205 - Switch of Mitochondrial Superoxide Dismutase (SOD2) into a Prooxidant Peroxidase in Manganese-deficient Cells and Mice

Abstract

Reactive oxygen species (ROS), in particular the superoxide radical anion O2•‒, are constantly produced during respiration and are increased in many human diseases. In mitochondria, the dismutation of O2•‒ is accelerated by the mitochondrial superoxide dismutase 2 or MnSOD2, 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 in mitochondria. We show that SOD2, which is normally bound to manganese, can incorporate iron and generate an alternative isoform with peroxidase activity, the FeSOD2. In this regard, a switch in metal cofactor changes SOD2 from an antioxidant to a prooxidant enzyme that utilizes H2O2 to promote oxidative stress. Moreover, we found that the formation of FeSOD2, which happens in cellulo and in vivo, causes changes in overall cellular metabolism and gene expression profiles. Cells in culture with FeSOD2 show a shift in metabolism from oxidative phosphorylation to glycolysis due to mitochondrial dysfunction. Mice showed accumulation of FeSOD2 in liver when fed a manganese-deficient diet or an iron-enriched diet. Their liver mitochondria showed high levels of protein radicals, including those of Complex I. More importantly, levels of protein radical formation correlated with FeSOD2. Hence, we provide evidence in support of the identification of the first mitochondrial metal peroxidase which is produced by the incorporation of iron into SOD2. We also show that the formation of FeSOD2 converts an antioxidant defense (MnSOD2) into a prooxidant enzyme that leads to cellular changes seen in multiple human diseases.