Reactive oxygen species and cell signaling. Review

Reactive oxygen species (ROS) is a term encompassing a group of highly reactive oxygen-derived molecules. In physiological systems, ROS production exists in concert with antioxidant defenses, which safeguard cells against higher, toxic levels of ROS. Oxidative stress, coined as “oxidative distress”, is “a serious imbalance between the generation of ROS and antioxidant defenses in favor of ROS, causing excessive oxidative damage to biomolecules”. At physiological levels, ROS are essential for many cellular processes, which is known as “oxidative eustress”. Oxidants like hydrogen peroxide (H2O2) activate signaling pathways like mitogen-activated protein kinases (MAPK)s and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). ROS activate transcription factors like nuclear factor erythroid 2–related factor 2 (Nrf2), hypoxia-inducible factor 1α (HIF-1α), activator protein 1 (AP-1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Redox signaling through H2O2 mainly occurs through reversible oxidation of protein cysteine thiolate residues (RS−) to form sulfenic acids (RSOH). An unresolved question is that the reaction rate of H2O2 with protein thiols is very low. In cells, the reaction of H2O2 with protein thiols is likely to be outcompeted by faster reactions of H2O2 with peroxiredoxins and glutathione peroxidases. A novel mechanism being explored is that H2O2 could react with peroxiredoxins that act as reactive redox sensor proteins, leading to peroxiredoxin-mediated relays. Very few redox signaling pathways have been well characterized. Improved understanding of precise mechanisms by which ROS regulate signaling pathways and the role of cellular sensors, is essential for deciphering their roles in physiological and pathological conditions.