Regulation of Cellular Gas Exchange, Oxygen Sensing, and Metabolic Control

Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O-2 for mitochondrial respiration. When O-2 uptake and delivery move out of homeostasis, cells have elaborate and diverse sensing and response systems to compensate. In this review, we explore the biophysics of O-2 and gas diffusion in the cell, how intracellular O-2 is regulated, how intracellular O-2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O-2 affects the redox state of the cell, as well as the NO, H2S, and CO concentrations. We also explore how these agents can affect various aspects of gas exchange and activate acute signaling pathways that promote survival. Two kinds of challenges to gas exchange are also discussed in detail: when insufficient O-2 is available for respiration (hypoxia) and when metabolic requirements test the limits of gas exchange (exercising skeletal muscle). This review also focuses on responses to acute hypoxia in the context of the original unifying theory of hypoxia tolerance as expressed by Hochachka and colleagues. It includes discourse on the regulation of mitochondrial electron transport, metabolic suppression, shifts in metabolic pathways, and recruitment of cell survival pathways preventing collapse of membrane potential and nuclear apoptosis. Regarding exercise, the issues discussed relate to the O-2 sensitivity of metabolic rate, O-2 kinetics in exercise, and influences of available O-2 on glycolysis and lactate production. (C) 2013 American Physiological Society.