Figure 1.

Production, elimination, and signaling of ROS. Mitochondria and NADPH oxidases (NOXs) are the main sources of superoxide (O₂^˙̄), which is converted to hydrogen peroxide (H₂O₂) by superoxide dismutases (SODs). H₂O₂ can subsequently (a) oxidize thiols within redox-regulated proteins to conduct cellular signaling or (b) be reduced to water by antioxidant systems largely composed of NRF2-regulated enzymes. The peroxiredoxin (PRX)/thioredoxin (TRX) and glutathione peroxidase (GPX)/glutathione (GSH) systems are fueled by NADPH. This key reducing equivalent is generated by a complex network of metabolic pathways and enzymes involving the pentose phosphate pathway (PPP), isocitrate dehydrogenases (IDHs), malic enzymes (MEs), and one-carbon metabolism. Interestingly, NADPH is also a substrate for the ROS-generating NOXs. This suggests that the antioxidant systems and ROS producers are equally important for biological processes, and they work in concert to regulate redox environments that permit the ROS-mediated signaling without incurring oxidative damage.