Jo S H, Son M K, Koh H J, Lee S M, Song I H, Kim Y O, Lee Y S, Jeong K S, Kim W B, Park J W, Song B J, Huh T L
Departments of Genetic Engineering and Biochemistry, Kyungpook National University, Taegu 702-701, Korea.
J Biol Chem. 2001 May 11;276(19):16168-76. doi: 10.1074/jbc.M010120200. Epub 2001 Feb 13.
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.
线粒体是产生活性氧（ROS）的主要细胞器，并且如在包括衰老在内的各种病理状态中所观察到的，是ROS诱导损伤的主要靶点。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（+）依赖性异柠檬酸脱氢酶（IDPm）在控制线粒体氧化还原平衡以及随后细胞对氧化损伤的防御中的作用。我们在本报告中证明，IDPm由ROS诱导，并且IDPm表达的降低显著提高了ROS的产生、DNA片段化、脂质过氧化以及同时发生的线粒体损伤，同时ATP水平显著降低。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。我们的结果强烈表明，IDPm是线粒体中主要的NADPH产生者，因此在细胞对氧化应激诱导损伤的防御中起关键作用。
