Abstract
Hepatocellular carcinoma (HCC) is a common cancer worldwide. Among many risk factors, hepatitis B virus (HBV) infection is the major risk for development of HCC. Mitochondria is a critical organelle for cellular functions, including ATP production, metabolism, calcium homeostasis, reactive oxygen species (ROS) signaling pathway and cell survival. Mitochondrial dynamics, including fusion and fission, is essential to maintain the number, biomass, morphology, and function of mitochondria. Previous studies have suggested HBx mutant and pre-S mutant large surface antigen (LHBs) play important roles in HCC. HBx have been demonstrated that promote aberrant mitochondrial dynamics. Researches focusing on the association between LHBs and mitochondria are limited. In this study, we aim to clarify the underlying mechanism and biological implication of LHBs on mitochondrial dynamics. We found that HBV or LHBs switched mitochondrial dynamic balanced towards fission through dynamic-related protein 1 (Drp1). Overexpression of a dominant-negative Drp1 suppressed mitochondria fission in hepatocytes. Besides, Drp1 also regulated autophagy and cell growth, in particularly under nutrient deprivation. Surprisingly, in the absence of Drp1, HBV production, viral secretion, and even cccDNA expression were all declined significantly. These results indicate that Drp1 plays an important role in HBV replication and virion production in hepatocytes. Understanding the mechanism of Drp1-involved HBV replication will be beneficial to develop a novel therapeutic strategy to control HBV replication in patients with chronic HBV infection.