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      Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia

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          Abstract

          Mitochondria use oxygen as the final acceptor of the respiratory chain, but its incomplete reduction can also produce reactive oxygen species (ROS), especially superoxide. Acute hypoxia produces a superoxide burst in different cell types, but the triggering mechanism is still unknown. Herein, we show that complex I is involved in this superoxide burst under acute hypoxia in endothelial cells. We have also studied the possible mechanisms by which complex I could be involved in this burst, discarding reverse electron transport in complex I and the implication of PTEN-induced putative kinase 1 (PINK1). We show that complex I transition from the active to ‘deactive’ form is enhanced by acute hypoxia in endothelial cells and brain tissue, and we suggest that it can trigger ROS production through its Na +/H + antiporter activity. These results highlight the role of complex I as a key actor in redox signalling in acute hypoxia.

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          Highlights

          • Complex I is involved in the superoxide burst produced by cells in acute hypoxia.

          • Complex I is deactivated in acute hypoxia.

          • Deactive complex I is involved in superoxide production in acute hypoxia, probably through its Na +/H + antiporter activity.

          • Complex I deactivation occurs in brain tissue hypoxia ex vivo and in vivo.

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          Most cited references35

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          Tricine-SDS-PAGE.

          Tricine-SDS-PAGE is commonly used to separate proteins in the mass range 1-100 kDa. It is the preferred electrophoretic system for the resolution of proteins smaller than 30 kDa. The concentrations of acrylamide used in the gels are lower than in other electrophoretic systems. These lower concentrations facilitate electroblotting, which is particularly crucial for hydrophobic proteins. Tricine-SDS-PAGE is also used preferentially for doubled SDS-PAGE (dSDS-PAGE), a proteomic tool used to isolate extremely hydrophobic proteins for mass spectrometric identification, and it offers advantages for resolution of the second dimension after blue-native PAGE (BN-PAGE) and clear-native PAGE (CN-PAGE). Here I describe a protocol for Tricine-SDS-PAGE, which includes efficient methods for Coomassie blue or silver staining and electroblotting, thereby increasing the versatility of the approach. This protocol can be completed in 1-2 d.
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            Reactive oxygen species and mitochondria: A nexus of cellular homeostasis

            Reactive oxygen species (ROS) are integral components of multiple cellular pathways even though excessive or inappropriately localized ROS damage cells. ROS function as anti-microbial effector molecules and as signaling molecules that regulate such processes as NF-kB transcriptional activity, the production of DNA-based neutrophil extracellular traps (NETs), and autophagy. The main sources of cellular ROS are mitochondria and NADPH oxidases (NOXs). In contrast to NOX-generated ROS, ROS produced in the mitochondria (mtROS) were initially considered to be unwanted by-products of oxidative metabolism. Increasing evidence indicates that mtROS have been incorporated into signaling pathways including those regulating immune responses and autophagy. As metabolic hubs, mitochondria facilitate crosstalk between the metabolic state of the cell with these pathways. Mitochondria and ROS are thus a nexus of multiple pathways that determine the response of cells to disruptions in cellular homeostasis such as infection, sterile damage, and metabolic imbalance. In this review, we discuss the roles of mitochondria in the generation of ROS-derived anti-microbial effectors, the interplay of mitochondria and ROS with autophagy and the formation of DNA extracellular traps, and activation of the NLRP3 inflammasome by ROS and mitochondria.
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              Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I.

              Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                21 April 2017
                August 2017
                21 April 2017
                : 12
                : 1040-1051
                Affiliations
                [a ]Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28006 Madrid, Spain
                [b ]Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas Alberto Sols, E-28029 Madrid, Spain
                [c ]Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28029 Madrid, Spain
                [d ]Servicio de Proteómica, Centro de Biología Molecular “Severo Ochoa (CBSMO), Consejo Superior de Investigaciones Científicas (CSIC) – UAM, E-28049 Madrid, Spain
                [e ]Unidad de Investigación, Hospital Santa Cristina, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria Princesa (IP), E-28009 Madrid, Spain
                [f ]Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, CH-8057 Zurich, Switzerland
                [g ]Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
                Author notes
                [* ]Corresponding author at: Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Princesa (IIS-IP), C/ Diego de León 62, E-28006 Madrid, Spain. amartinezruiz@ 123456salud.madrid.org
                Article
                S2213-2317(17)30127-1
                10.1016/j.redox.2017.04.025
                5430576
                28511347
                3bc4d41d-074f-4464-9d1c-c5f45d2253cb
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 February 2017
                : 28 March 2017
                : 18 April 2017
                Categories
                Research Paper

                hypoxia,oxygen sensing,superoxide,mitochondrial complex i,redox signalling

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