The reactive oxygen species (ROS) include superoxide anion, the hydroxyl radical, and the singlet oxygen. The mitochondria are not only a major site where a large amount of cellular ROS is generated, but also they are a main target of ROS; thus, various pathological states including aging have been reported to involve the mitochondrial dysfunctions and ROS generation. However, a catalase, a major enzyme that removes hydrogen peroxide, has been reported to be absent in most mitochondria of mammalian cells. Therefore, mitochondrial GSH is important to the mitochondrial defenses against ROS because it is a prerequisite to the roles of mitochondrial GPx and phospholipid hydrogenperoxide glutathione peroxidase (PHGPx), which play key roles in removing the peroxides in mitochondria. In addition to the role of reducing agent for the regeneration of GSH, NADPH is also necessary to the antioxidant function of the peroxiredoxin family in mitochondria. We have previously reported the isolation and molecular characterization of bovine mitochondrial NADP + -dependent isocitrate dehydrogenase (IDPm). Here, we first report that expression of cloned mouse IDPm cDNA reduces oxidative stress. Conversely, reduction of IDPm in mitochondria by the expression of antisense mouse IDPm cDNA increases spontaneous generation of ROS by stimulating mitochondrial injury. Our findings further support that IDPm is a major producer of mitochondrial NADPH by which the mitochondrial GSH pool required in defense against cellular oxidative stress is replenished.
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