Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response

Xu, Weiming; Liu, Lizhi; Charles, Ian G.; Moncada, Salvador

doi:10.1038/ncb1188

Cited by 164 publications

(141 citation statements)

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“…Studies using genetically targeted Ca 2+ -selective probes (such as the bioluminescent protein aequorin) or fluorescent dyes (such as rhod-2) have provided a direct and unambiguous readout of mitochondrial Ca 2+ changes in living cells following receptor stimulation. Recently we found that in NOgenerating cells there is a disruption in the respiratory chain and a decreased respiration rate that is accompanied by a mitochondrial Ca 2+ flux [11]. These findings are in agreement with previous reports showing that exogenous NO [12] and peroxynitrite [13,14] can result in the release of Ca 2+ from mitochondria.…”

Section: No and The Endoplasmic Reticulum Stress Responsesupporting

confidence: 93%

“…The NO-mediated ER stress response is diminished in rho 0 cells that are devoid of mitochondrial DNA. Therefore, our work has shown that NO signals, via mitochondrial respiration, to the ER stress response with consequences for cell survival or death [11].…”

Section: No and The Endoplasmic Reticulum Stress Responsementioning

confidence: 90%

“…S1P, in association with the site-2 protease located in the Golgi apparatus, cleaves the ER stress-regulated transmembrane transcription factor p90 ATF6. The resulting soluble transcription factor p50 ATF6 is then free to translocate to the nucleus where it subsequently activates ER stress-responsive genes, such as glucose regulated protein 78 (Grp78) [11].…”

Section: No and The Endoplasmic Reticulum Stress Responsementioning

confidence: 99%

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

Charles

Moncada

2005

Cell Res

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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.

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Section: No and The Endoplasmic Reticulum Stress Responsesupporting

confidence: 93%

Section: No and The Endoplasmic Reticulum Stress Responsementioning

confidence: 90%

Section: No and The Endoplasmic Reticulum Stress Responsementioning

confidence: 99%

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

Charles

Moncada

2005

Cell Res

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“…Interestingly, recent studies have revealed a role for S-nitrosylation in the regulation of vesicular trafficking in endothelial and epithelial cells (4, 7), platelets (5), and neurons (6). In addition, nitric oxide has been identified as a proximal mediator of ER stress responses, although the role of S-nitrosylation was not evaluated (27).…”

Section: Evaluation Of S-nitrosylation In Hasmc By Immunogold Electronmentioning

confidence: 99%

Identification of S-nitrosylation motifs by site-specific mapping of the S -nitrosocysteine proteome in human vascular smooth muscle cells

Greco

Hodara²,

Parastatidis³

et al. 2006

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

249

224

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S-nitrosylation, the selective modification of cysteine residues in proteins to form S-nitrosocysteine, is a major emerging mechanism by which nitric oxide acts as a signaling molecule. Even though nitric oxide is intimately involved in the regulation of vascular smooth muscle cell functions, the potential protein targets for nitric oxide modification as well as structural features that underlie the specificity of protein S-nitrosocysteine formation in these cells remain unknown. Therefore, we used a proteomic approach using selective peptide capturing and site-specific adduct mapping to identify the targets of S-nitrosylation in human aortic smooth muscle cells upon exposure to S-nitrosocysteine and propylamine propylamine NONOate. This strategy identified 20 unique S-nitrosocysteine-containing peptides belonging to 18 proteins including cytoskeletal proteins, chaperones, proteins of the translational machinery, vesicular transport, and signaling. Sequence analysis of the S-nitrosocysteine-containing peptides revealed the presence of acid͞base motifs, as well as hydrophobic motifs surrounding the identified cysteine residues. High-resolution immunogold electron microscopy supported the cellular localization of several of these proteins. Interestingly, seven of the 18 proteins identified are localized within the ER͞Golgi complex, suggesting a role for S-nitrosylation in membrane trafficking and ER stress response in vascular smooth muscle.nitric oxide ͉ proteomics ͉ S-nitrosothiols S -nitrosylation, the formal transfer of nitrosonium to a reduced cysteine, is a reversible and selective posttranslational modification that regulates protein activity, localization, and stability, and also functions as a general sensor for cellular redox balance (1-7). The formation of protein S-nitrosocysteine requires the removal of a single electron, i.e., the conversion of the nitrogen in nitric oxide from an oxidation state of 2 to 3. Several distinct pathways could satisfy the formation of protein S-nitrosocysteine adducts in biological systems, such as autooxidation of nitric oxide forming higher oxides of nitrogen, radical recombination of thiyl radical with nitric oxide, catalysis by metal centers, the direct reaction of nitric oxide with a reduced cysteine followed by electron abstraction, and transnitrosation reactions carried out by S-nitrosoglutathione, other small molecular mass S-nitrosothiols, and more recently, S-nitrosocysteine-containing proteins (8-10).In vascular smooth muscle cells, nitric oxide derived from endothelium regulates important biological functions beyond relaxation, such as phenotypic changes, proliferation, and commitment to undergo apoptosis (11,12). Previous studies have shown that the molecular mechanisms underlying the functions of nitric oxide in vascular smooth muscle are mediated by both soluble guanylate cyclase-dependent and independent mechanisms (12)(13)(14). It has been suggested that selective S-nitrosylation of protein targets are responsible for the guanylate cyclase-independent reg...

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“…While nitric oxide stimulates cellular damage, it also activates a number of signaling pathways that limit additional cellular damage and repair existing damage. In pancreatic ␤-cells, the protective responses activated by nitric oxide include (i) JNK-dependent induction of GADD45␣ (growth arrest and DNA damage-inducible protein 45␣) and DNA repair, (ii) activation of AMP-activated protein kinase (AMPK), resulting in enhanced metabolic recovery, and (iii) activation of the unfolded-protein response (UPR) (25,34,38,54,57,61).AMPK is a conserved heterotrimeric (␣, ␤, and ␥ subunits) serine/threonine kinase involved in sensing and responding to the energetic demand within eukaryotic cells (15). AMPK is activated by phosphorylation at threonine 172 in the catalytic ␣ subunit (19) in a constitutive fashion by the upstream kinase LKB1; however, this phosphorylation is rapidly removed by a phosphatase to maintain low basal activity (18,43).…”

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confidence: 99%

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

Meares

Hughes

Naatz

et al. 2011

Molecular and Cellular Biology

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While there can be detrimental consequences of nitric oxide production at pathological concentrations, eukaryotic cells have evolved protective mechanisms to defend themselves against this damage. The unfoldedprotein response (UPR), activated by misfolded proteins and oxidative stress, is one adaptive mechanism that is employed to protect cells from stress. Nitric oxide is a potent activator of AMP-activated protein kinase (AMPK), and AMPK participates in the cellular defense against nitric oxide-mediated damage in pancreatic ␤-cells. In this study, the mechanism of AMPK activation by nitric oxide was explored. The known AMPK kinases LKB1, CaMKK, and TAK1 are not required for the activation of AMPK by nitric oxide. Instead, this activation is dependent on the endoplasmic reticulum (ER) stress-activated protein IRE1. Nitric oxide-induced AMPK phosphorylation and subsequent signaling to AMPK substrates, including Raptor, acetyl coenzyme A carboxylase, and PGC-1␣, is attenuated in IRE1␣-deficient cells. The endoribonuclease activity of IRE1 appears to be required for AMPK activation in response to nitric oxide. In addition to nitric oxide, stimulation of IRE1 endoribonuclease activity with the flavonol quercetin leads to IRE1-dependent AMPK activation. These findings indicate that the RNase activity of IRE1 participates in AMPK activation and subsequent signaling through multiple AMPK-dependent pathways in response to nitrosative stress.Nitric oxide, an important mediator of both physiological and pathological processes, has been implicated in the development of a number of inflammatory diseases. When produced at low concentrations, nitric oxide can promote cell growth and survival. At high concentrations, such as those produced during inflammation by inducible nitric oxide synthase (iNOS), nitric oxide induces extensive cellular injury that includes DNA damage, inhibition of oxidative metabolism, and induction of endoplasmic reticulum (ER) stress (5, 12, 39). Pancreatic ␤-cells are exquisitely sensitive to oxidative damage, as glucose-stimulated insulin secretion requires the oxidation of glucose to CO 2 , resulting in the accumulation of ATP. Nitric oxide, produced in micromolar concentrations in response to interleukin 1 (IL-1) and gamma interferon (IFN-␥), mediates the damaging effects of these cytokines on ␤-cell function (3, 33). While nitric oxide stimulates cellular damage, it also activates a number of signaling pathways that limit additional cellular damage and repair existing damage. In pancreatic ␤-cells, the protective responses activated by nitric oxide include (i) JNK-dependent induction of GADD45␣ (growth arrest and DNA damage-inducible protein 45␣) and DNA repair, (ii) activation of AMP-activated protein kinase (AMPK), resulting in enhanced metabolic recovery, and (iii) activation of the unfolded-protein response (UPR) (25,34,38,54,57,61).AMPK is a conserved heterotrimeric (␣, ␤, and ␥ subunits) serine/threonine kinase involved in sensing and responding to the energetic demand within eukaryotic cel...

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Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response

Cited by 164 publications

References 30 publications

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

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

Identification of S-nitrosylation motifs by site-specific mapping of the S -nitrosocysteine proteome in human vascular smooth muscle cells

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

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