Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase

被引:462
作者
Jo, SH
Son, MK
Koh, HJ
Lee, SM
Song, IH
Kim, YO
Lee, YS
Jeong, KS
Kim, WB
Park, JW
Song, BJ
Huhe, TL
机构
[1] Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea
[2] Kyungpook Natl Univ, Dept Biochem, Taegu 702701, South Korea
[3] Kyungpook Natl Univ, TG Biotech Co Ltd, Taegu 702701, South Korea
[4] Yeungnam Univ, Coll Med, Dept Anat, Taegu 705717, South Korea
[5] NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA
[6] Dong A Pharmacia Co Ltd, Res Lab, Yongin 449900, Kyungi Do, South Korea
关键词
D O I
10.1074/jbc.M010120200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:16168 / 16176
页数:9
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