Nitric oxide and peroxynitrite cause irreversible increases in the K m for oxygen of mitochondrial cytochrome oxidase: In vitro and in vivo studies

Chris E. Cooper, Nathan A. Davies, Minas Psychoulis, Laura Canevari, Tim E. Bates, Michael S. Dobbie, Christopher S. Casley, Martyn A. Sharpe

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Mitochondrial cytochrome oxidase is competitively and reversibly inhibited by inhibitors that bind to ferrous heme, such as carbon monoxide and nitric oxide. In the case of nitric oxide, nanomolar levels inhibit cytochrome oxidase by competing with oxygen at the enzyme's heme-copper active site. This raises the Km for cellular respiration into the physiological range. This effect is readily reversible and may be a physiological control mechanism. Here we show that a number of in vitro and in vivo conditions result in an irreversible increase in the oxygen Km. These include: treatment of the purified enzyme with peroxynitrite or high (μM) levels of nitric oxide; treatment of the endothelial-derived cell line, b.End5, with NO; activation of astrocytes by cytokines; reperfusion injury in the gerbil brain. Studies of cell respiration that fail to vary the oxygen concentration systematically are therefore likely to significantly underestimate the degree of irreversible damage to cytochrome oxidase.

Original languageEnglish (US)
Pages (from-to)27-34
Number of pages8
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1607
Issue number1
DOIs
StatePublished - Oct 17 2003

Keywords

  • Cytochrome c oxidase
  • K
  • Mitochondria
  • Nitric oxide
  • Oxygen
  • Peroxynitrite

ASJC Scopus subject areas

  • Biophysics

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