Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling

Abstract

Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling.

© 2018 Wang et al.

Figures

Figure 1.

Reactions and transformations of the superoxide anion. SOD enzymes catalyze the dismutation of superoxide (O2•-), generating hydrogen peroxide (H2O2). The catalase (CAT), glutathione peroxidases (GPXs), and PRXs convert H2O2 into water. H2O2 can react with redox-active metals (e.g., iron) to generate the hydroxy radical (OH•) through the Fenton/Haber-Weiss reaction. The reaction between O2•- and nitric oxide (NO•) produces ONOO−, whose decomposition in turn gives rise to some highly oxidizing intermediates including NO2•, OH•, and CO3•- as well as, ultimately, stable NO3−. Therefore, raised O2•- levels can also decrease NO• bioavailability and generate ONOO− toxicity. O2•- by itself can reduce ferric iron (Fe3+) to ferrous iron (Fe2+) in iron–sulfur centers of proteins, leading to enzyme inactivation and concomitant loss of Fe2+ from the enzymes, which in turn fuels Fenton chemistry. The protonation of O2•- can form the more reactive hydroperoxyl radical (HO2•).

Figure 2.

SOD-dependent ROS signaling in mammalian cells. In aerobic organisms, many processes produce O2•-, including cytosolic xanthine oxidase (OX), the cytochrome P450-monooxygenases (CYP) in the ER, the mitochondrial ETC, and NADPH oxidase (NOX). NOX is a membrane-bound enzyme complex that can be found in the plasma membrane as well as within intracellular membrane structures or vesicles (Meitzler et al., 2014). O2•- produced by the plasma membrane–bound NOX (e.g., NOX2) can act both intra- and extracellularly. H2O2 produced by SOD3 outside the cell can transverse into the cell interior in part through aquaporin channels to initiate intracellular signaling, whereas O2•- could influx through the chloride channel-3 (Fisher, 2009). The intracellular NOX complexes produce ROS in the lumen of a vesicular compartment, where ROS acts locally or from which it enters the cytosol (Brown and Griendling, 2009). H2O2 has been implicated in ROS signaling through oxidative modification of critical redox-sensitive cysteines in signaling proteins. The relatively well-recognized targets of ROS signaling include protein phosphatases (PTPs), nonreceptor protein tyrosine kinases (PTKs), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and transcriptional factors (TFs). The signaling function of O2•- is yet largely uncharacterized. In C. elegans, it was shown that mitochondrial ROS act by signaling in part through the intrinsic apoptotic pathway, likely via H2O2, triggering processes that promote longevity (Yee et al., 2014). Compartmentalization of different forms of SOD provides an important mechanism for fine spatial control of ROS homeostasis and signaling, whose exact significance remains to be understood. CAT, catalase; GPX, glutathione peroxidase.