All eukaryotic cells utilize oxidative phosphorylation to maintain their high-energy
phosphate stores. Mitochondrial oxygen consumption is required for
ATP generation, and cell survival is threatened when cells are deprived of O(2). Consequently, all cells have the ability to sense O(2), and to activate adaptive processes that will enhance the likelihood of survival in anticipation that
oxygen availability might become limiting. Mitochondria have long been considered a likely site of
oxygen sensing, and we propose that the electron transport chain acts as an O(2) sensor by releasing
reactive oxygen species (ROS) in response to
hypoxia. The ROS released during
hypoxia act as signalling agents that trigger diverse functional responses, including activation of gene expression through the stabilization of the
transcription factor hypoxia-inducible factor (HIF)-alpha. The primary site of ROS production during
hypoxia appears to be
complex III. The paradoxical increase in ROS production during
hypoxia may be explained by an effect of O(2) within the mitochondrial inner membrane on: (a) the lifetime of the
ubisemiquinone radical in
complex III; (b) the relative release of mitochondrial ROS towards the matrix compartment versus the intermembrane space; or (c) the ability of O(2) to access the
ubisemiquinone radical in
complex III. In summary, the process of
oxygen sensing is of fundamental importance in biology. An ability to control the
oxygen sensing mechanism in cells, potentially using small molecules that do not disrupt oxygen consumption, would open valuable therapeutic avenues that could have a profound impact on a diverse range of diseases.