Oxygen—A Key Regulatory Metabolite in Metabolic Defense Against Hypoxia

Abstract

Two main defense strategies against hypoxia tolerant animals have been identified in earlier studies: (i) reduction in energy turnover and (ii) improved energetic efficiency of those metabolic processes that remain. Two model systems were developed from the highly anoxia tolerant aquatic turtle—(i) tissue slices of brain cortex (to probe cell level electrophysiological responses to oxygen limitation) and (ii) isolated liver hepatocytes (to probe signalling and defense). In the latter, a series of mechanisms underpinning hypoxia defense is initiated with an oxygen sensor (probably a heme protein) and a message transduction pathway leading to the specific activation of some genes (increased expression of several proteins) and to specific down regulation of other genes (decreased expression of several other proteins). The pathway seems similar to oxygen regulated schemes in other cells. The main roles for the oxygen sensing and signal transduction system appear to include coordinate down regulation of energy demand and energy supply pathways in metabolism. By this means, hypoxia tolerant cells stay in energy balance as they down regulate to extremely low levels of ATP turnover. The main ATP demand pathways in normoxia (protein synthesis, protein degradation, glucose synthesis, urea synthesis, and maintenance of electrochemical gradients) are all depressed to variable degree during anoxia or extreme hypoxia. However, Na+ K+ ATPase is the main energy sink in anoxia—despite significant reductions in cell membrane permeability (“channel arrest”). Turtle brain cortical cells also show lower permeability than do homologous hypoxia sensitive cells, but in this case under acute anoxia, there is no further change in cell membrane conductivity. These two models may supply guidelines for further studies of estuarine animals on how normoxic maintenance ATP turnover rates can be down regulated by an order of magnitude or more—to new hypometabolic steady states prerequisite for surviving prolonged hypoxia or anoxia