Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.
OBJECTIVE
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.
Okuda
Michiari
M
Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-0641, USA.
Li
Kui
K
Beard
Michael R
MR
Showalter
Lori A
LA
Scholle
Frank
F
Lemon
Stanley M
SM
Weinman
Steven A
SA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D003574:Cytochrome c Group / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D019698:Hepatitis C, Chronic / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000821:virology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000235:genetics* / Q000378:metabolism*
D000975:Antioxidants; D003574:Cytochrome c Group; D017382:Reactive Oxygen Species; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus