Seung-Hee Jo^‡§, Mi-Kyung Son^‡§, Ho-Jin Koh^‡, Su-Min Lee^¶∥, In-Hwan Song^**, Yong-Ou Kim^‡, Young-Sup Lee^∥, Kyu-Shik Jeong^‡, Won Bae Kim^§§, Jeen-Woo Park^∥, Byoung J. Song^‡ and Tae-Lin Huhe^¶‡¶¶

From the Departments of ^‡Genetic Engineering and^∥Biochemistry, Kyungpook National University, Taegu 702-701,^¶TG Biotech Co. Ltd., Kyungpook National University, Taegu 702-701, Korea, the ^**Department of Anatomy, College of Medicine, Yeungnam University, Taegu 705-717, Korea, the^‡Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852, the §§Research Laboratory, Dong-A Pharmacia Co. Ltd., Youngin, Kyungi-Do 449-900, Korea

Abstract
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.

Footnotes
* This work was supported by Grant 991473 from the Basic Research program of the Korea Science and Engineering Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) .

^§ These authors contributed equally to this work.

^¶¶ To whom correspondence should be addressed: Dept. of Genetic Engineering, College of Natural Sciences, Kyungpook National University, 1370 Sankyuk-dong, Puk-ku,Taegu 702-701, Korea. Tel.: 82-53-950-5387; Fax: 82-53-943-9755

² S.-H. Jo, M.-K. Son, H.-J. Koh, S.-M. Lee, I.-H. Song, Y.-O. Kim, Y. S. Lee, K.-S. Jeong, W. B. Kim, J.-W. Park, B. J. Song, and T.-L. Huh, unpublished data.