Cellular and molecular mechanisms of O₂ sensing

Molecular oxygen is required for mitochondrial energy generation, and all eukaryotic organisms have the capacity to sense the abundance of cellular O₂. When oxygen levels decrease, these sensors activate a wide range of transcriptional, translational, and posttranslational responses that protect the cell and the organism from the consequences of severe oxygen deprivation and O2-limited metabolism. A number of different mechanisms of oxygen sensing have been proposed, and it is likely that diverse cell types employ multiple means of sensing changes in molecular oxygen. However, growing evidence points to the mitochondria as an important site of O₂ sensing in diverse cell types. These organelles release reactive oxygen species (ROS) signals to the cytosol where they trigger transcriptional and posttranslational adaptive responses. Although the precise molecular mechanisms underlying the increase in ROS generation under low O₂ conditions are not fully understood, these signals appear to originate from complex III of the electron transport chain. The responses regulated by this mechanism include the stabilization of Hypoxia-Inducible Factor-1α and the acute vasoconstrictor response to alveolar hypoxia in the lung. Future studies of prolonged hypoxia are still needed to determine whether the responses to chronic hypoxia are also regulated by this pathway.