Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K(+) current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K(+) and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K(+) channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability.

Fig. 1

p13 sequence and predicted structure. Panel A shows the amino acid sequence of p13 with the mitochondrial targeting signal underlined. Panel B shows in silico analysis of p13’s structure using the ProtScale Software provided by the ExPASy Proteomics Server; graphs show the predicted scores for α-helix (Deleage & Roux), the transmembrane tendency, average flexibility, and total beta strand of the different regions of the protein. Panel C shows a hypothetical model of p13’s structure in the context of the inner mitochondrial membrane based on results of experimental data described in Ref. and in silico predictions shown in Panel B. Segments A–D of the protein represent, respectively, the amphipathic α-helical domain, the transmembrane domain, the hinge region and the C-terminal beta sheet hairpin. Panel C also shows a more detailed helical wheel model of the amphipathic α-helical domain of p13 (amino acids 20–35). Panel C does not indicate the matrix and intermembrane space faces of the inner membrane, as the topology of p13 has not been defined.

Fig. 2

Effects of p13 function at the mitochondrial level: a working model. p13 is inserted in the inner mitochondrial membrane (IM) and generates an inward K⁺ current in mitochondria. This effect may result either from the direct channel-forming ability of p13 (upper part of the scheme) or by its influence on cellular K⁺ channels located in the mitochondria (lower part of the scheme). This effect leads to IM depolarization that in turn increases the activity of the electron transport chain (ETC) which, by increasing H⁺ extrusion, dampens the depolarizing effect of p13. Furthermore, increased ETC activity results in increased ROS production which, along with membrane depolarization, may lower the opening threshold of the permeability transition pore (PTP).