Human Hepatitis B Virus-X Protein Alters Mitochondrial Function and Physiology in Human Liver Cells

Abstract

The hepatitis B virus-X protein (HBx) regulates fundamental aspects of mitochondrial physiology. We show that HBx down-regulates mitochondrial enzymes involved in electron transport in oxidative phosphorylation (complexes I, III, IV, and V) and sensitizes the mitochondrial membrane potential in a hepatoma cell line. HBx also increases the level of mitochondrial reactive oxygen species and lipid peroxide production. HBx does not activate apoptotic signaling, although it sensitizes hepatoma cells to apoptotic signaling, which is dependent on reactive oxygen species. Increased intrahepatic lipid peroxidation in HBx transgenic mice demonstrated that oxidative injury occurs as a direct result of HBx expression. Therefore, we conclude that mitochondrial dysfunction is a crucial pathophysiological factor in HBx-expressing hepatoma cells and provides an experimental rationale in the investigation of mitochondrial function in rapidly renewed tissues, as in hepatocellular carcinomas.