title: HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase.
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.
authors.affiliation: Theraptosis SA, Pasteur BioTop Research Laboratory, Institut Pasteur, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Lecoeur
authors.forename: A
authors.initials: A
authors.lastname: Borgne-Sanchez
authors.forename: O
authors.initials: O
authors.lastname: Chaloin
authors.forename: R
authors.initials: R
authors.lastname: El-Khoury
authors.forename: M
authors.initials: M
authors.lastname: Brabant
authors.forename: A
authors.initials: A
authors.lastname: Langonné
authors.forename: M
authors.initials: M
authors.lastname: Porceddu
authors.forename: J-J
authors.initials: JJ
authors.lastname: Brière
authors.forename: N
authors.initials: N
authors.lastname: Buron
authors.forename: D
authors.initials: D
authors.lastname: Rebouillat
authors.forename: C
authors.initials: C
authors.lastname: Péchoux
authors.forename: A
authors.initials: A
authors.lastname: Deniaud
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.forename: J-P
authors.initials: JP
authors.lastname: Briand
authors.forename: S
authors.initials: S
authors.lastname: Muller
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.forename: E
authors.initials: E
authors.lastname: Jacotot
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D045304:Cytochromes c / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D010085:Oxidative Phosphorylation; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D054322:tat Gene Products, Human Immunodeficiency Virus; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid