Received for publication February 15, 2006.
Revised June 16, 2006.
Accepted for publication June 19, 2006.

Mitochondrial NADP⁺-dependent Isocitrate Dehydrogenase Protects Cadmium-induced Apoptosis

Abstract

Cadmium is known to exhibit a high affinity for thiol groups and may therefore severely disturb many cellular functions. Recently, we 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 the 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 HEK293 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 when compared to the sense cells. When oxalomalate, a competitive inhibitor of IDPm, was administered to mice, inhibition of IDPm and Grx and enhanced susceptibility to apoptosis was observed upon their exposure to cadmium. These results suggest that IDPm plays an important protective role in cadmium-induced apoptosis by maintaining the cellular redox status and by the protection of Grx activity.

Key words: Fluorescence techniques, Mutagenesis/Chimeric approaches, Apoptosis, Glutathione, Metals and chelators, Oxidative stress/antioxidants