A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury
A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury
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DOI：
10.1073/pnas.0903250106
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发表时间：
2009-06-30
影响因子：
11.1
通讯作者：
Murphy, Michael P.
中科院分区：
文献类型：
--
作者：
Prime, Tracy A.;Blaikie, Frances H.;Murphy, Michael P.
一氧化氮（NO中心点）竞争性地抑制线粒体在细胞色素c氧化酶和s -亚硝酸盐硫醇蛋白上的氧气消耗。我们开发了线粒体靶向s -亚硝基硫醇（MitoS-NOs），选择性调节和保护线粒体功能。典型的MitoSNO1通过将s -亚硝基硫醇与亲脂性三苯基磷酸阳离子共价连接而产生，在膜电位的驱动下，在线粒体内迅速而广泛地积累，在那里它产生NO中心点和s -亚硝基硫醇蛋白。在缺氧条件下，mitosno1诱导的NO中心点的产生可逆地抑制了细胞色素c氧化酶的呼吸作用，增加了细胞外氧浓度。MitoSNO1也因其NO中心点生成而引起血管松弛。再灌注时输注MitoSNO1对心脏缺血-再灌注损伤具有保护作用，这与s -亚硝化后线粒体蛋白（如复合物I）的功能修饰一致。这些结果支持了选择性靶向NO中心点供体到线粒体是一种可逆调节呼吸和保护线粒体免受缺血再灌注损伤的有效策略。
Nitric oxide (NO center dot) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoS-NOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO center dot and S-nitrosated thiol proteins. MitoSNO1-induced NO center dot production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO center dot generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO center dot donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.