Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase
Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase
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DOI：
10.1074/jbc.m010120200
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发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Huhe, TL
中科院分区：
文献类型：
--
作者：
Jo, SH;Son, MK;Huhe, TL
线粒体是产生活性氧（ROS）的主要细胞器，并且如在包括衰老的各种病理状态中所观察到的，线粒体是ROS诱导的损伤的主要靶点。线粒体中谷胱甘肽再生所需的NADPH的产生对于通过谷胱甘肽还原酶和过氧化物酶系统清除线粒体ROS至关重要。我们研究了线粒体NADP（+）依赖的异柠檬酸脱氢酶（IDPm）在控制线粒体氧化还原平衡和随后的细胞防御氧化损伤中的作用。我们在这份报告中表明，IDPm是由ROS诱导的，IDPm的表达减少显着提高ROS的产生，DNA片段化，脂质过氧化，并伴随线粒体损伤与ATP水平显着降低。相反，IDPm蛋白的过量产生有效地保护细胞免受ROS诱导的损伤。IDPm对氧化损伤的保护作用可能归因于线粒体中谷胱甘肽再生所需的还原当量NADPH水平的增加。我们的研究结果强烈表明，IDPm是一个主要的NADPH生产者在线粒体中，因此在细胞防御氧化应激诱导的损伤中起着关键作用。
Mitochondria are the major organelles that produce reactive oxygen species (ROS) and the main target of ROS-induced damage as observed in various pathological states including aging. Production of NADPH required for the regeneration of glutathione in the mitochondria is critical for scavenging mitochondrial ROS through glutathione reductase and peroxidase systems. We investigated the role of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) in controlling the mitochondrial redox balance and subsequent cellular defense against oxidative damage. We demonstrate in this report that IDPm is induced by ROS and that decreased expression of IDPm markedly elevates the ROS generation, DNA fragmentation, lipid peroxidation, and concurrent mitochondrial damage with a significant reduction in ATP level. Conversely, overproduction of IDPm protein efficiently protected the cells from ROS-induced damage. The protective role of IDPm against oxidative damage may be attributed to increased levels of a reducing equivalent, NADPH, needed for regeneration of glutathione in the mitochondria. Our results strongly indicate that IDPm is a major NADPH producer in the mitochondria and thus plays a key role in cellular defense against oxidative stress-induced damage.