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

Cooper, Chris E. and Davies, Nathan A. and Psychoulis, Minas and Canevari, Laura and Bates, Tim E. and Dobbie, Michael S. and Casley, Christopher S. and Sharpe, Martyn A. (2003) Nitric oxide and peroxynitrite cause irreversible increases in the K(m) for oxygen of mitochondrial cytochrome oxidase: in vitro and in vivo studies. Biochimica et Biophysica Acta: general subjects, 1607 (1). pp. 27-34. ISSN 0006-3002

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Item Type:Article
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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 K(m) 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 K(m). These include: treatment of the purified enzyme with peroxynitrite or high (microM) 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.

Keywords:NO, Nitric oxide, peroxynitrite, cytochrome oxidase, mitochondria
Subjects:C Biological Sciences > C730 Metabolic Biochemistry
A Medicine and Dentistry > A100 Pre-clinical Medicine
C Biological Sciences > C710 Applied Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C100 Biology
Divisions:College of Science > School of Life Sciences
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ID Code:5245
Deposited On:08 Jun 2013 08:57

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