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HIV-1 Tat protein directly induces mitochondrial membrane permeabilization and inactivates cytochrome c oxidase.
- Source :
-
Cell death & disease [Cell Death Dis] 2012 Mar 15; Vol. 3, pp. e282. Date of Electronic Publication: 2012 Mar 15. - Publication Year :
- 2012
-
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.
- Subjects :
- 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid pharmacology
Animals
Brain drug effects
Brain enzymology
Cytochromes c metabolism
Electron Transport Complex IV metabolism
Humans
Ion Transport
Liver drug effects
Liver enzymology
Membrane Potential, Mitochondrial
Mice
Mice, Inbred BALB C
Mitochondria enzymology
Mitochondrial Membranes drug effects
Mitochondrial Membranes metabolism
Myocardium enzymology
Oxidative Phosphorylation
Permeability
Proto-Oncogene Proteins c-bcl-2 metabolism
tat Gene Products, Human Immunodeficiency Virus chemistry
tat Gene Products, Human Immunodeficiency Virus physiology
Electron Transport Complex IV antagonists & inhibitors
Mitochondria drug effects
tat Gene Products, Human Immunodeficiency Virus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 3
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 22419111
- Full Text :
- https://doi.org/10.1038/cddis.2012.21