Continuous exposure to high concentrations of nitric oxide leads to persistent inhibition of oxygen consumption by J774 cells as well as extraction of oxygen by the extracellular medium

Orsi, A; Beltrán, Belén; Clementi, Emilio; Hallén, Katarina; Feelisch, Martin; Moncada, Salvador

doi:10.1042/bj3460407

Cited by 29 publications

(9 citation statements)

References 22 publications

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“…These observations led to the proposal that NO-derived ONOO − formation may reversibly nitrosylate thiol groups of Complex I components [18]. Moreover, these data are in line with previous observations in intact cells exposed to NO [11,20]. However, in the present studies, Complex I activity was not restored by addition of either GSH or dithiothreitol.…”

Section: Discussionsupporting

confidence: 93%

“…The oxidative-nitrative effects through ONOO − formation will be evident after most of GSH is oxidized by alternative pathways. Indeed, it was demonstrated that GSH content was a key factor determining the action of NO on Complex I [11,20]. In intact cells with an active biosynthetic machinery, GSH may be kept at a high-enough concentration to sustain transnitrosylation and the S-nitrosylation pathway.…”

Section: Discussionmentioning

confidence: 99%

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Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation

Riobo

Clementi

Melani

et al. 2001

Biochemical Journal

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146

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This study was aimed at assessing the effects of long-term exposure to NO of respiratory activities in mitochondria from different tissues (with different ubiquinol contents), under conditions that either promote or prevent the formation of peroxynitrite. Mitochondria and submitochondrial particles isolated from rat heart, liver and brain were exposed either to a steady-state concentration or to a bolus addition of NO. NO induced the mitochondrial production of superoxide anions, hydrogen peroxide and peroxynitrite, the latter shown by nitration of mitochondrial proteins. Long-term incubation of mitochondrial membranes with NO resulted in a persistent inhibition of NADH:cytochrome c reductase activity, interpreted as inhibition of NADH:ubiquinone reductase (Complex I) activity, whereas succinate:cytochrome c reductase activity, including Complex II and Complex III electron transfer, remained unaffected. This selective effect of NO and derived species was partially prevented by superoxide dismutase and uric acid. In addition, peroxynitrite mimicked the effect of NO, including tyrosine nitration of some Complex I proteins. These results seem to indicate that the inhibition of NADH:ubiquinone reductase (Complex I) activity depends on the NO-induced generation of superoxide radical and peroxynitrite and that Complex I is selectively sensitive to peroxynitrite. Inhibition of Complex I activity by peroxynitrite may have critical implications for energy supply in tissues such as the brain, whose mitochondrial function depends largely on the channelling of reducing equivalents through Complex I.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation

Riobo

Clementi

Melani

et al. 2001

Biochemical Journal

Self Cite

146

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“…More recently, it has been shown that exposure of J774.A1 cells to pathological concentrations of NO not only inhibits complex I activity, but also results in decreased extraction of oxygen from the surrounding medium. This suggests a possible mechanism for damage to integrated mitochondrial function due to NO synthesis following hypoxia (Orsi et al ., 2000).…”

Section: Discussionmentioning

confidence: 99%

Activation of murine microglial cell lines by lipopolysaccharide and interferon‐γ causes NO‐mediated decreases in mitochondrial and cellular function

Moss¹,

Bates

2001

Eur J of Neuroscience

180

114

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Activation of murine microglial and macrophage cell lines with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) resulted in the induction of the inducible form of nitric oxide synthase (NOS) and the release of micromolar amounts of NO into the surrounding medium. The synthesis of NO was associated with increased cellular membrane damage as assessed by trypan blue dye exclusion and the leakage of lactate dehydrogenase into the cell culture medium. However, the synthesis and release of cytokines was largely unaffected. NO-mediated cell damage was also accompanied by a marked decrease in the intracellular levels of reduced glutathione and ATP. In addition, significant inhibition of mitochondrial respiratory chain enzyme activities was seen following cellular activation. However, citrate synthase activity (a mitochondrial matrix enzyme) was not detectable in the extracellular supernatants, suggesting preservation of the integrity of the mitochondrial inner membrane following activation. These effects were largely prevented by the addition of the NOS inhibitor, N-guanidino monomethyl L-arginine during the activation period. Our observations demonstrate that induction of NOS activity in microglia results in damage to the plasma membrane leading to a loss of glutathione, complex-specific inhibition of the mitochondrial electron transport chain and depletion of cellular ATP. Our data suggest that pharmacological modulation of NOS activity in activated microglia in vivo may prevent cellular damage to bystander cells such as neurons, astrocytes and oligodendrocytes, as well as to microglia themselves.

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“…1) (184). Below 0.2 lM, NO reversibly inhibits COX and controls mitochondrial respiration; at 0.3-0.5 lM, it inhibits electron transfer between cyts b and c1 (182,184), whereas relatively prolonged 0.5-1 lM NO exposure selectively inhibits the NADH dehydrogenase activity at mitochondrial complex I in intact cells (169) or isolated mitochondria (194), a hallmark of aging, sepsis, and neurodegenerative entities, such as Parkinson disease. Our studies revealed that the resultant segmental inhibition of the electron transfer chain at complexes I-III by NO is also followed by a very high burst of O 2 Á À production rate (Fig.…”

Section: B No and Mitochondrial Redox Metabolismmentioning

confidence: 99%

Mitochondrial Regulation of Cell Cycle and Proliferation

Arciuch

Elguero

Poderoso

et al. 2012

Antioxidants & Redox Signaling

349

171

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Eukaryotic mitochondria resulted from symbiotic incorporation of α-proteobacteria into ancient archaea species. During evolution, mitochondria lost most of the prokaryotic bacterial genes and only conserved a small fraction including those encoding 13 proteins of the respiratory chain. In this process, many functions were transferred to the host cells, but mitochondria gained a central role in the regulation of cell proliferation and apoptosis, and in the modulation of metabolism; accordingly, defective organelles contribute to cell transformation and cancer, diabetes, and neurodegenerative diseases. Most cell and transcriptional effects of mitochondria depend on the modulation of respiratory rate and on the production of hydrogen peroxide released into the cytosol. The mitochondrial oxidative rate has to remain depressed for cell proliferation; even in the presence of O₂, energy is preferentially obtained from increased glycolysis (Warburg effect). In response to stress signals, traffic of pro- and antiapoptotic mitochondrial proteins in the intermembrane space (B-cell lymphoma-extra large, Bcl-2-associated death promoter, Bcl-2 associated X-protein and cytochrome c) is modulated by the redox condition determined by mitochondrial O₂ utilization and mitochondrial nitric oxide metabolism. In this article, we highlight the traffic of the different canonical signaling pathways to mitochondria and the contributions of organelles to redox regulation of kinases. Finally, we analyze the dynamics of the mitochondrial population in cell cycle and apoptosis.

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Continuous exposure to high concentrations of nitric oxide leads to persistent inhibition of oxygen consumption by J774 cells as well as extraction of oxygen by the extracellular medium

Cited by 29 publications

References 22 publications

Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation

Nitric oxide inhibits mitochondrial NADH:ubiquinone reductase activity through peroxynitrite formation

Activation of murine microglial cell lines by lipopolysaccharide and interferon‐γ causes NO‐mediated decreases in mitochondrial and cellular function

Mitochondrial Regulation of Cell Cycle and Proliferation

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