title: Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization.
abstract: Hepatitis C virus (HCV) causes mitochondrial injury and oxidative stress, and impaired mitochondria are selectively eliminated through autophagy-dependent degradation (mitophagy). We investigated whether HCV affects mitophagy in terms of mitochondrial quality control. The effect of HCV on mitophagy was examined using HCV-Japanese fulminant hepatitis-1-infected cells and the uncoupling reagent carbonyl cyanide m-chlorophenylhydrazone as a mitophagy inducer. In addition, liver cells from transgenic mice expressing the HCV polyprotein and human hepatocyte chimeric mice were examined for mitophagy. Translocation of the E3 ubiquitin ligase Parkin to the mitochondria was impaired without a reduction of pentaerythritol tetranitrate-induced kinase 1 activity in the presence of HCV infection both in vitro and in vivo. Coimmunoprecipitation assays revealed that Parkin associated with the HCV core protein. Furthermore, a Yeast Two-Hybrid assay identified a specific interaction between the HCV core protein and an N-terminal Parkin fragment. Silencing Parkin suppressed HCV core protein expression, suggesting a functional role for the interaction between the HCV core protein and Parkin in HCV propagation. The suppressed Parkin translocation to the mitochondria inhibited mitochondrial ubiquitination, decreased the number of mitochondria sequestered in isolation membranes, and reduced autophagic degradation activity. Through a direct interaction with Parkin, the HCV core protein suppressed mitophagy by inhibiting Parkin translocation to the mitochondria. This inhibition may amplify and sustain HCV-induced mitochondrial injury.
authors.affiliation: Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Yanatori
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Anatomy, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kiyokage
authors.affiliation: Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Sohji
authors.initials: S
authors.lastname: Nishina
authors.affiliation: Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tomiyama
authors.affiliation: Department of Anatomy, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Toida
authors.affiliation: Department of Molecular Genetics, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Kishi
authors.affiliation: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan. Electronic address: khino@med.kawasaki-m.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hino
mesh_terms: D000818:Animals; D018936:Hepatitis C Antigens / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014758:Viral Core Proteins / Q000378:metabolism*
chemical_list: D018936:Hepatitis C Antigens; D014758:Viral Core Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein