The expanding network of redox signaling: new observations, complexities, and perspectives.

Abstract

Over thirty years ago, the observations that eventually led to the discovery of the NADPH oxidase were made by Baehner, Karnovsky, and colleagues (1–3). These have served as a focal point of interest in placing reactive oxygen species (ROS) in the conceptual forefront of the biomedical community. Over the last decade, the examination of the roles of oxygen and redox tone in regulating cell function has turned inward to the intracellular environment. Because oxidative metabolism is central to the biology and health of all humans, how we respond to conditions of low and high oxygen stress has become a critical consideration in biology and medicine. Humans live in a world where we continually balance the use of oxygen as a source of energy, and as a source of cellular injury. The generation of oxygen radicals secondary to mitochondrial disruption, the activation of cellular NADPH oxidases, the metabolism of xenobiotics, or other forms of oxidative stress can lead to mutations in DNA, lipid peroxidation, and protein damage. We have therefore evolved a marvelously complex system of both defense mechanisms and sensing mechanisms for changes in cellular redox tone. These include the enzymes superoxide dismutase, catalase, and glutathione peroxidase that detoxify ROS. We have also developed signaling mechanisms that utilize ROS to initiate processes that allow cells to survive exposure to oxidative stress within certain tolerances, but also, when stress and damage become too great, to ensure cell death. How these pathways are initiated and controlled on a molecular basis by ROS and also molecular oxygen is at the heart of what is generally considered redox signaling and the response to oxidative stress. The molecular species that fall under the term ROS include superoxide, hydrogen peroxide (H2O2), hydroxyl radical, and singlet oxygen. Each of these can play a role in a variety of intracellular processes. Finally, we have adapted these molecular species, particularly H2O2 and (NO), as signaling molecules in multiple biological processes.