Endotoxin-Stimulated Nitric Oxide Production Inhibits Expression of Cytochrome <i>c</i> Oxidase in ANA-1 Murine Macrophages

Wei, Junping; Guo, Hongtao; Kuo, Paul C.

doi:10.4049/jimmunol.168.9.4721

Cited by 22 publications

(25 citation statements)

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“…Regarding ATP biosynthesis, previous reports have demonstrated that the combinatory treatment of LPS with IFN-␥ remarkably reduced enzymatic activity of mitochondrial respiratory chain complexes in J774.1 cells as well as glial cells (7,46). Although an early study had surmised that LPS inhibited mitochondrial respiration through nitrosylation of the complexes (11), LPS is also known to repress production of the complexes at the mRNA level: intraperitoneal injection of LPS slightly decreased transcript levels of some components of the respiratory chain in rat whole blood cells (20) and decreased cytochrome c oxidase subunit I in complex IV by destabilizing its mRNA in murine macrophagelike ANA1 cells (72). The present study shows that an additional regulatory process, translational repression, participates in the attenuation of the respiratory chain, as follows: 1) a prominent decrease of transcript levels of the respiratory chain complexes in the polysomal fraction rather than the total cellular fraction, 2) a significant increase of transcript levels in the free mRNP fraction, and 3) a decrement of metabolically labeled Cox5a.…”

Section: Discussionmentioning

confidence: 99%

“…In the mouse macrophage-like cell line ANA-1, NO contributes to LPS-induced suppression of the mitochondrial respiratory chain through destabilization of the mRNAs of respiratory components (72). We thus evaluate whether NO also participates in translational repression of the complexes after LPS stimulation in J774.1 cells.…”

Section: Effect Of Lps On Translation In Macrophagesmentioning

confidence: 99%

“…One study demonstrated that treatment with LPS alone (100 ng/ml) attenuated the mitochondrial respiratory chain in an NO-dependent manner in another mouse macrophage-like cell line, ANA-1 (72). The difference in NO production ability of the cells could be the reason for the discrepancy.…”

Section: Effect Of Lps On Translation In Macrophagesmentioning

confidence: 99%

“…For example, the expression of TNF-␣, IL-1␤, IL-8, and cyclooxygenase 2 is controlled by the stability and/or translational activity of their mRNAs, at least in part depending on the AU-rich element in their 3Ј-untranslated region (3,4,21,26,34,69). Moreover, LPS stimulation also changed the stability of transcripts for cytochrome c oxidase subunit I, a component of the mitochondrial respiratory chain, indicating that posttranscriptional modulation also occurs in noninflammatory proteins in response to LPS stimulation (72). Although these studies shed new light on posttranscriptional gene regulation evoked by LPS, they focused on a limited number of genes and thus little is known about the gene regulatory mechanisms induced by LPS stimulation on a genome-wide scale.…”

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confidence: 99%

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Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells

Kitamura

Ito²,

Yuasa³

et al. 2008

Physiological Genomics

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Although Escherichia coli LPS is known to elicit various proinflammatory responses in macrophages, its effect on the translational states of transcripts has not yet been explored on a genome-wide scale. To address this, we investigated the mRNA profiles in polysomal and free messenger ribonucleoprotein particle (mRNP) fractions of mouse macrophage-like J774.1 cells, using Affymetrix Mouse Genome 430 2.0 GeneChips. Comparison of the mRNA profiles in total cellular, polysomal, and free mRNP fractions enabled us to identify transcripts that were modulated at the translational level by LPS: among 19,791 transcripts, 115 and 418 were up- and downregulated at 1, 2, or 4 h after LPS stimulation (100 ng/ml) in a translation-dependent manner. Interestingly, gene ontology-based analysis suggested that translation-dependent downregulated genes frequently include those encoding proteins in the mitochondrial respiratory chain. In fact, the mRNA levels of some transcripts for complexes I, IV, and V in the mitochondrial respiratory chain were translationally downregulated, eventually contributing to the decline of their protein levels. Moreover, the amount of metabolically labeled cytochrome oxidase subunit Va in complex IV was decreased without any change of its mRNA level in total cellular fraction after LPS stimulation. Consistently, the total amounts and activities of complexes I and IV were attenuated by LPS stimulation, and the attenuation was independent of nitric oxide. These results demonstrated that translational suppression may play a critical role in the LPS-mediated attenuation of mitochondrial oxidative phosphorylation in a nitric oxide-independent manner in J774.1 cells.

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Lps On Translation In Macrophagesmentioning

confidence: 99%

Section: Effect Of Lps On Translation In Macrophagesmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells

Kitamura

Ito²,

Yuasa³

et al. 2008

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…A role for NO in modulation of mitochondrial gene expression and protein synthesis has been demonstrated at several levels in nonvascular cells such as macrophages, where lipopolysaccharide-induced NO production decreased levels of cytochrome b and complex IV subunit I (4,5). In brown adipose tissue activation of soluble guanylate cyclase has been shown to control mitochondrial number (6).…”

mentioning

confidence: 99%

Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: Role of mitochondrial respiratory complexes and heat shock proteins

Ramachandran

Ceaser

Darley‐Usmar

2003

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

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The mechanisms of nitric oxide (NO) signaling include binding to the iron centers in soluble guanylate cyclase and cytochrome c oxidase and posttranslational modification of proteins by S-nitrosation. Low levels of NO control mitochondrial number in cells, but little is known of the impact of chronic exposure to high levels of NO on mitochondrial function in endothelial cells. The focus of this study is the interaction of NO with mitochondrial respiratory complexes in cell culture and the effect this has on iron homeostasis. We demonstrate that chronic exposure of endothelial cells to NO decreased activity and protein levels of complexes I, II, and IV, whereas citrate synthase and ATP synthase were unaffected. Inhibition of these respiratory complexes was accompanied by an increase in cellular S-nitrosothiol levels, modification of cysteines residues, and an increase in the labile iron pool. The NO-dependent increase in the free iron pool and inhibition of complex II was prevented by inhibition of mitochondrial protein synthesis, consistent with a major contribution of the organelle to iron homeostasis. In addition, inhibition of mitochondrial protein synthesis was associated with an increase in heat shock protein 60 levels, which may be an additional mechanism leading to preservation of complex II activity.

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Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

Campbell

Ziabreva

Reeve

et al. 2010

Annals of Neurology

318

251

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Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases.Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity.Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons.Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.

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Endotoxin-Stimulated Nitric Oxide Production Inhibits Expression of Cytochrome c Oxidase in ANA-1 Murine Macrophages

Cited by 22 publications

References 22 publications

Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells

Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells

Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: Role of mitochondrial respiratory complexes and heat shock proteins

Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

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