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      HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase

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          Abstract

          The Trans-activator protein (Tat) of human immunodeficiency virus (HIV) is a pleiotropic protein involved in different aspects of AIDS pathogenesis. As a number of viral proteins Tat is suspected to disturb mitochondrial function. We prepared pure synthetic full-length Tat by native chemical ligation (NCL), and Tat peptides, to evaluate their direct effects on isolated mitochondria. Submicromolar doses of synthetic Tat cause a rapid dissipation of the mitochondrial transmembrane potential (ΔΨ m) as well as cytochrome c release in mitochondria isolated from mouse liver, heart, and brain. Accordingly, Tat decreases substrate oxidation by mitochondria isolated from these tissues, with oxygen uptake being initially restored by adding cytochrome c. The anion-channel inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) protects isolated mitochondria against Tat-induced mitochondrial membrane permeabilization (MMP), whereas ruthenium red, a ryanodine receptor blocker, does not. Pharmacologic inhibitors of the permeability transition pore, Bax/Bak inhibitors, and recombinant Bcl-2 and Bcl-XL proteins do not reduce Tat-induced MMP. We finally observed that Tat inhibits cytochrome c oxidase (COX) activity in disrupted mitochondria isolated from liver, heart, and brain of both mouse and human samples, making it the first described viral protein to be a potential COX inhibitor.

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          Most cited references 46

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          Synthesis of proteins by native chemical ligation.

           S Kent,  P E Dawson,  T W Muir (1994)
          A simple technique has been devised that allows the direct synthesis of native backbone proteins of moderate size. Chemoselective reaction of two unprotected peptide segments gives an initial thioester-linked species. Spontaneous rearrangement of this transient intermediate yields a full-length product with a native peptide bond at the ligation site. The utility of native chemical ligation was demonstrated by the one-step preparation of a cytokine containing multiple disulfides. The polypeptide ligation product was folded and oxidized to form the native disulfide-containing protein molecule. Native chemical ligation is an important step toward the general application of chemistry to proteins.
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            Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases.

            Incubation of rat skeletal muscle mitochondria with the nitric oxide generator, S-nitrosoglutathione (GSNO) reversibly inhibited oxygen utilisation with all substrates tested. The visible absorption spectra of the inhibited mitochondria showed that cytochromes c+c1, b and a+a3 were reduced, indicating a block at the distal end of the respiratory chain. Analysis of the respiratory chain enzyme activities in the presence of GSNO localised the site of inhibition of cytochrome c oxidase alone. These results indicate that nitric oxide is capable of rapidly and reversibly inhibiting the mitochondrial respiratory chain and may be implicated in the cytotoxic effects of nitric oxide in the CNS and other tissues.
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              Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS.

              AIDS, caused by the retroviruses human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), has reached pandemic proportions. Therefore, it is critical to understand how HIV causes AIDS so that appropriate therapies can be formulated. Primarily, HIV infects and kills CD4(+) T lymphocytes, which function as regulators and amplifiers of the immune response. In the absence of effective anti-retroviral therapy, the hallmark decrease in CD4(+) T lymphocytes during AIDS results in a weakened immune system, impairing the body's ability to fight infections or certain cancers such that death eventually ensues. The major mechanism for CD4(+) T cell depletion is programmed cell death (apoptosis), which can be induced by HIV through multiple pathways. Death of HIV-infected cells can result from the propensity of infected lymphocytes to form short-lived syncytia or from an increased susceptibility of the cells to death. However, the apoptotic cells appear to be primarily uninfected bystander cells and are eradicated by two different mechanisms: either a Fas-mediated mechanism during activation-induced cell death (AICD), or as a result of HIV proteins (Tat, gp120, Nef, Vpu) released from infected cells stimulating apoptosis in uninfected bystander cells. There is also evidence that as AIDS progresses cytokine dysregulation occurs, and the overproduction of type-2 cytokines (IL-4, IL-10) increases susceptibility to AICD whereas type-1 cytokines (IL-12, IFN-gamma) may be protective. Clearly there are multiple causes of CD4(+) T lymphocyte apoptosis in AIDS and therapies that block or decrease that death could have significant clinical benefit.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                March 2012
                15 March 2012
                1 March 2012
                : 3
                : 3
                : e282
                Affiliations
                [1 ]Theraptosis S.A., Pasteur BioTop Research Laboratory, Institut Pasteur , Paris 75015, France
                [2 ]Institut Pasteur, Unité d'Immunophysiologie et Parasitisme Intracellulaire, Département de Parasitologie et Mycologie , Paris 75015, France
                [3 ]Theraptosis S.A., R&D Laboratories, Biocitech Technology Park , Romainville 93230, France
                [4 ]Mitologics S.A.S., Hôpital Robert Debré , Paris 75019, France
                [5 ]CNRS UPR 9021, Institut de Biologie Moléculaire et Cellulaire , Strasbourg 67000, France
                [6 ]Inserm U676, Hôpital Robert Debré , Paris 75019, France
                [7 ]Université Paris 7 UMR676, Faculté de Médecine Denis Diderot , Paris 75019, France
                [8 ]INRA, UR1196 Génomique et Physiologie de la Lactation, Plateau de Microscopie Électronique MIMA2 , Jouy-en-Josas 78352, France
                [9 ]CNRS FRE 2445, Université de Versailles/St Quentin , Versailles 78035, France
                [10 ]Inserm U769, Signalisation et Physiopathologie Cardiaque , Châtenay-Malabry 92296, France
                [11 ]Université Paris-Sud, Faculté de Pharmacie , Châtenay-Malabry 92296, France
                [12 ]Imperial College London, Department of Reproductive Biology, Cancer Division, Hammersmith Hospital , London W12 ONN, UK
                Author notes
                [* ]Inserm U676, Hôpital Robert Debré , 48 Boulevard Sérurier, Paris 75019, France. Tel: +33 1 40 03 19 32; Fax: +33 1 40 03 19 95; E-mail: etienne.jacotot@ 123456inserm.fr or e.jacotot@ 123456imperial.ac.uk
                [13]

                These authors shared senior co-authorship.

                Article
                cddis201221
                10.1038/cddis.2012.21
                3317353
                22419111
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                Categories
                Original Article

                Cell biology

                tat, mitochondria, cytochrome c oxidase, hiv-1

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