Mitochondrial Superoxide Dismutase: What the Established, the Intriguing, and the Novel Reveal About a Key Cellular Redox Switch

Abstract

Significance: Reactive oxygen species (ROS) are now widely recognized as central mediators of cell signaling. Mitochondria are major sources of ROS. Recent Advances: It is now clear that mitochondrial ROS are essential to activate responses to cellular microenvironmental stressors. Mediators of these responses reside in large part in the cytosol. Critical Issues: The primary form of ROS produced by mitochondria is the superoxide radical anion. As a charged radical anion, superoxide is restricted in its capacity to diffuse and convey redox messages outside of mitochondria. In addition, superoxide is a reductant and not particularly efficient at oxidizing targets. Because there are many opportunities for superoxide to be neutralized in mitochondria, it is not completely clear how redox cues generated in mitochondria are converted into diffusible signals that produce transient oxidative modifications in the cytosol or nucleus. Future Directions: To efficiently intervene at the level of cellular redox signaling, it seems that understanding how the generation of superoxide radicals in mitochondria is coupled with the propagation of redox messages is essential. We propose that mitochondrial superoxide dismutase (SOD2) is a major system converting diffusion-restricted superoxide radicals derived from the electron transport chain into highly diffusible hydrogen peroxide (H₂O₂). This enables the coupling of metabolic changes resulting in increased superoxide to the production of H₂O₂, a diffusible secondary messenger. As such, to determine whether there are other systems coupling metabolic changes to redox messaging in mitochondria as well as how these systems are regulated is essential.

Keywords: H2O2; MnSOD; SOD2; redox signaling.

FIG. 1.

Sources and potential obstacles to the diffusion of O₂^•− from the mitochondrial matrix to the extracellular space depicting SOD1 and cytochrome c as major obstacles present in the intermembrane space and SOD2 as a major sink in the matrix. O₂^•−, superoxide radical; SOD, superoxide dismutase; SOD2, mitochondrial superoxide dismutase. Color images are available online.

FIG. 2.

Structure of the SOD2 homotetramer with major known activating and inhibiting PTMs. Crystal structure was downloaded from Swiss PDB Viewer Protein Structure Database. PTM, post-translational modification. Color images are available online.

FIG. 3.

Schematic representation of the reactions catalyzed by MnSOD2 and FeSOD2, which exhibit SOD and pro-oxidant peroxidase activity, respectively. FeSOD2, iron-dependent superoxide dismutase; MnSOD, manganese-dependent superoxide dismutase. Color images are available online.

FIG. 4.

Diagram illustrating the potential for diffusion of either superoxide radicals or H₂O₂ from the mitochondrial matrix to the extramitochondrial space. H₂O₂, hydrogen peroxide. Color images are available online.

FIG. 5.

Diagram illustrating the hypothesis that SOD2 (functioning as a dismutase of superoxide) is essential to produce H₂O₂ signals necessary for the elimination of worn out mitochondria and the production of new functional mitochondria. Color images are available online.