Hydrogen peroxide sensing and signaling in physiology and disease: implications for therapy

Free radicals are highly reactive molecules that are ubiquitous in aerobic organisms. Among them, oxyradicals like superoxide (O₂^•-), hydrogen peroxide (H₂O₂), and hydroxyl radical (OH^•), collectively called reactive oxygen species (ROS), have drawn the most attention from researchers in the life sciences and biomedicine because these are the byproducts of aerobic metabolism that are responsible for the oxidative burden experienced by mammalian cells. However, it is now known this oxidative stress only occurs when cells are overwhelmed with ROS and that controlled bursts in free radical production orchestrate signaling pathways essential for organismal health. ROS like H₂O₂ is now a well-characterized second messenger that transmits signals through protein sulfur switches to activate cell stress coping strategies and induce pathways involved in proliferation, growth, and development. Additionally, defects in these redox systems have been found to be related to many diseases, which has led to the development of new therapeutic modalities to treat and prevent various disorders. In this Review, I will discuss the history of the Redox Biology and Medicine field and how these findings led to the discovery of the three known H₂O₂ signaling pathways that occur in cells; the floodgate, redox relay, and S-glutathionylation signaling mechanisms. Using this information and new findings generated with advanced molecular biology techniques that have quantified the cellular distance traveled by H₂O₂, I then propose that cells use these three redox signaling mechanisms to sense and transmit H₂O₂ signals over short and long cellular distances in mammalian cells.