442 - Oxidative Stress Induced by Formation of the Peroxidase FeSOD2 in Mitochondria of Cells

Abstract

Cellular aerobic respiration leads to the production of potentially deleterious reactive by-products such as the free radical superoxide anion (O2●–). Organisms have superoxide dismutases (SODs) to catalyze the conversion of O2●– to H2O2 and molecular oxygen. Superoxide dismutase 2 (SOD2) is a mitochondrial-resident protein essential for organisms to be able to cope with oxygen respiration. Even though SOD2 is primarily considered a cellular antioxidant enzyme, higher levels of this enzyme in some cells and tissues have been shown to be prooxidant and responsible for mitochondrial dysfunction. Here we explain this discrepancy by showing that the manganese-dependent SOD2 when alternatively incorporated with iron displays a prooxidant peroxidase activity, a gain of function that enables this enzyme to utilize H2O2 to oxidize other molecules. Human SOD2 incorporated with manganese (MnSOD2) displays negligible peroxidase activity in vitro, but a switch from manganese to iron (FeSOD2) promotes the prooxidant peroxidase activity while preventing its capacity to function as an antioxidant. We detected the formation of FeSOD2 in human cells that overexpress this protein. Human cells with FeSOD2 showed detrimental changes in mitochondrial function and gene expression profile, and showed a shift in metabolism from oxidative phosphorylation to glycolysis. They had higher synthesis of mitochondrial proteins, even though they did not show changes in mitochondrial mass, which suggests mitochondrial instability and dysfunction. Even more important, those cells showed higher susceptibility to oxidative stress induced by H2O2 or paraquat exposure. The formation of FeSOD2 in mitochondria could be prevented by cultivating cells with higher levels of manganese in the medium. The ratio of iron to manganese in combination with the level of SOD2 in cells is shown to be essential to determine the fate of SOD2 as an antioxidant or a prooxidant. Occurrence of this fundamental antioxidant enzyme in a prooxidant state when incorporated with iron represents an important biological source of free radical generation since formation of FeSOD2 impacts mitochondrial function, changes cellular bioenergetics and decreases overall cellular resistance to oxidative stress. Formation of FeSOD2 might be implicated in disease development in humans since higher levels of iron and SOD2 are commonly observed in diseases related to oxidative stress.