Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein

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  • Okuda, Michiari
    • Other Affiliation: Departments of Physiology and Biophysics, and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
  • Li, Kui
    • Other Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
  • Beard, Michael R.
    • Other Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
  • Showalter, Lori A.
    • Other Affiliation: Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas
  • Scholle, Frank
    • Other Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
  • Lemon, Stanley M.
    • Other Affiliation: Departments of Microbiology and Immunology, and Internal Medicine, University of Texas Medical Branch, Galveston, Texas
  • Weinman, Steven A.
    • Other Affiliation: Departments of Physiology and Biophysics, and Internal Medicine, University of Texas Medical Branch, Galveston, Texas
Abstract
  • Background and Aims: The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood. Indirect evidence suggests that oxidative stress and mitochondrial injury play a role. The aim of this study was to determine if the HCV core protein itself alters mitochondrial function and contributes to oxidative stress. Methods: HCV core protein was expressed in 3 different cell lines, and reactive oxygen species (ROS) and lipid peroxidation products were measured. Results: Core expression uniformly increased ROS. In 2 inducible expression systems, core protein also increased lipid peroxidation products and induced antioxidant gene expression as well. A mitochondrial electron transport inhibitor prevented the core-induced increase in ROS. A fraction of the expressed core protein localized to the mitochondria and was associated with redistribution of cytochrome c from mitochondrial to cytosolic fractions. Sensitivity to oxidative stress was also seen in HCV transgenic mice in which increased intrahepatic lipid peroxidation products occurred in response to carbon tetrachloride. Conclusions: Oxidative injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria. These results provide new insight into the pathogenesis of hepatitis C and provide an experimental rationale for investigation of antioxidant therapy.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Gastroenterology
Journal volume
  • 122
Journal issue
  • 2
Page start
  • 366
Page end
  • 375
Language
  • English
Version
  • Postprint
ISSN
  • 0016-5085

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