Inactivation of mitochondrial NADP+-dependent isocitrate dehydrogenase by hypochlorous acid.
Myeoloperoxidase catalyses the formation of hypochlorous acid (HOCl) via reaction of H(2)O(2) with Cl(-) ion. Although HOCl is known to play a major role in the human immune system by killing bacteria and other invading pathogens, excessive generation of this oxidant is known to cause damage to tissue. Recently, it was demonstrated that the control of mitochondrial redox balance and oxidative damage is one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) to supply NADPH for antioxidant systems. This study investigated whether the IDPm would be a vulnerable target of HOCl as a purified enzyme and in intact cells. Loss of enzyme activity was observed and the inactivation of IDPm was reversed by thiols. Transfection of HeLa cells with an IDPm small interfering RNA (siRNA) markedly enhanced HOCl-induced oxidative damage to cells. The HOCl-mediated damage to IDPm may result in the perturbation of the cellular antioxidant defense mechanisms and subsequently lead to a pro-oxidant condition.
Park
Sin Young
SY
School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu, South Korea.
Lee
Su-Min
SM
Shin
Seoung Woo
SW
Park
Jeen-Woo
JW
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000494:pharmacology*; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D013552:Swine
D000975:Antioxidants; D034741:RNA, Small Interfering; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D007521:Isocitrate Dehydrogenase