Oxalomalate regulates ionizing radiation-induced apoptosis in mice.
Ionizing radiation induces the production of reactive oxygen species, which play an important causative role in apoptotic cell death. Recently, we demonstrated that the control of mitochondrial redox balance and the cellular defense against oxidative damage are primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) by supplying NADPH for antioxidant systems. In this paper, we demonstrate that modulation of IDPm activity in the kidneys of mice regulates ionizing radiation-induced apoptosis. When oxalomalate, a competitive inhibitor of IDPm, was administered to mice, inhibition of IDPm and enhanced susceptibility of apoptosis reflected by DNA fragmentation, the changes in mitochondria function, and the modulation of apoptotic marker proteins were observed upon exposure to 2 Gy of gamma-irradiation. We also observed a significant difference in the mitochondrial redox status between the kidneys of the control and the oxalomalate-administered mice. This study indicates that IDPm may play an important role in regulating the apoptosis induced by ionizing radiation, presumably, through acting as an antioxidant enzyme.
Lee
Jin Hyup
JH
School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Korea.
Park
Jeen-Woo
JW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D053148:Caspase 3 / Q000378:metabolism; D002588:Cesium Radioisotopes; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010070:Oxalates / Q000494:pharmacology*; D018384:Oxidative Stress; D011839:Radiation, Ionizing
D002588:Cesium Radioisotopes; D010070:Oxalates; C015407:oxalomalic acid; D009249:NADP; D007521:Isocitrate Dehydrogenase; D053148:Caspase 3