Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.
Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I.
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作者：
在心肌梗死和卒中中，由于活性氧(ROS)生成增加造成的氧化损伤导致了心肌缺血-再灌注损伤。ROS增加的机制尚不清楚，也不清楚如何防止这种增加。一氧化氮供体和S亚硝酸盐对缺血心肌有保护作用，但其作用机制尚不清楚。在此，我们使用线粒体选择性的S亚硝化剂MitoSNO，在小鼠体内研究了心肌梗死再灌注期线粒体S亚硝化对心脏的保护作用。我们发现，这种保护是由于线粒体复合体I的S亚硝化作用所致，线粒体复合体I是NADH电子进入呼吸链的入口点。络合物I的可逆S亚硝化可减缓缺血组织再灌流关键的第一分钟线粒体的重新激活，从而减少ROS的产生、氧化损伤和组织坏死。对复合体I的抑制是通过Cys39对ND3亚单位的选择性S亚硝化来实现的，只有在缺血后，该亚单位才变得容易修饰。我们的结果表明，快速激活复合体I是缺血-再灌注损伤的主要病理特征，并表明通过修改半胱氨酸开关来阻止这种重新激活是一种强大的心脏保护机制，因此是一种合理的治疗策略。
Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not known, and it is unclear how this increase can be prevented. A wide variety of nitric oxide donors and S-nitrosating agents protect the ischemic myocardium from infarction, but the responsible mechanisms are unclear. Here we used a mitochondria-selective S-nitrosating agent, MitoSNO, to determine how mitochondrial S-nitrosation at the reperfusion phase of myocardial infarction is cardioprotective in vivo in mice. We found that protection is due to the S-nitrosation of mitochondrial complex I, which is the entry point for electrons from NADH into the respiratory chain. Reversible S-nitrosation of complex I slows the reactivation of mitochondria during the crucial first minutes of the reperfusion of ischemic tissue, thereby decreasing ROS production, oxidative damage and tissue necrosis. Inhibition of complex I is afforded by the selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischemia. Our results identify rapid complex I reactivation as a central pathological feature of ischemia-reperfusion injury and show that preventing this reactivation by modification of a cysteine switch is a robust cardioprotective mechanism and hence a rational therapeutic strategy.
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影响因子：
7.8
作者：
Chouchani, Edward T.;James, Andrew M.;Fearnley, Ian M.;Lilley, Kathryn S.;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
DOI：
10.1042/bj20100633
发表时间：
2010-08-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Chouchani ET;Hurd TR;Nadtochiy SM;Brookes PS;Fearnley IM;Lilley KS;Smith RA;Murphy MP
通讯作者：
Murphy MP
影响因子：
3.9
作者：
Bridges, Hannah R.;Birrell, James A.;Hirst, Judy
通讯作者：
Hirst, Judy
影响因子：
20.1
作者：
Bolli, R;Becker, L;Lathrop, DA
通讯作者：
Lathrop, DA