Molecular aspects of oxygen sensing in physiological adaptation to hypoxia

Oxygen is an essential substrate in aerobic metabolism for most eukaryotic organisms. Thus organisms and cells have developed numerous immediate and long-term compensatory mechanisms for dealing with oxygen deprivation. Adaptation to hypoxia at the organismal level includes reflex hyperventilation, polycythemia and angiogenesis, which lead to increased O2 delivery to the tissues. Adaptation at the cellular level involves a shift from oxidative phosphorylation to anaerobic glycolysis, increased glucose metabolism, and expression of hypoxic stress-related proteins. Regulation of many proteins participating in adaptation to hypoxia occurs at the level of gene expression. The most widespread molecular mechanism of hypoxia-dependent regulation is transcriptional induction via the binding of a transcription factor, hypoxia-inducible factor-1 (Hif-1), to the specific sequences on the regulated genes. Long-term induction of many proteins also requires an increase in mRNA stability, which is mediated by the binding of regulatory proteins to specific sequences within the mRNAs. The current theories of coupling between the O2 sensor and mechanisms controlling gene expression are discussed.