Switch of Mitochondrial Superoxide Dismutase into a Prooxidant Peroxidase in Manganese-Deficient Cells and Mice

Abstract

Superoxide radical anion (O) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O 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. Here 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 HO to promote oxidative stress. We found that FeSOD2 is formed in cultured cells and in vivo. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells and in vivo. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.

Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix

“…Overexpression of SOD2 will lower the steady-state superoxide concentration in the matrix, usually without affecting matrix hydrogen peroxide production or concentration, and will decrease effects caused by matrix superoxide. One caveat to SOD2 overexpression studies is that there needs to be an adequate supply of Mn and lack of excessive Fe, otherwise the overexpressed apoenzyme may incorporate Fe instead of Mn, making it a peroxidase with damaging pro-oxidant effects (Ganini et al 2018). Conversely, partial or complete SOD2 knockout will raise matrix superoxide concentration, amplifying its effects.…”

SOD2 acetylation and deacetylation: Another tale of Jekyll and Hyde in cancer

“…The authors conclude that it is not the fact that SOD2 expression is higher in cancer that is important, but that acetylation of SOD2 is also elevated coincidentally with higher protein expression. Previous studies, by this group and others, demonstrate that SOD acetylation on lysine 68 (SOD2 K68 ) results in a loss of dismutase activity and a gain of peroxidase activity (20)(21)(22). In enzymes, whose primary function is as a peroxidase, substrate H 2 O 2 is reduced to water and coupled to the oxidation of a specific substrate.…”

Mechanisms of Mitochondrial ROS Production in Assisted Reproduction: The Known, the Unknown, and the Intriguing

“…HO 2 ● is still relevant, because it can occur as a locally caged radical when a substrate protonates superoxide [ 5 , 95 ]. Active and abundant MnSOD will constrain superoxide to picomolar levels, to limit direct reactivity by catalyzing reaction 12 at a diffusion controlled rate ( k ~2 × 10 9 M −1 s −1 ) [ 220 ]; provided that it contains manganese as the iron ligated enzyme can produce ● OH [ 221 ]. As Imlay [ 220 ] calculates, even picomolar (10 −11/12 M) levels of superoxide are sufficient to inactivate enzymes iron-sulfur proteins like aconitase, with a half-time of ~20 min in E. coli .…”