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 (ΔΨm) 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.

Mitotoxicity in distal symmetrical sensory peripheral neuropathies

“…41,42 The mitotoxic effects of Vpr are also well established in several cell types. This protein binds to adenine nucleotide translocator and voltage-dependent anion channels, which induces mitochondrial swelling, loss of the mitochondrial membrane potential, and release of cytochrome c. 43 Vpr also decreases expression of several mitochondrial proteins, 44 reduces ATP production, and increases oxidative stress.…”

Human Immunodeficiency Virus Promotes Mitochondrial Toxicity

“…Nevertheless, the ability of Tat to cause a drastic inhibition of ATP synthase (Lecoeur et al 2012; Norman et al 2007) points to a disruption of mitochondrial function. Changes in ETC protein function lead to rapid dissipation of the mitochondrial membrane potential, inhibition of mitochondrial calcium uptake, and release of cytochrome c, a water-soluble component of ETC located within the inner membrane of mitochondria.…”

“…It is important to note that these findings were obtained in cortical and striatal cultures, respectively, suggesting that gp120 may activate different mechanisms of apoptosis depending upon cell types. Regardless of whether Tat and gp120 decrease ATP formation, when Tat or gp120–mediated mitochondrial membrane potential changes are blocked, neurons can be spared from undergoing apoptosis (Lecoeur et al 2012; Turchan et al 2001). This consideration indicates that the integrity of mitochondrial function is key to explain the neurotoxic properties of Tat and gp120 and that keeping this function intact could be a therapeutic target to improve neuronal survival following HIV infection.…”

“…The acute calcium overload caused by Tat can also trigger PTP complex formation. In more recent investigations, Tat was found to have no effect upon Bcl-2 and neither Bax-inhibiting peptide nor Bax channel inhibitor could alter Tat-induced cytochrome c release (Lecoeur et al 2012). Taken together, these data suggest Tat-induced PTP might be independent of the canonic Bax/Bak mediated mitochondrial PTP pathway.…”

Cloning, Expression and Purification of a Novel Multi-epitopic HIV-1 Vaccine Candidate: A Preliminary Study on Immunoreactivity

“…The most important role of this protein is in the late stages of HIV replication, assembly, maturation and release of a mature viral particle [7]. Tat in the HIV-1 virus triggers apoptosis, hence, has a significant role in the pathogenesis of this virus and is the first known inhibitor of cytochrome C oxidase (COX) activity [8,9]. The Pol gene codes for three enzymes; reverse transcriptase (RT), integrase and protease that are respectively responsible for amplification of viral genome, its integration into the host's genome and hydrolyzing the precursor polypeptides into functional proteins.…”