Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia

Abstract

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)-α. 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. The cells of the body require energy for self-repair, upkeep and maintenance, and for sustaining their tissue-or organspecific functions. The majority of these processes are endothermic and are therefore coupled to the hydrolysis of ATP, which provides the necessary free energy. The cellular pool of ATP and other high-energy phosphates provides a renewable energy supply that is required for survival. The majority of cells maintain the supply of ATP through oxidative phosphorylation, which couples the oxidation of metabolic substrates to the synthesis of ATP from ADP and inorganic phosphate in the mitochondria. That process consumes oxygen in proportion to the rate of ATP utilization by the cells. Hence, increases in metabolic activity are associated with increases in the rate of oxygen utilization. Multicellular organisms have developed elaborate systems for supplying O 2 to each cell in accordance with its metabolic activity and for adjusting the delivery when the metabolic needs change, as occurs in exercise. Although cells have a limited ability to generate ATP in the absence of oxygen, the loss of O 2 supply, even briefly, threatens survival. Not surprisingly, organisms have evolved a complex array of mechanisms to sustain the supply of oxygen to the cells of the body and to protect themselves in the event that oxygen availability becomes limiting. The ability to sense the level...

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