Historical perspectives of cellular oxygen sensing and responses to hypoxia.

The responses to acute and chronic hypoxia begin with oxygen sensing, and this historical perspective is written in line with this concept. The earliest pertinent work started with studies on fermentation in yeast in the 17th century, before the discovery of oxygen. It required 200 yr to localize the oxygen sensing within the cells and another 100 yr to discover the cellular oxidation reactions. Today, the consensus is that the mitochondrial respiratory chain is in part the site of oxygen sensing. In addition, membrane-bound NAD(P)H oxidase possibly takes part in oxygen sensing. Oxygen-sensing mechanisms occur in a tissue-specific fashion. For example, the carotid body responds to hypoxia promptly by eliciting a ventilatory response, whereas erythropoietin production in response to hypoxia requires more time, involving new expression of genes. The mechanism has therefore moved from the cells to genes.