Affiliation:
1. Suite 409 BioLife Science Building, Department of Biology, Center for Biotechnology, Temple University, 1900 N 12th Street, Philadelphia, PA 19122, USA.
Abstract
Evaluation of: Clippinger AJ, Bouchard MJ: Hepatitis B virus HBx protein localizes to mitochondria in primary rat hepatocytes and modulates mitochrondrial membrane potential. J. Virol. 82(14), 6798–6811 (2008). Over 350 million people are chronically infected with HBV, and a significant number of these individuals develop primary liver cancer. HBV encodes seven viral proteins, including the nonstructural Hepatitis B x (HBx) protein. The results of studies with immortalized or transformed cells and with HBx transgenic mice demonstrated that HBx can interact with mitochondria. However, no studies with normal hepatocytes have characterized the precise mitochondrial localization of HBx or the effect of HBx on mitochondrial physiology. We have used cultured primary rat hepatocytes as a model system to characterize the mitochondrial localization of HBx and the effect of HBx expression on mitochondrial physiology. We now show that a fraction of HBx co-localizes with density gradient-purified mitochondria and associates with the outer mitochondrial membrane. We also demonstrate that HBx regulates mitochondrial membrane potential in hepatocytes, and that this function of HBx varies depending upon the status of NF-κB activity. In primary rat hepatocytes, HBx activation of NF-κB prevented mitochondrial membrane depolarization; however, when NF-κB activity was inhibited, HBx induced membrane depolarization through modulation of the mitochondrial permeability transition pore. Collectively, these results define potential pathways through which HBx may act in order to modulate mitochondrial physiology, thereby altering many cellular activities and ultimately contributing to the development of HBV-associated liver cancer.