Adaptions to Hypoxia and Redox Stress
Essential Concepts Confounded by Misleading Terminology
Cells and organisms have developed a remarkable array of responses to adapt to hypoxic environments. In this Viewpoint, the author discusses the definitions and determinants of redox stress in hypoxia, the relationships among the changes in glucose metabolism, and the alterations in cell redox state.
The ability to adapt to hypoxia is a fundamental survival strategy for all living organisms. In part, these adaptive mechanisms likely evolved from primordial metabolic programs in the hypoxic environment of the Proterozoic Eon1 within which ATP is generated from atypical energy sources, such as hydrogen sulfide. The best-studied adaptive mechanism is, of course, stabilization of the transcription factor, hypoxia-inducible factor-1, which leads to changes in gene expression that enhance glycolysis and attenuate oxidative phosphorylation. In recent years, the transition from oxidative phosphorylation to glycolysis has also been demonstrated in normoxic environments and shown to be induced by mediators such as D(R)-2-hydroxyglutarate, an oncometabolite product of the neomorphic activity of mutant isocitrate dehydrogenases (IDH1 and IDH2),2 fumarate, and hydrogen sulfide. These and other related mechanisms decrease the cell’s metabolic dependence on molecular oxygen for ATP synthesis.
In addition to its effect on cellular energetics, the shift from oxidative phosphorylation to glycolysis in hypoxic environments serves another key purpose: it decreases the generation of potentially injurious reactive oxygen species (ROS). With hypoxia (but not anoxia), the mitochondrial electron transport chain becomes inefficient and leaks electrons to molecular oxygen, generating superoxide anion and hydrogen peroxide (by spontaneous or enzyme-catalyzed dismutation). The determinants of superoxide generation in these conditions include high proton motive force, increased ubiquinol/ubiquinone, and increased NADH/NAD+ in the setting of decreased ATP synthesis. The shift from oxidative phosphorylation to glycolysis offsets these adverse effects, in part, by decreasing carbon flux through the tricarboxylic acid cycle to limit further NADH generation, the …