Prevention of Mitochondrial Injury by Manganese Superoxide Dismutase Reveals a Primary Mechanism for Alkaline-induced Cell Death

Abstract

Alkalosis is a clinical complication resulting from various pathological and physiological conditions. Although it is well established that reducing the cellular proton concentration is lethal, the mechanism leading to cell death is unknown. Mitochondrial respiration generates a proton gradient and superoxide radicals, suggesting a possible link between 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 elevated levels of mitochondrial membrane potential, reactive oxygen species, and calcium which was accompanied by mitochondrial damage, DNA fragmentation, and cell death. Overexpression of manganese superoxide dismutase 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 target for alkalineinduced cell death and that free radical generation is an important and early event conveying cell death signals under alkaline conditions.

Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis

“…c remains to be identified. The generation of ROS has been implicated in apoptotic pathways triggered by various agents such as TNF-α [6], ceramide [7], glutamate [42], amyloid β-peptide [11], staurosporine [8], alkaline conditions [43] and the withdrawal of growth factors [44]. Superoxide radicals are produced in the mitochondria of cells that are undergoing apoptosis in response to ceramide, TNF-α and peroxynitrite.…”

Alterations of intracellular pH homeostasis in apoptosis: origins and roles

“…In this context, seeking a relationship between early apoptotic alkalinization and MAPK activation deserves more attention. At last, a role for a pH i change in apoptosis-related ROS production should also be tested due to the fact that (i) alkaline-induced cell death has been shown to be prevented by expression of manganese superoxide dismutase 69 and (ii) maneuvers that raise pH i potentiate oxidant production in endothelial cells. 70 In this regard, preliminary results from our group point to an inhibition by cariporide (an inhibitor of NHE1) of mitochondria-dependent ROS production detected upon PAH exposure of liver cells.…”

Enzymatic antioxidant system in vascular inflammation and coronary artery disease

“…to the less reactive radical H2O2, which in turn can be destroyed by CAT or GPX, protecting the dehydratase (dehydratase hydroxyacid, aconitase, 6 phosphogluconate dehydratase, fumarase A and B). In humans, there are three forms of SOD: cytosolic (Cu, Zn-SOD), mitochondrial (Mn-SOD) and extracellular (EC-SOD) [21] . The respiratory chain in the mitochondria is the major source of oxygen radicals.…”