Conformational Change of Mitochondrial Complex I Increases ROS Sensitivity During Ischemia
Conformational Change of Mitochondrial Complex I Increases ROS Sensitivity During Ischemia
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DOI：
10.1089/ars.2012.4698
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发表时间：
2013-11-01
影响因子：
6.6
通讯作者：
Galkin, Alexander
中科院分区：
文献类型：
--
作者：
Gorenkova, Natalia;Robinson, Emma;Galkin, Alexander
目的：心肌缺血/再灌注（I/R）与线粒体功能障碍和随后的心肌细胞死亡有关。过量活性氧（reactive oxygen species，ROS）的产生及其对线粒体酶的损伤被认为是再灌注损伤的重要机制。线粒体复合物I可以以两种相互转化的状态存在：活性（A）和失活或休眠（D）。我们研究了在体内缺血条件下几种组织中的活性/失活（A/D）平衡，并研究了两种形式的心脏酶对ROS的敏感性。结果如下：我们发现，在心脏中，复合物I在缺血时失活的t（1/2）为10 min，再灌注导致A/D平衡恢复到其初始水平。复合物I的超氧化物生成速率在D-型含量较高的缺血样品中较高。只有D-型容易受到H2 O2或超氧化物的抑制，而营业额依赖性激活的酶导致形成的A-型，这是不太敏感的活性氧。通过氧化还原差异凝胶电泳鉴定了最可能负责D型对ROS敏感性的ND 3亚基。创新：结合体内和生物化学的方法表明，在心肌I/R期间线粒体系统对ROS的敏感性可以受到复合物I的构象状态的显着影响，因此，这可能代表了在这种情况下的一个新的治疗靶点。结论：所提供的数据表明，在缺氧条件下复合物I转变为D-型可能是I/R期间促进心脏损伤的关键事件。抗氧化剂。氧化还原信号。19，1459-1468.
Aims: Myocardial ischemia/reperfusion (I/R) is associated with mitochondrial dysfunction and subsequent cardiomyocyte death. The generation of excessive quantities of reactive oxygen species (ROS) and resultant damage to mitochondrial enzymes is considered an important mechanism underlying reperfusion injury. Mitochondrial complex I can exist in two interconvertible states: active (A) and deactive or dormant (D). We have studied the active/deactive (A/D) equilibrium in several tissues under ischemic conditions in vivo and investigated the sensitivity of both forms of the heart enzyme to ROS. Results: We found that in the heart, t(1/2) of complex I deactivation during ischemia was 10min, and that reperfusion resulted in the return of A/D equilibrium to its initial level. The rate of superoxide generation by complex I was higher in ischemic samples where content of the D-form was higher. Only the D-form was susceptible to inhibition by H2O2 or superoxide, whereas turnover-dependent activation of the enzyme resulted in formation of the A-form, which was much less sensitive to ROS. The mitochondrial-encoded subunit ND3, most likely responsible for the sensitivity of the D-form to ROS, was identified by redox difference gel electrophoresis. Innovation: A combined in vivo and biochemical approach suggests that sensitivity of the mitochondrial system to ROS during myocardial I/R can be significantly affected by the conformational state of complex I, which may therefore represent a new therapeutic target in this setting. Conclusion: The presented data suggest that transition of complex I into the D-form in the absence of oxygen may represent a key event in promoting cardiac injury during I/R. Antioxid. Redox Signal. 19, 1459-1468.