Control of Mitochondrial Respiration by NO., Effects of Low Oxygen and Respiratory State

Brookes, Paul S.; Kraus, David W.; Shiva, Sruti; Doeller, Jeannette E.; Barone, Maria-Cecilia; Patel, Rakesh P.; Lancaster, Rachel B.; Darley‐Usmar, Victor

doi:10.1074/jbc.m211784200

Cited by 111 publications

(91 citation statements)

References 28 publications

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“…This explanation recently found experimental support by the observation that for the same level of COX inhibition by NO the rate of mitochondrial respiration was more inhibited at state 3 than at state 4 (24). However, the difference found was relatively small, and it does not explain the almost complete insensitivity of state 4 observed in some conditions.…”

Section: Effects Of No In State 3 and State 4 Respirationsupporting

confidence: 45%

See 1 more Smart Citation

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

Antunes

Boveris

Cadenas

2004

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

171

131

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The detailed molecular mechanism for the reversible inhibition of mitochondrial respiration by NO has puzzled investigators: The rate constants for the binding of NO and O 2 to the reduced binuclear center Cu B͞a3 of cytochrome oxidase (COX) are similar, and NO is able to dissociate slowly from this center whereas O 2 is kinetically trapped, which altogether seems to favor the complex of COX with O 2 over the complex of COX with NO. Paradoxically, the inhibition of COX by NO is observed at high ratios of O 2 to NO (in the 40 -500 range) and is very fast (seconds or faster). In this work, we used simple mathematical models to investigate this paradox and other important biological questions concerning the inhibition of COX by NO. The results showed that all known features of the inhibition of COX by NO can be accounted for by a direct competition between NO and O 2 for the reduced binuclear center Cu B͞a3 of COX. Besides conciliating apparently contradictory data, this work provided an explanation for the so-called excess capacity of COX by showing that the COX activity found in tissues actually is optimized to avoid an excessive inhibition of mitochondrial respiration by NO, allowing a moderate, but not excessive, overlap between the roles of NO in COX inhibition and in cellular signaling. In pathological situations such as COX-deficiency diseases and chronic inflammation, an excessive inhibition of the mitochondrial respiration is predicted.mitochondrial respiration ͉ mathematical model ͉ cytochrome-oxidasedeficiency diseases ͉ inflammation ͉ excess capacity of cytochrome oxidase T he paradigm that the respiratory chain is regulated by ADP and O 2 was recently updated to include the reversible inhibition of cytochrome oxidase (COX) by nitric oxide (NO) (1-6). The physiological role and the detailed molecular mechanism of this inhibition, as well as the reason for the apparent excess content of COX compared with other mitochondrial complexes, are fundamental questions of mitochondrial biochemistry that remain unsolved. Concerning the mechanism, the problem is particularly puzzling because the known characteristics of COX inhibition by NO are difficult to conciliate with the available kinetic rate constants for this inhibition. On the one hand, COX is inhibited rapidly, within a time scale of seconds, with half-inhibition of respiration attained at O 2 ͞NO ratios in the 40-500 range (4, 7), which apparently indicates that the interaction of COX with NO is stronger than that of COX with O 2 and very fast. On the other hand, the rate constants for the binding of O 2 and NO with the fully reduced binuclear center (Cu B ͞a 3 ) of COX are similar [1.4 ϫ 10 8 (8) and 4 ϫ 10 7 to 1 ϫ 10 8 M Ϫ1 ⅐s Ϫ1 (9, 10), respectively] and NO dissociates slowly from this center (0.01-0.13 s Ϫ1 ) (11, 12), whereas the apparent dissociation rate constant of O 2 with COX is virtually zero because, during the initial steps of reduction of oxygen by COX, oxygen is kinetically trapped (8). Accordingly, several investigators have noticed th...

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Section: Effects Of No In State 3 and State 4 Respirationsupporting

confidence: 45%

“…One consequence of NO inhibition is an increase of cytochrome c reduction (23,24). For example, cytochrome c is 50-77% reduced in the presence of NO produced by the specialized NO synthase of the inner mitochondrial membrane, vs. Ϸ6-15% cytochrome c reduction in the absence of NO (23,25).…”

Section: The Modelmentioning

confidence: 99%

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

Antunes

Boveris

Cadenas

2004

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

171

131

View full text Add to dashboard Cite

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“…NO has been known to influence respiration rates of cancer cells by targeting mitochondrial complexes, complex I and IV (41,42). Previous studies carried out primarily in liver cells showed that NO regulates mitochondrial respiration by targeting terminal enzyme of electron transport chain, cytochrome c oxidase by competing with oxygen (43). Inhibition of complex IV is rapid (milliseconds), reversible, and occurs at low NO concentrations (nmol/L), whereas inhibition of complex I occurs after a constant exposure of higher NO concentrations (44,45).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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“…This is important for hepatotoxicity because NO and peroxynitrite (ONOO − ) are known to mediate mitochondrial dysfunction [96,97] and increases in iNOS expression in fatty liver are correlated with nitration of mitochondrial proteins [53,98]. Moreover, NO regulates mitochondrial respiration through reversible binding at the redoxactive heme site in cytochrome c oxidase [99][100][101] and affects mitochondrial biogenesis through interactions with soluble guanylate cyclase [102]. Studies have shown that mitochondria from chronic alcohol-fed animals are more sensitive to the inhibitory effect of NO on respiration [90,103].…”

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

382

302

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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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Control of Mitochondrial Respiration by NO., Effects of Low Oxygen and Respiratory State

Cited by 111 publications

References 28 publications

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

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

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