Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization.

• Project/Area Number: 24659377
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kawasaki Medical School
• Principal Investigator: HARA Yuichi 川崎医科大学, 医学部, 講師 (60550952)
• Co-Investigator(Kenkyū-buntansha): NISHINA Sohji 川崎医科大学, 医学部, 講師 (70550961) ; HINO Keisuke 川崎医科大学, 医学部, 教授 (80228741)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HCV / マイトファジー / ミトコンドリア / 肝発癌 / 酸化ストレス / Parkin / C型肝炎ウイルス / mitophagy

Outline of Final Research Achievements

Background and aim: Hepatitis C virus (HCV) causes mitochondrial injury and oxidative stress, and impaired mitochondria are selectively eliminated through autophagy-dependent degradation (mitophagy). The basis of the hypothesis that if the impaired mitochondria was not removed by mitophagy which causes further oxidative stress and promotes hepatocarcinogenesis.Results:Translocation of the Parkin to the mitochondria was impaired in the presence of HCV infection both in vitro and in vivo. Parkin associated with the HCV core protein. Furthermore, a specific interaction between the HCV core protein and an N-terminal Parkin fragment. The suppressed Parkin translocation to the mitochondria inhibited autophagic degradation. Production of ROS was reinforced after mitophagy had been inhibited by HCV. Conclusion:Through a direct interaction with Parkin, the HCV core protein suppressed mitophagy by inhibiting Parkin translocation to the mitochondria.

Research Products

• [Journal Article] Branched-chain amino acids reduce hepatic iron accumulation and oxidative stress in hepatitis C virus polyprotein-expressing mice. (2015)
  • Author(s): Korenaga M, Nishina S, Korenaga K, Tomiyama Y, Yoshioka N, Hara Y, Sasaki Y, Shimonaka Y, Hino K.
  • Journal Title: Liver Int. Volume: 35 Issue: 4 Pages: 1303-14
  • DOI: 10.1111/liv.12675
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. (2014)
  • Author(s): Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, Toida K, Kishi F, Kato N, Imamura M, Chayama K, Hino K.
  • Journal Title: Am J Pathol. 2014 Volume: 184 Issue: 11 Pages: 3026-39
  • DOI: 10.1016/j.ajpath.2014.07.024
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of AMPK/PGC-1alpha signaling (2014)
  • Author(s): Tomiyama Y, Nishina S, Hara Y, Kawase T, Hino K
  • Journal Title: Hepatol Res Volume: (in press) Issue: 10 Pages: 229-39
  • DOI: 10.1111/hepr.12254
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial reactive oxygen species as a mystery voice in hepatitis C (2014)
  • Author(s): Hino K, Hara Y, Nishina S
  • Journal Title: Hepatol Res Volume: 44 Issue: 2 Pages: 123-32
  • DOI: 10.1111/hepr.12247
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic oxidative stress in ovariectomized transgenic mice expression the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate-activated protein kinase/proliferator-activated receptor gamma co-activator 1 alpha signaling. (2013)
  • Author(s): Yasuyuki Tomiyama Sohoji Nishina Yuichi hara Keisuke Hino
  • Journal Title: Hepatol Res Volume: １４ Pages: 1-11
  • Peer Reviewed
• [Journal Article] Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease. (2013)
  • Author(s): Keiko Korenaga , Masaaki Korenaga, Fusako Teramoto, Toshiko Suzuki,Sohoji Nishina, Kyo Sasaki, Yoshihiro Nakashima,Yasuyuki Tomiyama, Naoko Yoshioka, Yuichi Hara, Takuya Moriya, Keisuke Hino
  • Journal Title: Hepatol Res Volume: 43 Pages: 1284-1294
  • Peer Reviewed
• [Journal Article] Iron metabolic disorder in chronic hepatitis C:Mechanisms and relevance to hepatocarcinogenesis. (2013)
  • Author(s): Keisuke Hino, Sohoji Nishina, Yuichi hara
  • Journal Title: J Gastroenterol Hepatol Volume: 28 Pages: 93-98
  • Peer Reviewed
• [Journal Article] Risk factors for survival and the development of hepatocellular carcinoma in patients with primary biliary cirrhosis. (2013)
  • Author(s): Tomiyama Yasuyuki,Kazuyuki Takenaka ,Takahiro Kodama,Miwa Kawanaka , Kyo Sasaki,Sohoji Nishina , Naoko Yoshioka, Yuichi Hara Y, Keisuke Hino
  • Journal Title: Hepatol Res Volume: 52 Pages: 1553-1559
  • NAID: 130003365701
  • Peer Reviewed
• [Journal Article] Clinical usefulness of non-protein respiratory quoitient measurement in non-alcholic fatty liver disease (2013)
  • Author(s): Korenaga Keiko
  • Journal Title: Hepatol Res Volume: in press
  • Peer Reviewed
• [Journal Article] Risk factors for survival and development of hepatocellular carcinoma in primary billiary cirrhosis (2013)
  • Author(s): Tomiyama Yasuyuki
  • Journal Title: Intern Med Volume: in press
  • Peer Reviewed
• [Journal Article] Iron metabolic disorder in chronic hepatitis C: Mechanisms and relevance to hepatocarcinogenesis (2013)
  • Author(s): Hino K, Nishina S, Hara Y
  • Journal Title: J Gastroenterol Hepatol Volume: 28 Suppl 4 Issue: S4 Pages: 93-8
  • DOI: 10.1111/jgh.12243
  • Peer Reviewed
• [Journal Article] Iron metabolic disorder: insights from recent evidence (2012)
  • Author(s): Hino Keisuke
  • Journal Title: Cin J Gastroenterol Volume: 5 Pages: 251-256
  • Peer Reviewed
• [Presentation] HCVコアタンパクによるmitophagyの抑制 (2015)
  • Author(s): 原裕一
  • Organizer: 肝臓フォーラム（西部）
  • Place of Presentation: 大阪市
  • Year and Date: 2015-02-28
• [Presentation] HCVとミトコンドリアのバイオジェネーシスとの関連性 (2014)
  • Author(s): 原 裕一, 仁科 惣治, 日野 啓輔
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-30
• [Presentation] Supressed Mitophagy in Transgenic mice Expressing Hepatitis C Virus Polyprotein (2013)
  • Author(s): Yuichi Hara, Izumi Yanatori , Emi Kiyokage , Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida , Masanori Ikeda , Fumio Kishi , Nobuyuki Kato , Michio Imamura , Kazuaki Chayama , Keisuke Hino
  • Organizer: Cell Symposia : Mitochondria
  • Place of Presentation: Rua Latino Coelho, 1Lisbon,Portugal
  • Invited
• [Presentation] HCVコア蛋白とParkinとの相互作用によるマイトファジーの抑制 (2013)
  • Author(s): 原 裕一 仁科惣治
  • Organizer: DDW
  • Place of Presentation: グランドプリンスホテル、東京、日本
  • Invited
• [Presentation] Suppressed mitophagy in transgenic mice expressing hepatitis C virus polyprotein (2013)
  • Author(s): Yuichi Hara, Izumi Yanatori , Emi Kiyokage , Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida , Masanori Ikeda , Fumio Kishi , Nobuyuki Kato , Michio Imamura , Kazuaki Chayama , Keisuke Hino
  • Organizer: The 2nd JSGE International Topic Conference
  • Place of Presentation: Kagosima castle park hotel,Kagoshima, Japan
  • Invited
• [Presentation] Hepatitis C virus core protein suppresses mitophagy (2013)
  • Author(s): Yuichi Hara, Izumi Yanatori , Emi Kiyokage , Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida , Masanori Ikeda , Fumio Kishi , Nobuyuki Kato , Michio Imamura , Kazuaki Chayama , Keisuke Hino
  • Organizer: AASLD
  • Place of Presentation: Walter E. Washington Convention Center, Washington, USA
  • Invited
• [Presentation] HCVコア蛋白とParkinとの相互作用よるmitophagyの抑制及びHCV増殖に対する影響 (2013)
  • Author(s): 原 裕一 仁科惣治 日野啓輔
  • Organizer: 日本肝臓学会西部会
  • Place of Presentation: 長良川国際会議場・岐阜都ホテル,岐阜、日本
  • Invited
• [Presentation] Supressed Mitophagy in Transgenic moice Expressing Hepatitis C Virus Polyprotein (2013)
  • Author(s): Hara Yuichi
  • Organizer: The 2nd JSGE International Topic Conference
  • Place of Presentation: shiroyamakankohotel, kagoshima
• [Presentation] Hepatitis C Virus proteins supress mitophagy by interacting with Parkin (2012)
  • Author(s): Hara Yuichi
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Hepatitis c virus proteins suppress comoensatory induction of reactive oxygen species-detoxifying enzymes following oxidative stress in the absence of estrogen (2012)
  • Author(s): Tomiyama Yasuyuki
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Hepatitis C Virus core protein supress mitophagy by interacting with Parkin (2012)
  • Author(s): Hara Yuichi
  • Organizer: International symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Palazzo del cinema,Lido-Venice,Italy
• [Presentation] Hepatitis C Virus core protein supress mitophagy by interacting with Parkin (2012)
  • Author(s): Hara Yuichi
  • Organizer: JSH Single Topic Conference
  • Place of Presentation: Keioplazahotel,Tokyo
• [Book] The Liver Cancer Journal (2015)
  • Author(s): 日野啓輔, 原 裕一
  • Total Pages: 6
  • Publisher: メディカルレビュー社
• [Book] 酸化ストレスの医学 (2014)
  • Author(s): 原 裕一 日野啓輔
  • Total Pages: 280
  • Publisher: 診断と治療社
• [Book] C型肝炎の診療を極める (2013)
  • Author(s): 原 裕一 日野啓輔
  • Total Pages: 320
  • Publisher: 文光堂
• [Book] C型肝炎のすべて (2012)
  • Author(s): 原 裕一
  • Total Pages: 385
  • Publisher: アークメディア
• [Book] 肝発癌のすべて (2012)
  • Author(s): 原 裕一
  • Total Pages: 444
  • Publisher: アークメディア
• [Book] 消化器の臨床 (2012)
  • Author(s): 原 裕一
  • Total Pages: 120
  • Publisher: ヴァンメディカル