Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase.
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.
Departments of Genetic Engineering and Biochemistry, Kyungpook National University, Taegu 702-701, Korea.
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Koh
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Lee
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Kim
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Jeong
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Park
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Huh
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Huhe
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000502:physiology; D002417:Cattle; D002470:Cell Survival; D003001:Cloning, Molecular; D053938:DNA Fragmentation; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D017382:Reactive Oxygen Species / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013482:Superoxide Dismutase / Q000378:metabolism; D013552:Swine
D000906:Antibodies; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+); D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase