Hydrogen peroxide inhibits caspase-dependent apoptosis by inactivating procaspase-9 in an iron-dependent manner
Hydrogen peroxide inhibits caspase-dependent apoptosis by inactivating procaspase-9 in an iron-dependent manner
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DOI：
10.1016/j.freeradbiomed.2007.06.020
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发表时间：
2007-11-15
影响因子：
7.4
通讯作者：
Galaris, Dimitrios
中科院分区：
文献类型：
--
作者：
Barbouti, Alexandra;Amorgianiotis, Christos;Galaris, Dimitrios
细胞凋亡是细胞死亡的一种生理形式，它的扰动可能导致与不需要的细胞积累或过度的细胞损失有关的几种疾病的发展。我们之前已经证明，持续存在低浓度H2O2（由葡萄糖氧化酶作用产生）能够抑制caspase介导的Jurkat细胞凋亡。本研究的主要目的是阐明H2O2这种抑制作用的确切分子机制。结果表明，线粒体外膜渗透、线粒体释放细胞色素c、Apaf-1寡聚、procaspase-9向凋亡体募集等事件正常发生，但在凋亡过程中存在H2O2时，执行caspase的进一步激活被中断。从本研究的结果来看，procaspase-9自激活的抑制可能是由于该分子中敏感半胱氨酸残基的可逆氧化。值得注意的是，在缺铁条件下，在H2O2的存在下，caspase-9的活化和随后的caspase级联正常进行，这表明对procaspase-9活化的抑制是一个铁依赖性的过程。总的来说，这些结果强调了可用的细胞内铁离子在与凋亡细胞死亡相关的信号机制中的潜在作用。(C) 2007爱思唯尔公司版权所有。
Apoptosis represents a physiological form of cell death, the perturbation of which may contribute to the development of several diseases connected with accumulation of unwanted cells or excessive cell loss. We have previously shown that the continuous presence of low concentrations of H2O2 (generated by the action of glucose oxidase) was able to inhibit caspase-mediated apoptosis in Jurkat cells. The main purpose of the present study was to elucidate the exact molecula r mechanism(s) underlying this inhibitory action of H2O2. The results presented show that events like outer mitochondrial membrane permeabilization, release of cytochrome c from mitochondria, oligomerization of Apaf-1, and recruitment of procaspase-9 to apoptosomes were taking place normally, but further advancement toward activation of the execution caspases was interrupted when H2O2 was present during the apoptotic process. From the results presented in this work, it emerges that the inhibition of procaspase-9 autoactivation was probably due to the reversible oxidation of sensitive cysteine residues in this molecule. Remarkably, caspase-9 activation and the ensuing caspase cascade proceeded normally in the presence of H2O2 under conditions of iron deprivation, indicating that the inhibition of procaspase-9 activation was an iron-dependent process. Collectively, these results highlighted the potential role of available intracellular iron ions in signaling mechanisms related to apoptotic cell death. (C) 2007 Elsevier Inc. All rights reserved.