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Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis.
Mol Pharmacol. 2006 Sep; 70(3):1053-61.MP

Abstract

Cadmium is known to exhibit high affinity for thiol groups and may therefore severely disturb many cellular functions. We have demonstrated that the control of mitochondrial redox balance and oxidative damage is one of the primary functions of mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm). When exposed to cadmium, IDPm was susceptible to loss of enzyme activity and structural alterations. Site-directed mutagenesis confirms that binding of cadmium occurs to a Cys379 of IDPm. We examined the antioxidant mechanism-mediated protective role of IDPm against cadmium-induced apoptosis with human embryonic kidney 293 cells transfected with the IDPm cDNA in sense and antisense orientations. As a result, we observed a clear inverse relationship between the amount of IDPm expressed in target cells and their susceptibility to cadmium-induced modulation of cellular redox status and apoptosis. In addition, loss of glutaredoxin (Grx, thioltransferase) activity by cadmium was more pronounced in antisense cells compared with the sense cells. When oxalomalate, a competitive inhibitor of IDPm, was administered to mice, inhibition of IDPm and Grx and enhanced susceptibility to apoptosis were observed upon their exposure to cadmium. These results suggest that IDPm plays an important protective role in cadmium-induced apoptosis by maintaining cellular redox status and by protection of Grx activity.

Authors+Show Affiliations

School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16785314

Citation

Kil, In Sup, et al. "Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Protects Cadmium-induced Apoptosis." Molecular Pharmacology, vol. 70, no. 3, 2006, pp. 1053-61.
Kil IS, Shin SW, Yeo HS, et al. Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis. Mol Pharmacol. 2006;70(3):1053-61.
Kil, I. S., Shin, S. W., Yeo, H. S., Lee, Y. S., & Park, J. W. (2006). Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis. Molecular Pharmacology, 70(3), 1053-61.
Kil IS, et al. Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Protects Cadmium-induced Apoptosis. Mol Pharmacol. 2006;70(3):1053-61. PubMed PMID: 16785314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial NADP+-dependent isocitrate dehydrogenase protects cadmium-induced apoptosis. AU - Kil,In Sup, AU - Shin,Seoung Woo, AU - Yeo,Hyun Seok, AU - Lee,Young Sup, AU - Park,Jeen-Woo, Y1 - 2006/06/19/ PY - 2006/6/21/pubmed PY - 2006/9/29/medline PY - 2006/6/21/entrez SP - 1053 EP - 61 JF - Molecular pharmacology JO - Mol Pharmacol VL - 70 IS - 3 N2 - Cadmium is known to exhibit high affinity for thiol groups and may therefore severely disturb many cellular functions. We have demonstrated that the control of mitochondrial redox balance and oxidative damage is one of the primary functions of mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm). When exposed to cadmium, IDPm was susceptible to loss of enzyme activity and structural alterations. Site-directed mutagenesis confirms that binding of cadmium occurs to a Cys379 of IDPm. We examined the antioxidant mechanism-mediated protective role of IDPm against cadmium-induced apoptosis with human embryonic kidney 293 cells transfected with the IDPm cDNA in sense and antisense orientations. As a result, we observed a clear inverse relationship between the amount of IDPm expressed in target cells and their susceptibility to cadmium-induced modulation of cellular redox status and apoptosis. In addition, loss of glutaredoxin (Grx, thioltransferase) activity by cadmium was more pronounced in antisense cells compared with the sense cells. When oxalomalate, a competitive inhibitor of IDPm, was administered to mice, inhibition of IDPm and Grx and enhanced susceptibility to apoptosis were observed upon their exposure to cadmium. These results suggest that IDPm plays an important protective role in cadmium-induced apoptosis by maintaining cellular redox status and by protection of Grx activity. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16785314/Mitochondrial_NADP+_dependent_isocitrate_dehydrogenase_protects_cadmium_induced_apoptosis_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16785314 DB - PRIME DP - Unbound Medicine ER -