Overexpression of mitochondrial methionine sulfoxide reductase B2 protects leukemia cells from oxidative stress-induced cell death and protein damage
Overexpression of mitochondrial methionine sulfoxide reductase B2 protects leukemia cells from oxidative stress-induced cell death and protein damage
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DOI：
10.1074/jbc.m708580200
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发表时间：
2008-06-13
影响因子：
4.8
通讯作者：
Petropoulos, Isabelle
中科院分区：
文献类型：
--
作者：
Cabreiro, Filipe;Picot, Cedric R.;Petropoulos, Isabelle
根据线粒体衰老理论，线粒体功能障碍增加细胞内活性氧化物质的产生，导致大分子氧化，最终导致细胞死亡。在这项研究中，我们研究了线粒体蛋氨酸亚砜还原酶B2在抗氧化应激中的作用。我们首次报道了急性t淋巴细胞白血病MOLT-4细胞系线粒体中蛋氨酸亚砜还原酶B2的过表达，其中蛋氨酸亚砜还原酶A缺失，通过清除活性氧显着保护过氧化氢诱导的氧化应激。过氧化氢的加入引起细胞内活性氧的逐渐增加，导致线粒体膜电位的丧失和蛋白质羰基的积累，而在蛋氨酸亚砜还原酶b2过表达的细胞中，细胞内活性氧和蛋白质氧化仍然很低，线粒体膜电位得到高度维持。此外，在这些细胞中，凋亡标志物聚（adp -核糖）聚合酶-1的切割减少，以及在晚期和早期凋亡阶段annexin - v阳性细胞的百分比较低，显示出延迟的凋亡。我们还为蛋氨酸亚砜还原酶B2对蛋白质氧化损伤的保护机制提供了证据。我们的研究结果强调，在氧化应激下，蛋氨酸亚砜还原酶B2的过度表达通过其清除作用减少细胞内活性氧的积累，从而导致线粒体完整性的保存，从而有助于细胞存活和蛋白质维持。
According to the mitochondrial theory of aging, mitochondrial dysfunction increases intracellular reactive oxidative species production, leading to the oxidation of macromolecules and ultimately to cell death. In this study, we investigated the role of the mitochondrial methionine sulfoxide reductase B2 in the protection against oxidative stress. We report, for the first time, that overexpression of methionine sulfoxide reductase B2 in mitochondria of acute T-lymphoblastic leukemia MOLT-4 cell line, in which methionine sulfoxide reductase A is missing, markedly protects against hydrogen peroxide-induced oxidative stress by scavenging reactive oxygen species. The addition of hydrogen peroxide provoked a time-gradual increase of intracellular reactive oxygen species, leading to a loss in mitochondrial membrane potential and to protein carbonyl accumulation, whereas in methionine sulfoxide reductase B2-overexpressing cells, intracellular reactive oxygen species and protein oxidation remained low with the mitochondrial membrane potential highly maintained. Moreover, in these cells, delayed apoptosis was shown by a decrease in the cleavage of the apoptotic marker poly(ADP-ribose) polymerase-1 and by the lower percentage of Annexin-V-positive cells in the late and early apoptotic stages. We also provide evidence for the protective mechanism of methionine sulfoxide reductase B2 against protein oxidative damages. Our results emphasize that upon oxidative stress, the overexpression of methionine sulfoxide reductase B2 leads to the preservation of mitochondrial integrity by decreasing the intracellular reactive oxygen species build-up through its scavenging role, hence contributing to cell survival and protein maintenance.