Causes and consequences of mitochondrial reactive oxygen species generation in hepatitis C.
Hepatitis C virus has developed mechanisms to alter the redox state of hepatocytes and this is associated with changes in mitochondrial structure and function. Chronic hepatitis C patients manifest hepatic oxidative stress and this is exacerbated by alcohol consumption and associated with fibrosis progression. Several viral proteins, including core and NS5a appear to contribute to reactive oxygen species (ROS) generation by mechanisms that involve both mitochondria and endoplasmic reticulum (ER). Hepatitis C virus (HCV) core protein localizes to both ER and mitochondria and has effects at both sites. At the mitochondria a chain of events is initiated by core binding, which consists of increased Ca(2+) uptake, increased mitochondrial superoxide production, oxidation of the mitochondrial glutathione pool, inhibition of electron transport complex I activity, and sensitization of mitochondria to Ca(2+)- and ROS-induced membrane permeability transition. These effects have been observed in isolated mitochondria, cells bearing full-length HCV replicons, and liver mitochondria derived from HCV transgenic mice. In addition to these direct effects on mitochondria, core protein has been shown to causes a state of ER stress and an increase in the efficiency of ER to mitochondria Ca(2+) transfer. The resulting oxidized redox state has a number of potential consequences for liver function. It interferes with the antiviral innate immune responses and potentiates fibrosis and carcinogenesis. Alcohol exacerbates these effects by increasing core-induced ROS production, further oxidizing the mitochondrial glutathione pool. The resulting mitochondrial effects may contribute to liver injury and oxidative stress seen in chronic hepatitis C.
Wang
Ting
T
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-0620, USA.
Weinman
Steven A
SA
D000438:Alcohols / Q000633:toxicity*; D000818:Animals; D006526:Hepatitis C / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000438:Alcohols; D017382:Reactive Oxygen Species