Differential regulation of metabolism by nitric oxide and<i>S</i>-nitrosothiols in endothelial cells

Diers, Anne R.; Broniowska, Katarzyna A.; Darley‐Usmar, Victor; Hogg, Neil

doi:10.1152/ajpheart.00210.2011

Cited by 26 publications

(30 citation statements)

References 51 publications

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“…No change in basal OCR was observed for the cells over the course of the experiment with any treatments. The lack of effect of NO on basal respiration has been observed in other cells and is likely due to the fact that basal respiration is largely controlled by the availability of ADP, which is low under unstressed conditions, and not by the activity of the target for NO, cytochrome c oxidase (17;27;44;45). After a total of 250 min a mitochondrial profile was established by the sequential addition of inhibitors of oxidative phosphorylation as described previously (46).…”

Section: Resultsmentioning

confidence: 86%

Inhibition of autophagy and glycolysis by nitric oxide during hypoxia–reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons

Benavides

Liang

Dodson

et al. 2013

Free Radical Biology and Medicine

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Excessive nitric oxide (NO) production is known to damage mitochondrial proteins and the autophagy repair pathway and so can potentially contribute to neurotoxicity. Accordingly, we hypothesized that protection against protein damage from reactive oxygen and nitrogen species (ROS/RNS) under conditions of low oxygen by the autophagy pathway in neurons would be impaired by NO and enhance bioenergetic dysfunction. Rat primary cortical neurons maintained the same basal cellular respiration in hypoxia as normoxia, whereas NO exposed cells exhibited a gradual decrease in mitochondrial respiration in hypoxia. Upon reoxygenation, the respiration in NO treated cells did not recover to pre-hypoxic levels. Hypoxia-reoxygenation in the presence of NO was associated with inhibition of autophagy and the inability to recovery during reoxygenation was exacerbated by the inhibitor of autophagy, 3-methyladenine. The effects of hypoxia could be recapitulated by inhibiting glycolytic flux under normoxic conditions. Under both normoxic and hypoxic conditions NO exposure induced immediate stimulation of glycolysis but prolonged NO exposure, associated with irreversible inhibition of mitochondrial respiration in hypoxia, inhibited glycolysis. Importantly, we found that NO inhibited basal respiration under normoxic conditions only when glucose was absent from the media or glycolysis was inhibited by 2-deoxy-D-glucose, revealing a novel NO-dependent mechanism for the inhibition of mitochondrial respiration which is modulated by glycolysis. Taken together these data suggest an oxygen-dependent interaction between mitochondrial respiration, glycolysis and autophagy in protecting neuronal cells exposed to NO. Importantly, they indicate that mitochondrial dysfunction is intimately linked to a failure of glycolytic flux induced by exposure to NO. In addition, these studies provide new insights into understanding how autophagy and NO may play an interactive role in neuroinflammation-induced cellular damage which is pertinent to our understanding of the pathology neurodegenerative diseases in which excessive NO is generated.

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Section: Resultsmentioning

confidence: 86%

Inhibition of autophagy and glycolysis by nitric oxide during hypoxia–reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons

Benavides

Liang

Dodson

et al. 2013

Free Radical Biology and Medicine

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“…We also found that LA increased the mitochondrial antioxidant capacity, and partially restored mitochondrial enzyme activity and increased ATP yield during sepsis in which an excess of NO had been produced [21]. Other investigators have also reported that the exposure of endothelial cells to small molecular S -nitrosothiols significantly down-regulates their mitochondrial function [22]. Therefore, we hypothesized that inflammation-induced excess NO production increases protein S -nitrosylation, which may result in diminished oxidative phosphorylation and decreased energy production in some mitochondrial enzymes.…”

Section: Introductionmentioning

confidence: 70%

Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress

Hiller

DeKroon

Hamlett

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background S-nitrosylation of mitochondrial enzymes involved in energy transfer under nitrosative stress may result in ATP deficiency. We investigated whether α-lipoic acid, a powerful antioxidant, could alleviate nitrosative stress by regulating S-nitrosylation, which could result in retaining the mitochondrial enzyme activity. Methods In this study, we have identified the S-nitrosylated forms of subunit 1 of dihydrolipoyllysine succinyltransferase (complex III), and subunit 2 of the α-ketoglutarate dehydrogenase complex by implementing a fluorescence-based differential quantitative proteomics method. Results We found that the activities of these two mitochondrial enzymes were partially but reversibly inhibited by S-nitrosylation in cultured endothelial cells, and that their activities were partially restored by supplementation of α-lipoic acid. We show that protein S-nitrosylation affects the activity of mitochondrial enzymes that are central to energy supply, and that α-lipoic acid protects mitochondrial enzymes by altering S-nitrosylation levels. Conclusions Inhibiting protein S-nitrosylation with α-lipoic acid seems to be a protective mechanism against nitrosative stress. General significance Identification and characterization of these new protein targets should contribute to expanding the therapeutic power of α-lipoic acid and to a better understanding of the underlying antioxidant mechanisms.

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“…In fact, studies have demonstrated that NO inhibits glycolytic flux [57]. Along these lines, proteomics and other biochemical analyses have found evidence for S-nitrosylation of glycolysis-related proteins, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and aldolase [47, 58].…”

Section: Tca Cycle Enzymes As Targets Of S-nitrosylationmentioning

confidence: 99%

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

Nakamura

Lipton

2017

Trends in Endocrinology & Metabolism

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The prevalence of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, is currently a major public health concern due to the lack of efficient disease-modifying therapeutic options. Recent evidence suggests that mitochondrial dysfunction and nitrosative/oxidative stress are key common mediators of pathogenesis. In this review, we highlight molecular mechanisms linking nitric oxide (NO)-dependent post-translational modifications, such as cysteine S-nitrosylation and tyrosine nitration, to abnormal mitochondrial metabolism. We further discuss the hypothesis that pathological levels of NO compromise brain energy metabolism via aberrant S-nitrosylation of key enzymes in the tricarboxylic acid cycle and oxidative phosphorylation, contributing to neurodegenerative conditions. A better understanding of these pathophysiological events may provide a potential pathway for designing novel therapeutics to ameliorate neurodegenerative disorders.

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Differential regulation of metabolism by nitric oxide andS-nitrosothiols in endothelial cells

Cited by 26 publications

References 51 publications

Inhibition of autophagy and glycolysis by nitric oxide during hypoxia–reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons

Inhibition of autophagy and glycolysis by nitric oxide during hypoxia–reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons

Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

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