PREVENTION OF MITOCHONDRIAL INJURY BY MANGANESE SUPEROXIDE-DISMUTASE REVEALS A PRIMARY MECHANISM FOR ALKALINE-INDUCED CELL-DEATH

Alkalosis is a clinical complication resulting from various pathologic al and physiological conditions, Although it is well established that reducing the cellular proton concentration is lethal, the mechanism le ading to cell death is unknown. Mitochondrial respiration generates a proton gradient and superoxide radicals, suggesting a possible link be tween oxidative stress, mitochondrial integrity, and alkaline-induced cell death. Manganese superoxide dismutase removes superoxide radicals in mitochondria, and thus protects mitochondria from oxidative injury . Cells cultured under alkaline conditions were found to exhibit eleva ted levels of mitochondrial membrane potential, reactive oxygen specie s, and calcium which was accompanied by mitochondrial damage, DNA frag mentation, and cell death. Overexpression of manganese superoxide dism utase reduced the levels of intracellular reactive oxygen species and calcium, restored mitochondrial transmembrane potential, and prevented cell death. The results suggest that mitochondria are the primary tar get for alkaline-induced cell death and that free radical generation i s an important and early event conveying cell death signals under alka line conditions.