Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: Implications for oxygen sensing and hypoxic signaling in eukaryotes
Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: Implications for oxygen sensing and hypoxic signaling in eukaryotes
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DOI：
10.1016/j.cmet.2006.02.011
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发表时间：
2006-04-01
期刊：
影响因子：
29
通讯作者：
Poyton, RO
中科院分区：
文献类型：
--
作者：
Castello, PR;David, PS;Poyton, RO
真核细胞通过上调缺氧核基因（缺氧信号）来响应低氧浓度。虽然以前已经表明，线粒体呼吸链是缺氧信号所必需的，但其在这一过程中的潜在作用尚不清楚。在这里，我们发现，酵母和大鼠肝线粒体产生一氧化氮（NO）在溶解氧浓度低于20 μ M。这种NO的产生是亚硝酸盐（NO2-）依赖性的，需要电子供体，并且通过细胞色素c氧化酶以pH依赖性方式进行。酵母线粒体NO的产生受YHb黄素血红蛋白NO氧化还原酶的影响，刺激缺氧核基因CYC 7的表达，并伴随着蛋白质酪氨酸硝化的增加。这些研究结果表明，在缺氧或缺氧条件下的线粒体呼吸链的替代作用，并表明，naturally产生的NO参与缺氧信号，可能通过一个途径，涉及蛋白质酪氨酸硝化。
Eukaryotic cells respond to low-oxygen concentrations by upregulating hypoxic nuclear genes (hypoxic signaling). Although it has been shown previously that the mitochondrial respiratory chain is required for hypoxic signaling, its underlying role in this process has been unclear. Here, we find that yeast and rat liver mitochondria produce nitric oxide (NO) at dissolved oxygen concentrations below 20 mu M. This NO production is nitrite (NO2-) dependent, requires an electron donor, and is carried out by cytochrome c oxidase in a pH-dependent fashion. Mitochondrial NO production in yeast is influenced by the YHb flavohemoglobin NO oxidoreductase, stimulates expression of the hypoxic nuclear gene CYC7, and is accompanied by an increase in protein tyrosine nitration. These findings demonstrate an alternative role for the mitochondrial respiratory chain under hypoxic or anoxic conditions and suggest that mitochondrially produced NO is involved in hypoxic signaling, possibly via a pathway that involves protein tyrosine nitration.