Diverting Glycolysis to Combat Oxidative Stress

Abstract

Reactive oxygen species (ROS) are an intricate part of normal cellular physiology. In excess, however, ROS can damage all three major classes of macromolecules and compromise cell viability. We briefly discuss the physiology of ROS but focus on the mechanisms cells use to preserve redox homeostasis upon oxidative stress, with particular emphasis on glycolysis. ROS inhibits multiple glycolytic enzymes, including glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2, and phosphofructokinase-1. Consistently, glycolytic inhibition promotes flux into the oxidative arm of the pentose phosphate pathway to generate NADPH. NADPH is critically important, as it provides the reducing power that fuels the protein-based antioxidant systems and recycles oxidized glutathione. The unique ability of pyruvate kinase M2 inhibition to promote serine synthesis in the context of oxidative stress is also discussed.