Functional analyses of P13II, a mitochondrial protein of human T-cell leukemia virus type-1

HTLV-1 encodes several accessory proteins of incompletely defined function. We recently showed that one of these proteins, named p13II, accumulates in the inner mitochondria membrane and disrupts mitochondrial morphology. Analysis of the effects of p13II on isolated mitochondria showed that a synthetic peptides spanning the active region of the protein induces changes in the permeability of mitochondria to K+ and modulates their inner membrane potential and Ca2 +-retention capacity. These changes are not affected by cyclosporin A, an inhibitor of the permeability transition pore or by ruthenium red, an inhibitor of the calcium uniporter, suggesting that p13II does not act by modulating these mitochondrial channels. These latter features, along with the ion-selectivity of the permeability changes, distinguish the activities of p13II from those described for HIV-1 Vpr, another viral protein targeted to mitochondria.Analysis of the effects of p13II on cell growth revealed that it significantly reduces the incidence and growth rate of tumors in in vivo models of oncogenesis and interferes with cell proliferation in vitro. Preliminary analyses suggest that these effects might result from the ability of p13II to modulate Ca2 +- signaling. These findings provide novel clues into the function of p13II as a regulator of cell growth, and underscore a link between mitochondria, Ca2 + signaling and tumorigenicity.