Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production.
Hepatitis C infection causes a state of chronic oxidative stress, which may contribute to fibrosis and carcinogenesis in the liver. Previous studies have shown that expression of the HCV core protein in hepatoma cells depolarized mitochondria and increased reactive oxygen species (ROS) production, but the mechanisms of these effects are unknown. In this study we examined the properties of liver mitochondria from transgenic mice expressing HCV core protein, and from normal liver mitochondria incubated with recombinant core protein. Liver mitochondria from transgenic mice expressing the HCV proteins core, E1 and E2 demonstrated oxidation of the glutathione pool and a decrease in NADPH content. In addition, there was reduced activity of electron transport complex I, and increased ROS production from complex I substrates. There were no abnormalities observed in complex II or complex III function. Incubation of control mitochondria in vitro with recombinant core protein also caused glutathione oxidation, selective complex I inhibition, and increased ROS production. Proteinase K digestion of either transgenic mitochondria or control mitochondria incubated with core protein showed that core protein associates strongly with mitochondria, remains associated with the outer membrane, and is not taken up across the outer membrane. Core protein also increased Ca(2+) uptake into isolated mitochondria. These results suggest that interaction of core protein with mitochondria and subsequent oxidation of the glutathione pool and complex I inhibition may be an important cause of the oxidative stress seen in chronic hepatitis C.
Korenaga
Masaaki
M
Center for Hepatitis Research, Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, 77555, USA.
Wang
Ting
T
Li
Yanchun
Y
Showalter
Lori A
LA
Chan
Tehsheng
T
Sun
Jiaren
J
Weinman
Steven A
SA
D000818:Animals; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000378:metabolism*; D018936:Hepatitis C Antigens / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
D006512:Hepatitis B Core Antigens; D018936:Hepatitis C Antigens; D017382:Reactive Oxygen Species; D042967:Electron Transport Complex I; D005978:Glutathione