This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Machida, K. Articles by Lai, M. M. C. Search for Related Content PubMed PubMed Citation Articles by Machida, K. Articles by Lai, M. M. C.

Hepatitis C Virus Triggers Mitochondrial Permeability Transition with Production of Reactive Oxygen Species, Leading to DNA Damage and STAT3 Activation

Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, California 90033,¹ Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan²

Received 14 February 2006/ Accepted 2 May 2006

Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinomas and non-Hodgkin's B-cell lymphomas. Previously, we reported that HCV infection causes cellular DNA damage and mutations, which are mediated by nitric oxide (NO). NO often damages mitochondria, leading to induction of double-stranded DNA breaks (DSBs) and accumulation of oxidative DNA damage. Here we report that HCV infection causes production of reactive oxygen species (ROS) and lowering of mitochondrial transmembrane potential (_m) in in vitro HCV-infected cell cultures. The changes in membrane potential could be inhibited by BCL-2. Furthermore, an inhibitor of ROS production, antioxidant N-acetyl-L-cysteine (NAC), or an inhibitor of NO, 1400W, prevented the alterations of _m. The HCV-induced DSB was also abolished by a combination of NO and ROS inhibitors. These results indicated that the mitochondrial damage and DSBs in HCV-infected cells were mediated by both NO and ROS. Among the HCV proteins, core, E1, and NS3 are potent ROS inducers: their expression led to DNA damage and activation of STAT3. Correspondingly, core-protein-transgenic mice showed elevated levels of lipid peroxidation and oxidatively damaged DNA. These HCV studies thus identified ROS, along with the previously identified NO, as the primary inducers of DSBs and mitochondrial damage in HCV-infected cells.

This article has been cited by other articles:

• Machida, K., Kondo, Y., Huang, J. Y., Chen, Y.-C., Cheng, K. T.-H., Keck, Z., Foung, S., Dubuisson, J., Sung, V. M.-H., Lai, M. M. C. (2008). Hepatitis C Virus (HCV)-Induced Immunoglobulin Hypermutation Reduces the Affinity and Neutralizing Activities of Antibodies against HCV Envelope Protein. J. Virol. 82: 6711-6720 [Abstract] [Full Text]  
• Huang, H., Chen, Y., Ye, J. (2007). Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E. Proc. Natl. Acad. Sci. USA 104: 18666-18670 [Abstract] [Full Text]  
• Moriishi, K., Mochizuki, R., Moriya, K., Miyamoto, H., Mori, Y., Abe, T., Murata, S., Tanaka, K., Miyamura, T., Suzuki, T., Koike, K., Matsuura, Y. (2007). Critical role of PA28{gamma} in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc. Natl. Acad. Sci. USA 104: 1661-1666 [Abstract] [Full Text]