Nitroxia: The pathological consequence of dysfunction in the nitric oxide–cytochrome c oxidase signaling pathway

Shiva, Sruti; Oh, Joo–Yeun; Landar, Aimee; Ulasova, Elena; Venkatraman, Aparna; Bailey, Shannon M.; Darley‐Usmar, Victor

doi:10.1016/j.freeradbiomed.2004.10.037

Cited by 107 publications

(84 citation statements)

References 77 publications

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“…While it is known that chronic alcohol consumption results in cytochrome c oxidase defects [82,90,104], it is likely that this alteration in NO responsiveness may be due to alcohol-dependent changes in interactions of NO with sites other than Complex IV. It is postulated that this disruption in NO signaling contributes to alcohol hepatotoxicity through inhibition of ATP synthesis, increased ROS, and inability to adapt to hypoxic stress [105]. This concept is supported because increased sensitivity to NO is absent in iNOS − /− mice exposed to chronic alcohol [90].…”

Section: Interplay Between Nitric Oxide and Mitochondria In Fatty LIVmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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Section: Interplay Between Nitric Oxide and Mitochondria In Fatty LIVmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

Self Cite

388

302

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“…Although the NO reductase activity of the enzyme is too slow to constitute a physiological mechanism for the removal of NO (22), there is strong evidence in favor of the oxidation of NO to NO 2 Ϫ both by the purified enzyme (23,24) and by cells (25). Nevertheless, the possibility that cytochrome c oxidase constitutes a significant metabolic route for NO remains controversial (26,27) and has been directly challenged (28).…”

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Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation

Palacios-Callender

Hollis

Mitchison

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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One of the many routes proposed for the cellular inactivation of endogenous nitric oxide (NO) is by the cytochrome c oxidase of the mitochondrial respiratory chain. We have studied this possibility in human embryonic kidney cells engineered to generate controlled amounts of NO. We have used visible light spectroscopy to monitor continuously the redox state of cytochrome c oxidase in an oxygentight chamber, at the same time as which we measure cell respiration and the concentrations of oxygen and NO. Pharmacological manipulation of cytochrome c oxidase indicates that this enzyme, when it is in turnover and in its oxidized state, inactivates physiological amounts of NO, thus regulating its intra-and extracellular concentrations. This inactivation is prevented by blocking the enzyme with inhibitors, including NO. Furthermore, when cells generating low concentrations of NO respire toward hypoxia, the redox state of cytochrome c oxidase changes from oxidized to reduced, leading to a decrease in NO inactivation. The resultant increase in NO concentration could explain hypoxic vasodilation.hypoxia ͉ mitochondrial respiration ͉ nitric oxide inactivation ͉ nitric oxide synthase D espite much research on its metabolic fate, the way in which the concentration of nitric oxide (NO) is regulated in cells and tissues is at present unresolved. Many routes for its inactivation have been discussed, including interaction with superoxide ions (1), hemoglobin (2-4) or myoglobin (5), accelerated autoxidation favored by partition within cell membranes (6), and interactions with free radicals derived from eicosanoid lipoxygenase (7), cyclo-oxygenase (8), different peroxidases (9), or catalase (10). Interactions with a flavohemoglobin-like NO dioxygenase (11-13) or with an unknown protein (14), and simple partitioning within mitochondrial membranes (15), have also been suggested.Before the discovery of NO as a biological mediator (16) it had been shown that isolated cytochrome c oxidase, the terminal enzyme in the mitochondrial electron transport chain, catalyzes both the oxidation and reduction of NO (17). More recent evidence has suggested that cytochrome c oxidase may provide a metabolic route for NO, either by interaction of NO with the reduced enzyme, leading to the formation of N 2 O, (18,19) or by interaction of NO with the oxidized enzyme, forming nitrite (NO 2 Ϫ ; 20, 21). Although the NO reductase activity of the enzyme is too slow to constitute a physiological mechanism for the removal of NO (22), there is strong evidence in favor of the oxidation of NO to NO 2 Ϫ both by the purified enzyme (23, 24) and by cells (25). Nevertheless, the possibility that cytochrome c oxidase constitutes a significant metabolic route for NO remains controversial (26, 27) and has been directly challenged (28).Clarifying the route(s) of the cellular inactivation of NO will be important for a fuller understanding of its biological functions. We have therefore investigated the role of cytochrome c oxidase in the metabolic fate of NO by using our met...

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“…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].…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Landar

Darley‐Usmar

2007

Biochemical Journal

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Haem is used as a versatile receptor for redox active molecules; most notably NO (nitric oxide) and oxygen. Three haemcontaining proteins, myoglobin, haemoglobin and cytochrome c oxidase, are now known to bind NO, and in all these cases competition with oxygen plays an important role in the biological outcome. NO also binds to the haem group of sGC (soluble guanylate cyclase) and initiates signal transduction through the formation of cGMP in a process that is oxygen-independent. From biochemical studies, it has been shown that sGC is substantially more sensitive to NO than is cytochrome c oxidase, but a direct comparison in a cellular setting under various oxygen levels has not been reported previously. In this issue of the Biochemical Journal, Cadenas and co-workers reveal how oxygen can act as the master regulator of the relative sensitivity of the cytochrome c oxidase and sGC signalling pathways to NO. These findings have important implications for our understanding of the interplay between NO and oxygen in both physiology and the pathology of diseases associated with hypoxia.Key words: cytochrome c oxidase, haem (heme), mitochondria, nitric oxide, redox signalling.Nitric oxide (NO) is an unusual signalling molecule since its biological responses are primarily governed by its chemical reactivity [1]. In fact, the first signalling function of NO was revealed with the discovery that NO serves as a ligand for the haem group in sGC (soluble guanylate cyclase), resulting in increased cGMP production and activation of downstream signalling cascades. 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]. Using an elegant experimental model that allows the controlled formation of NO from iNOS (inducible NO synthase) in cells that contain both COX and sGC, the authors have compared the response of these two signalling pathways with the concentration of NO measured extracellularly. Several endpoints were selected to assess the activity of sGC and COX. These include production of cGMP and phosphorylation of VASP (vasodilator-stimulated phosphoprotein) for the sGC pathway, and oxygen consumption and AMPK (AMP-activated protein kinase) phosphorylation for the COX pathway. The acti...

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Nitroxia: The pathological consequence of dysfunction in the nitric oxide–cytochrome c oxidase signaling pathway

Cited by 107 publications

References 77 publications

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilation

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

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