Cytochrome b5 reductase is the component from neuronal synaptic plasma membrane vesicles that generates superoxide anion upon stimulation by cytochrome c

Samhan-Arias, Alejandro K.; Cordas, Cristina M.; Moura, Isabel; Moura, José J. G.; Gutiérrez‐Merino, Carlos

doi:10.1016/j.redox.2017.11.021

Cited by 18 publications

(42 citation statements)

References 27 publications

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“…Louis, MO, USA) were assessed by HPLC with fluorescence detection, as a quantitative measure of plasma superoxide anion levels, as described [37][38][39] . 2-EOH present in the samples was quantified by comparing with a calibration curve based on the reaction xanthine-xanthine oxidase from the method described by Michalski and cols 40 .…”

Section: Analysis Of Circulating 2-hydroxyethidium (2-eoh) Plasma Lementioning

confidence: 99%

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

Jiménez‐Altayó

Ortiz‐Romero

Puertas-Umbert

et al. 2020

Sci Rep

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Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26-28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3-4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological 'brake' against the detrimental effects of stenosis. Williams-Beuren syndrome (WBS) [OMIM 194050] is a rare congenital multisystem disorder caused by a recurrent heterozygous deletion of 26-28 contiguous genes on chromosome band 7q11.23 1. This syndrome affects males and females equally with a prevalence that is estimated to range between 1/7,500 and 1/10,000 2. Mainly due to elastin (ELN) haploinsufficiency, this condition is commonly characterized by cardiovascular alterations that can occur early in life 3 , can evolve into potentially serious complications, and are the main cause of death in WBS patients 1,4. Supravalvular aortic stenosis is the most frequent cardiovascular anomaly, affecting approximately 70% of patients 1,5 , and it is a potentially life-threatening condition 6,7. Surgery may be required and drug treatments for this disorder and other cardiovascular manifestations in WBS generally not differ from that in the general population 8. Therefore, a thorough analysis of the pathophysiological mechanisms of aortic disease in WBS is needed to define more safe and effective personalized therapies. Mouse models of elastin deficiency have provided valuable insights into the mechanisms responsible for the development of aortic anomalies in WBS. Thus, partial rescue of Eln −/− by transgenic expression of human ELN 9,10 is sufficient to cause a similar aortic phenotype to typical WBS patients 11-15. However, there is increasing evidence that other genes besides Eln may be relevant in modulating the WBS cardiovascular phenotype. Various

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Section: Analysis Of Circulating 2-hydroxyethidium (2-eoh) Plasma Lementioning

confidence: 99%

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

Jiménez‐Altayó

Ortiz‐Romero

Puertas-Umbert

et al. 2020

Sci Rep

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“…Therefore, these results suggested a major contribution of lipid rafts to overall ROS/RNS production in our mature CGN cul- Previous works have shown that deregulation of several redox systems associated with neuronal lipid rafts can produce over shots of ROS and/or RNS, namely, superoxide anion by Cb5R3 [57,58], nitric oxide by nNOS [30,31,59,60], and hydrogen peroxide and superoxide anion by cytochromes P450 [61]. All these redox systems are flavoproteins, and DPI, a broad spectrum flavoprotein inhibitor, produced more than 90% inhibition of ROS/RNS production monitored by the dyes used in this work.…”

Section: The Production Of Ros That Is Inhibited By Mβcd Decreased During Cgn Maturation and This Is Reverted By Cb5r3silencingmentioning

confidence: 52%

“…This attenuation of ROS production in mature CGN can be reverted by silencing the expression of Cb5R3 to approximately 50%. Cb5R3 is a redox protein associated with lipid rafts, whose expression level increases approximately 2.5-fold from 5DIV to 9-10DIV [22], and whose deregulation leads to an overshot of superoxide anion production by CGN [16] and also of rat brain synaptic plasma membranes [14,57]. Therefore, our results show that Cb5R3 plays a major role in the attenuation of the overall ROS production in mature CGN, and reveal a major role of this protein as an antioxidant cellular defense against CGN exposure to extracellular neurotoxic oxidative insults.…”

Section: The Production Of Ros That Is Inhibited By Mβcd Decreased During Cgn Maturation and This Is Reverted By Cb5r3silencingmentioning

confidence: 99%

Cholesterol-Rich Plasma Membrane Submicrodomains Can Be a Major Extram- itochondrial Source of Reactive Oxygen Species in Partially Depolarized Mature Cerebellar Granule Neurons in Culture

2019

Journal of Neurophysiology and Neurological Disorders

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Excessive production of reactive oxygen and nitrogen species can elicit neuronal cell death and brain neurodegeneration. In previous studies, we have shown that lipid rafts nanodomains of mature cerebellar granule neurons (CGN) contain most of the neuronal nitric oxide synthase and also of cytochrome b 5 reductase isoform 3 (Cb5R3), which is the component of neuronal synaptic plasma membrane vesicles that generates superoxide anion upon stimulation by cytochrome c. In this work, we show that CGN maturation in vitro elicits between two-and three-fold increase of the overall lipid rafts, and a similar increase of the expression of neuronal nitric oxide synthase and Cb5R3. Only 5-15 min incubation of CGN with millimolar concentrations of methyl-β-cyclodextrin led to more than 90% attenuation of the kinetics of reactive oxygen species (ROS) production monitored by dihydro dichlorofluorescein diacetate (H 2 DCF-DA), dihydroethidium (DHE) and 4,5-diaminofluorescein diacetate (DAF2-DA). In contrast, the results obtained using H 2 DCF-DA and DHE pointed out that preincubation of CGN with 2,4-dinitrophenol or carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) only produced a decrease of 38±5% and 42±5% of the rate of ROS production, respectively. In addition, superoxide dismutase added to the extracellular medium of CGN also elicited more than 90% attenuation of the increase of DHE fluorescence that monitors superoxide anion production. CGN maturation leads to a large decrease of the production of ROS detected by H 2 DCF-DA, and this attenuation of ROS production in mature CGN can be reverted by silencing the expression of Cb5R3 to approximately 50%. The kinetics of ROS/reactive nitrogen species (RNS) production by CGN detected with DAF2-DA revealed the occurrence of a spreading ROS/RNS wave rapidly propagating along the neuronal plasma membrane. In conclusion, our results point out that redox systems associated with lipid rafts make a large contribution to total ROS/RNS production in mature CGN cultures under partially depolarizing conditions.

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“…Over stimulation and clustering of CYB5R3 induced oxidative stress-mediated apoptosis of cerebellar granule neurons [ 386 ]. Independent of respiratory chain activities, the ascorbate-dependent NADH: cytochrome c oxidoreductase oxidation of NADH at CYB5R3 centers in lipid rafts is also a major source of extracellular superoxide [ 376 , 387 , 388 , 389 , 390 ] that can initiate lipid peroxidation. In Wistar rats, the deregulation of CYB5R3 promptly triggers apoptosis due to the overproduction of superoxide anions at neuronal plasma membranes [ 368 , 387 ].…”

Section: The Interdependence Between Membranes and Membraneless Organellesmentioning

confidence: 99%

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

Loh¹,

Reíter

2021

Antioxidants

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Biomolecular condensates are membraneless organelles (MLOs) that form dynamic, chemically distinct subcellular compartments organizing macromolecules such as proteins, RNA, and DNA in unicellular prokaryotic bacteria and complex eukaryotic cells. Separated from surrounding environments, MLOs in the nucleoplasm, cytoplasm, and mitochondria assemble by liquid–liquid phase separation (LLPS) into transient, non-static, liquid-like droplets that regulate essential molecular functions. LLPS is primarily controlled by post-translational modifications (PTMs) that fine-tune the balance between attractive and repulsive charge states and/or binding motifs of proteins. Aberrant phase separation due to dysregulated membrane lipid rafts and/or PTMs, as well as the absence of adequate hydrotropic small molecules such as ATP, or the presence of specific RNA proteins can cause pathological protein aggregation in neurodegenerative disorders. Melatonin may exert a dominant influence over phase separation in biomolecular condensates by optimizing membrane and MLO interdependent reactions through stabilizing lipid raft domains, reducing line tension, and maintaining negative membrane curvature and fluidity. As a potent antioxidant, melatonin protects cardiolipin and other membrane lipids from peroxidation cascades, supporting protein trafficking, signaling, ion channel activities, and ATPase functionality during condensate coacervation or dissolution. Melatonin may even control condensate LLPS through PTM and balance mRNA- and RNA-binding protein composition by regulating N6-methyladenosine (m6A) modifications. There is currently a lack of pharmaceuticals targeting neurodegenerative disorders via the regulation of phase separation. The potential of melatonin in the modulation of biomolecular condensate in the attenuation of aberrant condensate aggregation in neurodegenerative disorders is discussed in this review.

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Cytochrome b5 reductase is the component from neuronal synaptic plasma membrane vesicles that generates superoxide anion upon stimulation by cytochrome c

Cited by 18 publications

References 27 publications

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

Cholesterol-Rich Plasma Membrane Submicrodomains Can Be a Major Extram- itochondrial Source of Reactive Oxygen Species in Partially Depolarized Mature Cerebellar Granule Neurons in Culture

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

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