The mechanism of cytochrome C oxidase inhibition by nitric oxide

Antunes, Fernando

doi:10.2741/2118

Cited by 19 publications

(17 citation statements)

References 54 publications

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“…Cytochrome c oxidase (CcOX) is considered a preferential target of NO because of the presence of heme groups for which NO has great binding affinity (Antunes and Cadenas, 2007). Therefore, we measured the activity of CcOX after BSO treatment and found that it was maximally reduced after 48 hours (-60%).…”

Section: Bso-mediated Cell Growth Arrest Results In Cell Death and Ismentioning

confidence: 99%

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Aquilano

Baldelli

Cardaci

et al. 2011

Journal of Cell Science

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Glutathione (GSH) levels progressively decline during aging and in neurodegenerative disorders. However, the contribution of such event in mediating neuronal cell death is still uncertain. In this report, we show that, in neuroblastoma cells as well as in primary mouse cortical neurons, GSH decrease, induced by buthionine sulfoximine (BSO), causes protein nitration, S-nitrosylation and DNA strand breaks. Such alterations are also associated with inhibition of cytochrome c oxidase activity and microtubule network disassembly, which are considered hallmarks of nitric oxide (NO) toxicity. In neuroblastoma cells, BSO treatment also induces cell proliferation arrest through the ERK1/2-p53 pathway that finally results in caspase-independent apoptosis, as evident from the translocation of apoptosis-inducing factor from mitochondria towards nuclei. A deeper analysis of the signaling processes indicates that the NO-cGMP pathway is involved in cell proliferation arrest and death. In fact, these events are completely reversed by L-NAME, a specific NO synthase inhibitor, indicating that NO, rather than the depletion of GSH per se, is the primary mediator of cell damage. In addition, the guanylate cyclase (GC) inhibitor LY83583 is able to completely block activation of ERK1/2 and counteract BSO toxicity. In cortical neurons, NMDA (N-methyl-D-aspartic acid) treatment results in GSH decrease and BSO-mediated NO cytotoxicity is enhanced by either epidermal growth factor (EGF) or NMDA. These findings support the idea that GSH might represent the most important buffer of NO toxicity in neuronal cells, and indicate that the disruption of cellular redox buffering controlled by GSH makes neuronal cells susceptible to endogenous physiological flux of NO.

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Section: Bso-mediated Cell Growth Arrest Results In Cell Death and Ismentioning

confidence: 99%

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Aquilano

Baldelli

Cardaci

et al. 2011

Journal of Cell Science

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“…[NO] mt is around nanomolar ranges (3,4,58,179,194) and at this concentration of NO, it is able to compete with oxygen and interact with COX reversibly (3,4,58,194), interfere with electron flow that results in a decrease in ATP production (62), depolarization of DJ m (180,181), and an increase in ROS generation (142,156) (Fig. 3).…”

Section: Regulation Of Etc Activity By Mitochondrial No Signalingmentioning

confidence: 99%

Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

O‐Uchi

Ryu

Jhun

et al. 2014

Antioxidants & Redox Signaling

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Significance: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently. Recent Advances: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca 2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K + channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling. Critical Issues: Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation. Future Directions: Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters. Antioxid. Redox Signal. 21, 987-1006.

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“…Equation (5) (Bellamy et al 2002;Antunes & Cadenas, 2007;Rodriguez-Juarez et al 2007), yielding an estimated K NO of 2.9 nM (Fig. 6C).…”

Section: Quantifying No Inhibition Of Respiration In Inos-expressing mentioning

confidence: 99%

“…6A and B We incorporated competitive NO-mediated inhibition of CcO into the model of O 2 diffusion and consumption by a cerebellar slice. While inhibition of respiration by NO can have both competitive and non-competitive components, when ATP production is high the competitive component predominates (Antunes & Cadenas, 2007) and the Hill coefficient of NO-mediated inhibition of respiration is 1 (Mason et al 2006). In brain, respiration rate and ATP production are particularly high (the brain accounts for 20% of total resting body O 2 consumption, of which more than 90% is used by neurons; Attwell & Laughlin, 2001) so, compared to other tissues, inhibition of respiration by NO should be essentially competitive in nature, with a Hill coefficient near to 1.…”

Section: Quantifying No Inhibition Of Respiration In Inos-expressing mentioning

confidence: 99%

“…F, after 24 h the initial [O 2 ] was significantly increased in LPS-IFNγ -treated slices (Student's t test, versus 4 h; n = 6 slices, P = 0.001) unlike in control slices (n = 4-6; P = 0.06) or LPS-IFNγ -and 1400W-treated slices (n = 6; P = 0.26). (Bellamy et al 2002;Antunes & Cadenas, 2007;Rodriguez-Juarez et al 2007) are plotted against the [O 2 ] at which they were obtained. Fitting with eqn (4) yields a K NO value of 2.9 nM.…”

Section: No From Inos Reduces O 2 Consumption In Organotypic Slicesmentioning

confidence: 99%

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Assessing the physiological concentration and targets of nitric oxide in brain tissue

Hall

Attwell

2008

The Journal of Physiology

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Low nanomolar concentrations of nitric oxide activate guanylyl cyclase to produce cGMP, which has diverse physiological effects. Higher concentrations inhibit mitochondrial respiration at cytochrome c oxidase and this has been proposed to be important physiologically, increasing oxygen permeation into tissue (by reducing the oxygen use of cells near blood vessels), activating AMP kinase, and regulating the relationship between cerebral blood flow and oxygen use. It is unclear, however, whether nitric oxide can accumulate physiologically to concentrations at which inhibition of respiration occurs. In rat cerebellar slices, we activated nitric oxide production from each isoform of nitric oxide synthase. Only activation of inducible nitric oxide synthase, which is expressed pathologically, caused any significant inhibition of respiration. Modelling oxygen and nitric oxide concentrations predicted that, in vivo, physiological nitric oxide levels are too low to affect respiration. Even pathologically, the nitric oxide concentration may only rise to 2.5 nm, producing a 1.5% inhibition of respiration. Thus, under physiological conditions, nitric oxide signals do not inhibit respiration but are well-tuned to the dynamic range of guanylyl cyclase activation.

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The mechanism of cytochrome C oxidase inhibition by nitric oxide

Cited by 19 publications

References 54 publications

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Nitric oxide is the primary mediator of cytotoxicity induced by GSH depletion in neuronal cells

Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

Assessing the physiological concentration and targets of nitric oxide in brain tissue

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