Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation.
Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation.
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DOI：
10.1007/s12035-012-8344-z
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发表时间：
2013-02
影响因子：
5.1
通讯作者：
Huettemann, Maik
中科院分区：
文献类型：
--
作者：
Sanderson, Thomas H.;Reynolds, Christian A.;Kumar, Rita;Przyklenk, Karin;Huettemann, Maik
中风和循环停止会干扰流向大脑的血液，从而导致相当大的组织损伤。减少或预防脑缺血患者神经系统损伤的主要方法是迅速恢复缺血组织的血流。然而，矛盾的是，在遭受脑缺血事件的患者中，血流的恢复会导致额外的损伤并加剧神经认知缺陷。线粒体通过产生过多的活性氧（ROS），从而破坏细胞成分，引发细胞死亡，在再灌注损伤中起关键作用。在这篇综述中，我们总结了目前对再灌注过程中线粒体ROS生成机制的理解，特别是线粒体膜电位在脑缺血/再灌注病理中的作用。此外，我们提出了ROS生成的时间模型，其中由缺血引起的关键氧化磷酸化蛋白（OxPhos）的翻译后修饰在重新引入氧气时诱导过度活跃状态。过度活跃的OxPhos产生高线粒体膜电位，这种情况已知会产生过多的ROS。这种状态会导致ROS在再灌注时“爆发”，从而对线粒体造成结构和功能损伤，并诱导细胞死亡信号，最终导致组织损伤。最后，我们提出，旨在调节线粒体膜电位的这种不适应超极化的策略可能是一种新的治疗干预措施，并提出了具体的研究，证明了这种治疗方式的细胞保护作用。
Stroke and circulatory arrest cause interferences in blood flow to the brain that result in considerable tissue damage. The primary method to reduce or prevent neurologic damage to patients suffering from brain ischemia is prompt restoration of blood flow to the ischemic tissue. However, paradoxically, restoration of blood flow causes additional damage and exacerbates neurocognitive deficits among patients who suffer a brain ischemic event. Mitochondria play a critical role in reperfusion injury by producing excessive reactive oxygen species (ROS) thereby damaging cellular components, and initiating cell death. In this review, we summarize our current understanding of the mechanisms of mitochondrial ROS generation during reperfusion, and specifically, the role the mitochondrial membrane potential plays in the pathology of cerebral ischemia/reperfusion. Additionally, we propose a temporal model of ROS generation in which post-translational modifications of key oxidative phosphorylation proteins (OxPhos) caused by ischemia, induce a hyperactive state upon reintroduction of oxygen. Hyperactive OxPhos generates high mitochondrial membrane potentials, a condition known to generate excessive ROS. Such a state would lead to a ‘burst’ of ROS upon reperfusion, thereby causing structural and functional damage to the mitochondria and inducing cell death signalling that eventually culminate in tissue damage. Finally, we propose that strategies aimed at modulating this maladaptive hyperpolarization of the mitochondrial membrane potential may be a novel therapeutic intervention and present specific studies demonstrating the cytoprotective effect of this treatment modality.
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影响因子：
3.5
作者：
Ankarcrona, M;Dypbukt, JM;Nicotera, P
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