Nitric oxide: orchestrating hypoxia regulation through mitochondrial respiration and the endoplasmic reticulum stress response

Abstract

Mitochondria have long been considered to be the powerhouse of the living cell, generating energy in the form of the molecule ATP via the process of oxidative phosphorylation. In the past 20 years, it has been recognised that they also play an important role in the implementation of apoptosis, or programmed cell death. More recently it has become evident that mitochondria also participate in the orchestration of cellular defence responses. At physiological concentrations, the gaseous molecule nitric oxide (NO) inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competition with oxygen. This interaction underlies the mitochondrial actions of NO, which range from the physiological regulation of cell respiration, through mitochondrial signalling, to the development of "metabolic hypoxia" -a situation in which, although oxygen is available, the cell is unable to utilise it.

Ultrastructure and histochemistry of rat myocardial capillary endothelial cells in response to diabetes and hypertension

“…Hypoxia is known to upregulate transcription factor HIF1 activating expression of genes involved in angiogenesis [43]. However, it was demonstrated that co-existence of both hypoxia and lower NO concentration caused a rapid decrease in HIF1 [44,45] that may represent one of the mechanisms involved in anti-angiogenic efect of NO.…”

Neuronal Nitric Oxide Synthase Plays a Key Role in CNS Demyelination

“…Thus, it has been documented that NO exerts several actions on cell respiration, particularly that NO is able to inhibit complex IV in the respiratory chain on mitochondria (Brunori et al, 2004). As a result of this inhibition, NO has been reported to posses both pro-apoptotic and anti-apoptotic effects (Beltran et al, 2000;Xu et al, 2005). Because apoptosis appears to be the main mechanism leading to oligodendrocyte death in this model (Arnett et al, 2002), it is possible that differences in time, dose, and site of NO secretion by the different NOS isoforms in response to cuprizone may lead to divergent effects in oligodendrocyte apoptosis and, therefore, explain the differences between the various NOS mutant strains and wild-type mice.…”

Evidence for oxygen as the master regulator of the responsiveness of soluble guanylate cyclase and cytochrome c oxidase to nitric oxide

“…The very high levels of NO shown in the present study are capable of inhibiting oxygen consumption by the mitochondria sufficient to decrease ATP synthesis. This can create a condition we have called 'nitroxia', which is associated with high levels of NO, oxygen and impaired mitochondrial bioenergetics [5,6]. The highly reducing status of the mitochondrial respiratory chain in the presence of oxygen will then promote superoxide formation.…”

“…However, the story became more complex with the recognition that NO serves as a ligand for other haem proteins such as COX (cytochrome c oxidase) in the mitochondria and haemoglobin in the red blood cell [2,3]. The fact that NO interacts with the haem groups that normally bind oxygen essentially expanded the role of NO in cell signalling from a simple haem ligand to a regulatory modulator of oxygen-sensitive processes [4][5][6].…”

“…However, the story became more complex with the recognition that NO serves as a ligand for other haem proteins such as COX (cytochrome c oxidase) in the mitochondria and haemoglobin in the red blood cell [2,3]. The fact that NO interacts with the haem groups that normally bind oxygen essentially expanded the role of NO in cell signalling from a simple haem ligand to a regulatory modulator of oxygen-sensitive processes [4][5][6].Since both COX and sGC frequently co-exist within the same cell, the relative sensitivity of the two pathways to NO should determine the ultimate biological effect. It has been shown that activation of sGC occurs at much lower concentrations of NO than inhibition of COX, but these studies have not addressed the sensitivity of these pathways using endogenous NO formation; nor have they investigated the influence of oxygen on this relative sensitivity in a cellular setting [7].…”