A direct role for hepatitis B virus X protein in inducing mitochondrial membrane permeabilization

Summary Hepatitis B virus X protein ( HB x) acts as a multifunctional protein that regulates intracellular signalling pathways during HBV infection. It has mainly been studied in terms of its interaction with cellular proteins. Here, we show that HB x induces membrane permeabilization independently of the mitochondrial permeability transition pore complex. We generated mitochondrial outer membrane‐mimic liposomes to observe the direct effects of HB x on membranes. We found that HB x induced membrane permeabilization, and the region comprising the transmembrane domain and the mitochondrial‐targeting sequence was sufficient for this process. Membrane permeabilization was inhibited by nonselective channel blockers or by N ‐(n‐nonyl)deoxynojirimycin ( N N ‐ DNJ ), a viroporin inhibitor. Moreover, N N ‐ DNJ inhibited HB x‐induced mitochondrial depolarization in Huh‐7 cells. Based on the results of this study, we can postulate that the HB x protein itself is sufficient to induce mitochondrial membrane permeabilization. Our finding provides important information for a strategy of HB x targeting during HBV treatment.