Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria

Helicobacter pylori infection causes peptic ulcers and gastric cancer. A major toxin secreted by H. pylori is the bipartite vacuolating toxin, VacA. The toxin is believed to enter host cells as two subunits, the p55 subunit and the p33 subunit. At the biochemical level it has been shown that VacA forms through the assembly of large multimeric pores comprised of both the p33 and p55 subunits in biological membranes. One of the major target organelles of the VacA toxin is the mitochondria. Since, only the p33 subunit has been reported to be translocated into mitochondria and that the p55 subunit is not imported, it has been contentious as to whether VacA assembles into pores in a mitochondrial membrane. Here we show that the p55 protein is imported into mitochondria along with the p33 protein subunit. The p33 subunit integrally associates with the mitochondrial inner membrane and both the p33 and p55 subunits are exposed to the mitochondrial inter-membrane space. Their co-localisation suggests that they could re-assemble and form a pore in the inner mitochondrial membrane.