Controlling mitochondrial H₂O₂ formation by redox switches

Mitochondria are responsible for furnishing all cells in the human body with the requisite energy to perform meaningful “work”. This energy is provided in the form of ATP which is generated by using the Gibbs free energy liberated by the oxidation of nutrients via a process called oxidative phosphorylation (OXPHOS). OXPHOS begins when electrons are mobilized from nutrients in the Krebs cycle and then systematically passed through a series of electron-conducting protein complexes to the terminal electron acceptor molecular oxygen (O₂). Electron transfer is coupled to the pumping of protons into the intermembrane space generating a substoichiometic form of Gibbs free energy that is utilized to drive the formation of ATP. Unfortunately, electron transfer reactions in mitochondria are not perfectly coupled to ATP formation. Indeed, electrons can prematurely exit the chain to generate reactive oxygen species (ROS). The two most important ROS produced by mitochondria are superoxide (O2^●-) and hydrogen peroxide (H₂O₂). O₂^●- is the proximal ROS generated by mitochondria as a consequence of the monovalent reduction of O₂ at an electron donating center. H₂O₂ is produced from the dismutation of O₂^●- by superoxide dismutase (SOD). Mitochondria are quantifiably the most important source of ROS in the cell. Over production of ROS due to inefficient electron transfer has been linked to oxidative stress, oxidative damage, cell death, and the pathogenesis of numerous disorders. Indeed, ROS production by mitochondria formed a central tenet of the “free radical theory of aging” hypothesis which postulates that the finite existence of aerobic organisms is associated with an increased free radical burden. Paradoxically when generated at low amounts mitochondrial H₂O₂ fulfills an important signaling function and is required to coordinate mitochondrial function with changes in cellular physiology. In fact, low grade cellular H₂O₂ production has even been shown to enhance longevity. Thus, low grade mitochondrial ROS production has many cellular benefits and are only a danger when produced in excess, a dichotomy referred to as mitohormesis. It is important to consider though how H₂O₂ formation is controlled in mitochondria. Levels can be monitored by antioxidant defense however; with the observation that mitochondria contain up to 11 sites for H₂O₂ formation control over its production is also crucial. Here, I discuss how H₂O₂ formation can be controlled by cysteine-driven redox switches. The importance of glutathione (GSH), the chief antioxidant required to quench H₂O₂, in driving the redox switch mediated control of mitochondrial H₂O₂ emission will also be discussed in the context of the controlling the mitokine function of H₂O₂. Further, I also emphasize the importance of these redox switches in governing H₂O₂ emission from the 11 potential ROS producing sites in mitochondria.