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The University of Chicago, Pulmonary and Critical Care Medicine, Chicago, Illinois 60637
Hypoxia elicits a variety of adaptive responses at the tissue level, at the cellular level, and at the molecular level. A physiological response to hypoxia requires the existence of an O2 sensor coupled to a signal transduction system, which in turn activates the functional response. Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O2 sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O2 binding or release at different PO2 levels. Other studies suggest that ion channels may change conductance as a function of PO2, allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O2 species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O2 sensors by increasing their generation of ROS during hypoxia. These oxidant signals appear to act as second messengers in the adaptive responses to hypoxia in a variety of cell types. Such observations contribute to a growing awareness that mitochondria do more than just generate ATP, in that they initiate signaling cascades involved in adaptive responses to hypoxia and that they participate in the control of cell death pathways.
hypoxia; reactive oxygen species; NADPH; erythropoietin; hypoxia-inducible factor-1
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