(155e) Reactive Oxygen Species as Intracellular Second Messengers

There has been a great deal of research devoted to elucidating the regulatory processes that control cellular metabolism. In most of these studies, metabolism is viewed as the cellular "engine", which responds passively to both nutritional "fuel" availability as well as the collective molecular "throttle" of intracellular signaling networks. However, a new picture is emerging wherein metabolism plays an active role in communicating cellular status back to these signaling networks via the production of intracellular second messengers. Chief among these putative second messengers are reactive oxygen species (ROS), especially H₂O₂, which are produced by several metabolic pathways (e.g., mitochondrial respiration, NADPH oxidases, etc.) and are known to modulate cell-cycle events including proliferation and apoptosis. For instance, ROS have been shown to activate MAPK signaling pathways by inhibiting phosphatase activities. Furthermore, elevated ROS are proposed to contribute to the maintenance of constitutive HIF activation in many tumor cells. In this presentation, I will outline some recent results from my lab that illustrate the central role of ROS in modulating cell fate. I will draw from two specific examples, one where ROS serve to enhance proliferation in Myc-overexpressing lymphoma cells, and another where excess ROS accumulation triggers apoptosis in hepatic cells exposed to toxic levels of saturated fatty acids.