Mitochondrial superoxide flashes: From discovery to new controversies

Introduction Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated during normal physiological processes are highly reactive with cellular lipids, DNA, and proteins. Superoxide and nitric oxide are the primary ROS and RNS, respectively, produced in cells, and both species react with other molecules and each other to form a diverse array of additional ROS and RNS (e.g., hydrogen peroxide, hydroxyl radical, peroxynitrite, hyperchlorite, singlet oxygen). ROS/RNS were originally thought to represent noxious species produced during oxidative stress that are primarily destructive to cells. Indeed, high levels of ROS and RNS have long been known to promote cell damage and death. However, recent evidence indicates that the production of low to moderate levels of ROS/RNS is critical for the proper regulation of many essential cellular processes including gene expression, signal transduction, and muscle adaptation to endurance exercise training (Reid, 2001; Dröge, 2002; Powers et al., 2011). Cellular levels of ROS reflect a delicate balance between ROS production and detoxification. Cellular production of ROS in skeletal muscle, with superoxide as the primal species, originates from three principal sources: (1) membrane-associated NADPH oxidase, (2) cytosolic xanthine and xanthine oxidase, and (3) the mitochondrial electron transport chain (ETC). Cellular RNS levels are generated primarily by nitric oxide synthase (to produce nitric oxide) or its subsequent reaction with superoxide to produce peroxynitrite. ROS detoxification involves several cellular antioxidant defense systems including superoxide dismutase (SOD; converting superoxide to H2O2), catalase (breaking down H2O2 to oxygen and water), thioredoxin reductase/thioredoxin (catalyzing the formation/reduction of protein disulfide