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Mitochondrial NADP(+)-dependent isocitrate dehydrogenase deficiency increases cisplatin-induced oxidative damage in the kidney tubule cells

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Author(s)
Min Jung KongSang Jun HanJee In KimJeen-Woo ParkKwon Moo Park
Keimyung Author(s)
Kim, Jee In
Department
Dept. of Molecular Medicine (분자의학)
Journal Title
Cell Death & Disease
Issued Date
2018
Volume
9
Issue
5
Abstract
Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) plays an important role in the formation of NADPH, which is critical for the maintenance of mitochondrial redox balance. Cis-diamminedichloroplatinum II (cisplatin), an effective anticancer drug, induces oxidative stress-related nephrotoxicity, limiting its use. Therefore, we investigated whether IDH2, which is a critical enzyme in the NADPH-associated mitochondrial antioxidant system, is involved in cisplatin nephrotoxicity. Idh2 gene-deleted (Idh2-/-) mice and wild-type (Idh2 +/+ ) littermates were treated with cisplatin, with or without 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (Mito-T), a mitochondria-specific antioxidant. Cisplatin-induced renal functional and morphological impairments were greater in Idh2-/- mice than in Idh2 +/+ mice. Mito-T mitigated those impairments in both Idh2-/- and Idh2 +/+ mice and this mitigation was greater in Idh2-/- than in Idh2 +/+ mice. Cisplatin impaired IDH2 function in the mitochondria, decreasing mitochondrial NADPH and GSH levels and increasing H2O2 generation; protein, lipid, and DNA oxidation; mitochondrial damage; and apoptosis. These cisplatin-induced changes were much more severe in Idh2-/- mice than in Idh2 +/+ mice. Mito-T treatment attenuated cisplatin-induced alterations in both Idh2-/- and Idh2 +/+ mice and this mitigation was greater in Idh2-/- than in Idh2 +/+ mice. Altogether, these data demonstrate that cisplatin induces the impairment of the mitochondrial IDH2-NADPH-GSH antioxidant system and IDH2 deficiency aggravates cisplatin-induced mitochondrial oxidative damage, inducing more severe nephrotoxicity. This suggests that the mitochondrial IDH2-NADPH-GSH antioxidant system is a target for the prevention of cisplatin-induced kidney cell death.
Keimyung Author(s)(Kor)
김지인
Publisher
School of Medicine (의과대학)
Citation
Min Jung Kong et al. (2018). Mitochondrial NADP(+)-dependent isocitrate dehydrogenase deficiency increases cisplatin-induced oxidative damage in the kidney tubule cells. Cell Death & Disease, 9(5), 488–488. doi: 10.1038/s41419-018-0537-6
Type
Article
ISSN
2041-4889
DOI
10.1038/s41419-018-0537-6
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41357
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
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