Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress
Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress
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DOI：
10.1016/j.freeradbiomed.2004.09.005
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发表时间：
2004-12-01
影响因子：
7.4
通讯作者：
Fiskum, G
中科院分区：
文献类型：
--
作者：
Kowaltowski, AJ;Fenton, RG;Fiskum, G
Bcl-2家族蛋白可防止多种形式的细胞死亡，包括急性氧化应激。以前的研究表明，抗凋亡蛋白Bcl-2的过度表达增加细胞的氧化还原能力。在这里，我们报告说，细胞系转染Bcl-2矛盾地表现出线粒体过氧化氢的产生率增加。使用分离的线粒体，我们确定，增加H2 O2释放的结果从氧化还原烟酰胺腺嘌呤二核苷酸连接的底物。抗凋亡Bcl-2家族蛋白Bcl-xL和Mcl-1在过表达时也增加线粒体H2 O2释放。慢性暴露的细胞低水平的线粒体解偶联剂羰基氰化物4-（三氟甲氧基）苯腙Bcl-xL过表达细胞的H2 O2生产率降低，导致在一个降低的能力，以消除外源性H2 O2和增强细胞死亡的条件下，急性氧化应激。我们的研究结果表明，慢性和轻度升高H2 O2释放Bcl-2，Bcl-xL，和Mcl-1过表达线粒体导致增强细胞抗氧化防御和保护急性氧化应激引起的死亡。(C)2004年爱思唯尔公司All rights reserved.
Bcl-2 family proteins protect against a variety of forms of cell death, including acute oxidative stress. Previous studies have shown that overexpression of the antiapoptotic protein Bcl-2 increases cellular redox capacity. Here we report that cell lines transfected with Bcl-2 paradoxically exhibit increased rates of mitochondrial H2O2 generation. Using isolated mitochondria, we determined that increased H2O2 release results from the oxidation of reduced nicotinamide adenine dinucleotide-linked substrates. Antiapoptotic Bcl-2 family proteins Bcl-xL and Mcl-1 also increase mitochondrial H2O2 release when overexpressed. Chronic exposure of cells to low levels of the mitochondrial uncoupler carbonyl cyanide 4-(triflouromethoxy)phenylhydrazone reduced the rate of H2O2 production by Bcl-xL overexpressing cells, resulting in a decreased ability to remove exogenous H2O2 and enhanced cell death under conditions of acute oxidative stress. Our results indicate that chronic and mild elevations in H2O2 release from Bcl-2, Bcl-xL, and Mcl-1 overexpressing mitochondria lead to enhanced cellular antioxidant defense and protection against death caused by acute oxidative stress. (C) 2004 Elsevier Inc. All rights reserved.