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

Abstract

Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O2 for mitochondrial respiration. When O2 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 O2 and gas diffusion in the cell, how intracellular O2 is regulated, how intracellular O2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O2 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 O2 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 O2 sensitivity of metabolic rate, O2 kinetics in exercise, and influences of available O2 on glycolysis and lactate production.

Hydrogen Sulfide as an Oxygen Sensor

“…Initial sensing and coping mechanisms reflected in response to ischemia/reperfusion injury and pre-and postconditioning are only briefly discussed here in the context of acute O 2 sensing. Chronic responses involving metabolic control are described in an excellent review by Clanton et al (22) and are beyond the scope of the present discussion.…”

“…A number of mechanisms have been suggested, but none has achieved unequivocal support. Their pros and cons have been extensively reviewed (22,37,47,54,144,155,184,187). The intent of the present review is to examine the evidence suggesting that the O 2 -dependent metabolism of H 2 S is an O 2 sensor.…”

Joint-level mechanics of the walk-to-run transition in humans

“…In contrast, joint work reflects the joint's mechanical function over a portion of the stride. Similar to the overall metabolic rate, the longer time over which these variables fluctuate might preclude them from causing the transition step itself [although AMP-activated protein kinase (Winder, 2001) and/or other cellular mechanisms (Clanton et al, 2013) may provide acute sensing of the energy/work state of a muscle]. However, the increase in joint mechanical work at the ankle and hip during fast walking above that required for running offers a reasonable explanation, together with instantaneous peaks in joint power and moments, for why humans avoid walking at these speeds and instead choose to either walk slower or run faster.…”

Skeletal muscle interleukin-6 regulation in hyperthermia

“…Though it seems counterintuitive that cells would use autocrine/paracrine pathways to accomplish this, such strategies are very common as a means of promoting survival pathways in response to extreme stress exposures. They comprise the basic response elements in initiating states of preconditioning (7).…”