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

被引:57
作者
Cooper, CE
Davies, NA
Psychoulis, M
Canevari, L
Bates, TE
Dobbie, MS
Casley, CS
Sharpe, MA
机构
[1] Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England
[2] Inst Neurol, Dept Neurochem, London WC1N 3BG, England
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS | 2003年 / 1607卷 / 01期
基金
英国惠康基金;
关键词
cytochrome c oxidase; nitric oxide; mitochondria; K-m; oxygen; peroxynitrite;
D O I
10.1016/j.bbabio.2003.08.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (muM) 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. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:27 / 34
页数:8
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