Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells

Superoxide radical anion and other Reactive Oxygen Species are constantly produced during respiration. In mitochondria, the dismutation of the superoxide radical anion is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. We show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases. Previously characterized MCF-7 derived cells, neo, and SOD2-overexpressing cells, Mn11, were grown in medium with and without manganese supplementation. We grew those cells for 21 days before cells were collected. We then compared the gene expression of Mn11 cells supplemented or not with manganese versus neo cells supplemented or not with manganese to show the specific effects of manganese incorporation into SOD2, excluding the possible background effects associated with manganese supplementation to the parental cell line.