title: Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein.
abstract: Patients with long-lasting hepatitis C virus (HCV) infection are at major risk of hepatocellular carcinoma (HCC). Iron accumulation in the livers of these patients is thought to exacerbate conditions of oxidative stress. Transgenic mice that express the HCV core protein develop HCC after the steatosis stage and produce an excess of hepatic reactive oxygen species (ROS). The overproduction of ROS in the liver is the net result of HCV core protein-induced dysfunction of the mitochondrial respiratory chain. This study examined the impact of ferric nitrilacetic acid (Fe-NTA)-mediated iron overload on mitochondrial damage and ROS production in HCV core protein-expressing HepG2 (human HCC) cells (Hep39b cells). A decrease in mitochondrial membrane potential and ROS production were observed following Fe-NTA treatment. After continuous exposure to Fe-NTA for six days, cell toxicity was observed in Hep39b cells, but not in mock (vector-transfected) HepG2 cells. Moreover, mitochondrial iron ((59)Fe) uptake was increased in the livers of HCV core protein-expressing transgenic mice. This increase in mitochondrial iron uptake was inhibited by Ru360, a mitochondrial Ca(2+) uniporter inhibitor. Furthermore, the Fe-NTA-induced augmentation of mitochondrial dysfunction, ROS production, and cell toxicity were also inhibited by Ru360 in Hep39b cells. Taken together, these results indicate that Ca(2+) uniporter-mediated mitochondrial accumulation of iron exacerbates hepatocyte toxicity caused by the HCV core protein.
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Konomi
authors.initials: K
authors.lastname: Ito
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yoshizumi
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fujie
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Tsutsumi
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hidetake
authors.initials: H
authors.lastname: Fujinaga
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Shinzawa
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: t.horie@thu.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005290:Ferric Compounds; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000139:chemically induced / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism*; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives; D017382:Reactive Oxygen Species / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics*
chemical_list: D005290:Ferric Compounds; D017382:Reactive Oxygen Species; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D007501:Iron; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate
keywords: Ca(2+) uniporter; Fenton reaction; Hepatitis C virus; Reactive oxygen species; Ru360