Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology
Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology
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DOI：
10.1152/ajpcell.00310.2006
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发表时间：
2007-06-01
影响因子：
5.5
通讯作者：
Giulivi, Cecilia
中科院分区：
文献类型：
--
作者：
Cooper, Chris E.;Giulivi, Cecilia
一氧化氮（NO）是一种细胞间信号分子;在其许多不同的作用中，通过激活血红素酶（可溶性鸟苷酸环化酶）来控制血流和血压。越来越多的证据表明，NO的另一个靶点是线粒体耗氧血红素/铜酶，细胞色素c氧化酶。本文综述了这种相互作用的分子机制及其可能的生理作用的后果。细胞色素氧化酶中的氧反应位点含有血红素铁（a（3））和铜（Cu-B）中心。NO以氧竞争性（在血红素a（3）处）和氧非依赖性（在Cu-B处）方式抑制细胞色素氧化酶。在抑制氧消耗之前，可以观察到酶和底物（细胞色素c）氧化还原状态的变化。生理后果可以通过对氧消耗的直接“代谢”效应或通过线粒体氧化还原状态变化和自由基产生的间接“信号”效应来介导。详细的动力学表明，但不能证明，细胞色素氧化酶可以为NO的目标，即使在鸟苷酸环化酶，其主要的高亲和力的目标，没有完全激活的情况下。在体内器官和全身措施NO合酶抑制表明一个可能的作用NO抑制细胞色素氧化酶。然而，一个详细的映射NO和氧气水平，结合细胞色素氧化酶/NO结合的直接措施，在生理学上仍有待。
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.