Lack of Oxygen Deactivates Mitochondrial Complex I IMPLICATIONS FOR ISCHEMIC INJURY?
Lack of Oxygen Deactivates Mitochondrial Complex I IMPLICATIONS FOR ISCHEMIC INJURY?
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DOI：
10.1074/jbc.m109.054346
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Moncada, Salvador
中科院分区：
文献类型：
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作者：
Galkin, Alexander;Abramov, Andrey Y.;Moncada, Salvador
对于S-亚硝基硫醇和过氧亚硝酸盐干扰线粒体复合物I的活性，酶从其活性（A）到其失活、休眠（D）状态的预先转变是必要的。现在，我们证明积累的D-型复合物I在人肾上皮细胞长时间缺氧后。缺氧后复氧时，呼吸率恢复正常有一个初始延迟。这是由于D型的积累及其缓慢的底物依赖性再转化为A型。恢复到A-形式可以通过长时间孵育内源性产生的NO。我们建议，缺氧过渡从A-形式的D-形式的复合物I可能是保护性的，因为它会起到减少电子爆发和形成的自由基在复氧。然而，这可能成为一个早期的病理生理事件时，NO依赖的S-亚硝基硫醇或过氧亚硝酸盐的形成在结构上修改复合物I的D-形式，并阻碍其返回到活性状态。这些观察结果提供了一种机制，以解释严重的细胞损伤后缺氧和复氧时，伴随着NO的产生。
For S-nitrosothiols and peroxynitrite to interfere with the activity of mitochondrial complex I, prior transition of the enzyme from its active (A) to its deactive, dormant (D) state is necessary. We now demonstrate accumulation of the D-form of complex I in human epithelial kidney cells after prolonged hypoxia. Upon reoxygenation after hypoxia there was an initial delay in the return of the respiration rate to normal. This was due to the accumulation of the D-form and its slow, substrate-dependent reconversion to the A-form. Reconversion to the A-form could be prevented by prolonged incubation with endogenously generated NO. We propose that the hypoxic transition from the A-form to the D-form of complex I may be protective, because it would act to reduce the electron burst and the formation of free radicals during reoxygenation. However, this may become an early pathophysiological event when NO-dependent formation of S-nitrosothiols or peroxynitrite structurally modifies complex I in its D-form and impedes its return to the active state. These observations provide a mechanism to account for the severe cell injury that follows hypoxia and reoxygenation when accompanied by NO generation.