oxygen regulation, COX5A, COX5B, hypoxic gene expression, OLE1, yeast, positive feedback loop
MeSH terms
Electron Transport Complex IV, Hemeproteins, Isoenzymes, Mitochondria, Nitric Oxide, Oxygen, Saccharomyces cerevisiae, Stearoyl-CoA Desaturase, Signal Transduction, Reactive Oxygen Species, Mitochondrial Proteins, Saccharomyces cerevisiae Proteins, Fatty Acid Desaturases, Cytochromes c2, Dioxygenases

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