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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<jats:sup>2+<\/jats:sup> uptake, increased mitochondrial superoxide production, oxidation of the mitochondrial glutathione pool, inhibition of electron transport complex I activity, and sensitization of mitochondria to Ca<jats:sup>2+<\/jats:sup>\u2010 and ROS\u2010induced membrane permeability transition. These effects have been observed in isolated mitochondria, cells bearing full\u2010length 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<jats:sup>2+<\/jats:sup> 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\u2010induced 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.<\/jats:p>","DOI":"10.1111\/j.1440-1746.2006.04591.x","type":"journal-article","created":{"date-parts":[[2006,8,22]],"date-time":"2006-08-22T10:30:51Z","timestamp":1156242651000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Causes and consequences of mitochondrial reactive oxygen species generation in hepatitis C"],"prefix":"10.1111","volume":"21","author":[{"given":"Ting","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A","family":"Weinman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,8,22]]},"reference":[{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2005.12.001"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.2001.00747.x"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510260118"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1155\/2003\/710693"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.30983"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171311298"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2005.02.004"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100698200"},{"key":"e_1_2_9_10_2","first-page":"4365","article-title":"Oxidative stress in the absence of inflammation in a mouse model for hepatitis c virus\u2010associated hepatocarcinogenesis","volume":"61","author":"Moriya K","year":"2001","journal-title":"Cancer Res."},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.10567"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506412200"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.10.045"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.15.7958-7968.2004"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.2.1271-1281.2005"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414139200"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1243"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.08.012"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.08.014"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04193"},{"key":"e_1_2_9_21_2","first-page":"17","article-title":"Hepatitis C virus protease NS3\/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity","volume":"102","author":"Li XD","year":"2005","journal-title":"Proc. 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