Mitochondrial alterations induced by the p13 II protein of human T-cell leukemia virus type 1: Critical role of arginine residues

Human T-cell leukemia virus type 1 encodes a number of "accessory" proteins of unclear function; one of these proteins, p13 ^II, is targeted to mitochondria and disrupts mitochondrial morphology. The present study was undertaken to unravel the function of p13 ^II through (i) determination of its submitochondrial localization and sequences required to alter mitochondrial morphology and (ii) an assessment of the biophysical and biological properties of synthetic peptides spanning residues 9-41 (p13 ^9-41), which include the amphipathic mitochondrial-targeting sequence of the protein. p13 ^9-41 folded into an α helix in micellar environments. Fractionation and immunogold labeling indicated that full-length p13 ^II accumulates in the inner mitochondrial membrane. p13 ^9-41 induced energy-dependent swelling of isolated mitochondria by increasing inner membrane permeability to small cations (Na ⁺, K ⁺) and released Ca ²⁺ from Ca ²⁺-preloaded mitochondria. These effects as well as the ability of full-length p13 ^II to alter mitochondrial morphology in cells required the presence of four arginines, forming the charged face of the targeting signal. The mitochondrial effects of p13 ^9-41 were insensitive to cyclosporin A, suggesting that full-length p13 ^II might alter mitochondrial permeability through a permeability transition pore-independent mechanism, thus distinguishing it from the mitochondrial proteins Vpr and X of human immunodeficiency virus type 1 and hepatitis B virus, respectively.