Novel Functions of Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx) as an Anti-Apoptotic Factor.

Abstract

Phospholipid hydroperoxide glutathione peroxidase (PHGPx) which is a selenoprotein and a key enzyme in the protection of biomembranes exposed to oxidative stress. Involvement of mitochondrial PHGPx in apoptosis was studied using RBL2H3 cells that overexpressed mitochondrial PHGPx. The elevation of hydroperoxides in mitochondria, release of cytochrome c, the activation of caspase and the fragmentatoin of DNA associated with apoptosis sequentially occurred in control cells upon exposure of cells to hypoglycemia with 2-deoxyglucose (2DG). Overexpression of mitochondrial PHGPx prevented the rise of hydroperoxide in the earliest event of apoptosis and then blocked apoptosis. Mitochondrial PHGPx overexpressing cells were also resistant to apoptosis induced by etoposide, staurosporine and UV irradiation, which mediate apoptosis through the mitochondrial pathway. These results indicate that mitochondrial PHGPx might play a critical role as an anti-apoptotic factor in the mitochondrial-death pathways. PHGPx was exclusively expressed in the mitochondria of human spermatozoa. We found dramatic decrease in the expression of mitochondrial PHGPx in the spermatozoa of 10% of infertile males. Mitochondrial PHGPx-deficient spermatozoa lost the mitochondrial membrane potential and showed an abnormal mitochondrial morphology. Failure of the expression of mitochondrial PHGPx might cause a dysfuction of the mitochondria in spermatozoa and a defect in spermatogenesis in which apoptosis occurs.