Mechanisms of the interaction of nitroxyl with mitochondria.
Mechanisms of the interaction of nitroxyl with mitochondria.
复制标题
硝酰基与线粒体相互作用的机制。
DOI：
10.1042/bj20031758
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Darley-Usmar,VictorM
中科院分区：
文献类型：
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作者：
Shiva,Sruti;Crawford,JackH;Ramachandran,Anup;Ceaser,ErinK;Hillson,Tess;Brookes,PaulS;Patel,RakeshP;Darley-Usmar,VictorM
现在认为，NO·（一氧化氮）及其氧化还原同系物可能在线粒体功能的生理调节中发挥作用。NO·对细胞色素氧化酶的抑制具有可逆性和氧依赖性。与此相反，过氧亚硝酸盐，NO·与超氧化物反应的产物，不可逆地抑制几种呼吸复合物。然而，很少有人知道HNO（硝酰基）对线粒体功能的影响。这一点尤其重要，因为HNO已被证明比NO·更具细胞毒性，可能在体内产生，并具有NO和过氧亚硝酸盐的某些特征，引起生物学反应。在本研究中，我们提出的证据表明，分离的线粒体，在不存在或存在的底物，转化HNO到NO·的过程中，这是依赖于线粒体浓度以及浓度的HNO供体Angeli的盐。此外，HNO能够通过抑制复合物I和II来抑制线粒体呼吸，最可能是通过修饰蛋白质中的特定半胱氨酸残基。使用蛋白质组学方法，线粒体蛋白硫醇的广泛修饰被证明。从这些数据可以看出，HNO与线粒体的相互作用机制与NO·或过氧亚硝酸盐的作用机制不同，包括NO·的产生、巯基的修饰以及复合物I和II的抑制。
It is now thought that NO•(nitric oxide) and its redox congeners may play a role in the physiological regulation of mitochondrial function. The inhibition of cytochromecoxidase by NO•is characterized as being reversible and oxygen dependent. In contrast, peroxynitrite, the product of the reaction of NO•with superoxide, irreversibly inhibits several of the respiratory complexes. However, little is known about the effects of HNO (nitroxyl) on mitochondrial function. This is especially important, since HNO has been shown to be more cytotoxic than NO•, may potentially be generatedin vivo, and elicits biological responses with some of the characteristics of NO and peroxynitrite. In the present study, we present evidence that isolated mitochondria, in the absence or presence of substrate, convert HNO into NO•by a process that is dependent on mitochondrial concentration as well as the concentration of the HNO donor Angeli's salt. In addition, HNO is able to inhibit mitochondrial respiration through the inhibition of complexes I and II, most probably via modification of specific cysteine residues in the proteins. Using a proteomics approach, extensive modification of mitochondrial protein thiols was demonstrated. From these data it is evident that HNO interacts with mitochondria through mechanisms distinct from those of either NO•or peroxynitrite, including the generation of NO•, the modification of thiols and the inhibition of complexes I and II.