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

<b><i>Significance:</i></b> Reactive oxygen species (ROS) are now widely recognized as central mediators of cell signaling. Mitochondria are major sources of ROS. <b><i>Recent Advances:</i></b> 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. <b><i>Critical Issues:</i></b> 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. <b><i>Future Directions:</i></b> 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.