**3.5. Hepatitis B virus targets mitochondria**

Hepatitis B virus x protein (HBx) is potentially essential for viral replication, and it has oncogenic properties in animal models [67]. HBx sensitizes hepatocytes to apoptosis induced by stimuli such TNF-α [68]. Studies of the overexpression of HBx showed that this protein causes apoptosis by causing a perinuclear clustering of mitochondria and a loss of the MMP [69]. Studies of HBx mutants identified that certain hydrophobic residues (a mitochondrial targeting sequence, MTS) are important for its induction of mitochondrial localization, loss of MMP, and cell death [70]. The HBx protein usually interacts with at least two mitochondrial proteins, heat shock protein 60 (HSP60) [71] and HVDAC3 [72]. The interaction of HBx with these two proteins (which are important in maintaining mitochondrial integrity) ultimately disrupts mitochondrial function in infected cells. These two mitochondrial proteins play major roles in chronic liver disease and carcinogenesis. Therefore, HBx plays a major role in the pathogenesis of HBV infection due to its alteration of host cell mitochondria.
