Cellular oxygen sensing by mitochondria: old questions, new insight

Abstract

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 O(2) 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 O(2) sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O(2) binding or release at different PO(2) levels. Other studies suggest that ion channels may change conductance as a function of PO(2), allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O(2) species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O(2) 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.

Influence of Hypoxia on Nitric Oxide Synthase Activity and Gene Expression in Children With Congenital Heart Disease

“…Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O 2 sensors. 15 This study showed that changes in the pattern of NOS isoforms underlie the pathophysiological consequences of hypoxia in cyanotic congenital heart disease. This raises the possibility that changes in reactive nitrogen species may be involved in adaptive mechanisms to chronic hypoxia.…”

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

“…Later on, Obeso et al (1999) and by He et al (2005) found, respectively, that maximal pharmacological inhibition of NADPH oxidase did not abolished the release of neurotransmitters elicited by hypoxia in chemoreceptor cells and that NADPH oxidase knockout mice cells exhibited normal or even exaggerated sensitivity to hypoxia. More recently it has been suggested that in chemoreceptor cells hypoxia would increase (Chandel and Schumacker, 2000) or decrease mitochondrial ROS production (Porwol et al, 2001). Mitochondria would represent the O 2 -sensor, and altered levels of mitochondrial ROS would gain cell cytoplasm to oxidize SH or to reduce S S groups in K + channels leading to their inhibition.…”

Changes in the Mitochondrial Proteome during the Anoxia to Air Transition in Rice Focus around Cytochrome-containing Respiratory Complexes

“…Many experiments have been conducted on tissues that develop in the presence of O 2 and are assessed during short term oxygen deprivation. Such studies have shown that mammalian mitochondria may function as oxygen sensors and secondary messengers by increasing their generation of reactive oxygen species during the early stages of oxygen deprivation (5). Induction of some "hypoxic nuclear genes" in both mammals and yeast requires mitochondrial respiration and cytochrome c oxidase has been shown to function as a key oxygen sensor during this process (6).…”