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Growing evidence supports a link between mitochondrial dysfunction and liver fibrogenesis and mitochondrial quality control\u2010based therapy has emerged as a new therapeutic target. We investigated the protective mechanisms of melatonin against mitochondrial dysfunction\u2010involved liver fibrosis, focusing on mitophagy and mitochondrial biogenesis. Rats were treated with carbon tetrachloride (<jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>l<jats:sub>4<\/jats:sub>) dissolved in olive oil (0.5 <jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content>\/kg, twice a week, i.p.) for 8 wk. Melatonin was administered orally at 2.5, 5, and 10 mg\/kg once a day. Chronic <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>l<jats:sub>4<\/jats:sub> exposure induced collagen deposition, hepatocellular damage, and oxidative stress, and melatonin attenuated these increases. Increases in <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> and protein expression levels of transforming growth factor <jats:italic>\u03b2<\/jats:italic>1 and <jats:italic>\u03b1<\/jats:italic>\u2010smooth muscle actin in response to <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>l<jats:sub>4<\/jats:sub> were attenuated by melatonin. Melatonin attenuated hallmarks of mitochondrial dysfunction, such as mitochondrial swelling and glutamate dehydrogenase release. Chronic <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>l<jats:sub>4<\/jats:sub> exposure impaired mitophagy and mitochondrial biogenesis, and melatonin attenuated this impairment, as indicated by increases in mitochondrial <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> and in protein levels of <jats:styled-content style=\"fixed-case\">PTEN<\/jats:styled-content>\u2010induced putative kinase 1 (<jats:styled-content style=\"fixed-case\">PINK<\/jats:styled-content>1); Parkin; peroxisome proliferator\u2010activated receptor\u2010gamma coactivator 1<jats:italic>\u03b1<\/jats:italic> (<jats:styled-content style=\"fixed-case\">PGC<\/jats:styled-content>\u20101<jats:italic>\u03b1<\/jats:italic>); nuclear respiratory factor 1 (<jats:styled-content style=\"fixed-case\">NRF<\/jats:styled-content>1); and transcription factor A, mitochondrial (<jats:styled-content style=\"fixed-case\">TFAM<\/jats:styled-content>). <jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content>l<jats:sub>4<\/jats:sub>\u2010mediated decreases in mitochondrial fission\u2010 and fusion\u2010related proteins, such as dynamin\u2010related protein 1 (<jats:styled-content style=\"fixed-case\">DRP<\/jats:styled-content>1) and mitofusin 2, were also attenuated by melatonin. Moreover, melatonin induced <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\u2010activated protein kinase (<jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>) phosphorylation. These results suggest that melatonin protects against liver fibrosis via upregulation of mitophagy and mitochondrial biogenesis, and may be useful as an anti\u2010fibrotic treatment.<\/jats:p>","DOI":"10.1111\/jpi.12319","type":"journal-article","created":{"date-parts":[[2016,2,16]],"date-time":"2016-02-16T15:22:43Z","timestamp":1455636163000},"page":"383-393","source":"Crossref","is-referenced-by-count":213,"title":["Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride\u2010induced liver fibrosis"],"prefix":"10.1111","volume":"60","author":[{"given":"Jung\u2010Woo","family":"Kang","sequence":"first","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University Suwon Gyeonggi\u2010do Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong\u2010Min","family":"Hong","sequence":"additional","affiliation":[{"name":"School of Pharmacy Sungkyunkwan University Suwon Gyeonggi\u2010do 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