Restoration of mitophagy as a strategy for inhibiting hepatocarcinogenesis

• Project/Area Number: 25670374
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kawasaki Medical School
• Principal Investigator: HINO Keisuke 川崎医科大学, 医学部, 教授 (80228741)
• Co-Investigator(Kenkyū-buntansha): HARA Yuichi 川崎医科大学, 医学部, 講師 (60550952) ; NISHINA Sohji 川崎医科大学, 医学部, 講師 (70550961)
• Project Period (FY): 2013-04-01 – 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 酸化ストレス / ミトコンドリア / 活性酸素種 / 鉄 / Ｃ型肝炎ウイルス / マイトファジー / C型肝炎ウイルス / mitophagy / Parkin / autophagy

Outline of Final Research Achievements

Oxidative stress is amplified through the suppression of mitophagy by hepatitis C virus (HCV) and plays an important role in hepatocarcinogenesis. In the present study we investigated whether iron chelation could restore mitophagy supressed by HCV. Iron chelator, deferiprone (DFP) increased LC3-II expression and mitophagosomes in HCV-infected cells. DFP also decreased mitochondrial membrane potential and reactive oxygen species (ROS) production, but not ATP production. In addition, DFP decreased mitochondrial ferrous iron content in dose dependent manner regardless of HCV infection. These results indicated that iron chelation restores mitophagy suppressed by HCV. The mechanisms underlying mitophagy induced by iron chelation remains to be unknown, but decrease in mitochondrial ferrous iron and disrupted mitochondrial function may be critical for inducing mitophagy.

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] 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] 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] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Tanak Y, Kurosaki M, Asahina Y, Izumi N, Orito E, Hiasa Y, Honda M, Kaneko S, Mita E, Suzuki K, Hino K, Tanaka E, Mochida S, Mawatari Y, Ohashi J, Kawashima M, Tokunaga K, Mizokami, et al M
  • Journal Title: PLOS One Volume: 9
  • 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] Risk factors for survival and the development of hepatocellular carcinoma in patients with primary biliary cirrhosis (2013)
  • Author(s): Tomiyama Y, Takenaka K, Kodama T, Kawanaka M, sasaki K, Nishina S, Yoshioka N, Hara Y, Hino K
  • Journal Title: Intern Med Volume: 52 Pages: 1553-9
  • NAID: 130003365701
  • Peer Reviewed
• [Journal Article] Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease (2013)
  • Author(s): Korenaga K1, Korenaga M, Teramoto F, Suzuki T, Nishina S, Sasaki K, Nakashima Y, Tomiyama Y, Yoshioka N, Hara Y, Moriya T, Hino K.
  • Journal Title: Hepatol Res. Volume: 43 Issue: 12 Pages: 1284-1294
  • DOI: 10.1111/hepr.12095
  • Peer Reviewed
• [Journal Article] First jejunal vein oriented mesenteric excision for pancreatoduodenectomy (2013)
  • Author(s): Nakamura M, Nakashima H, Tsutsumi K, Matsumoto H, Muta Y, Ueno D, Yoshida K, Hino K, Urakami A, Tanaka M
  • Journal Title: J Gastroenterol Volume: 48 Issue: 8 Pages: 989-95
  • DOI: 10.1007/s00535-012-0697-6
  • NAID: 10031195125
  • Peer Reviewed
• [Journal Article] Treatment of nonalcoholic steatohepatitis with vitamins E and C: a pilot study (2013)
  • Author(s): Kawanaka M, Nishino K, Suehiro M, Goto D, Urata N, Oka T, Kawamoto H, Nakamura H, Yodoi J, Hino K, Yamada G
  • Journal Title: Hepatic Medicine: Evidence and Research Volume: 5 Pages: 11-16
  • Peer Reviewed
• [Presentation] 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
  • Organizer: 5th World Congress on Targeting Mitochondria
  • Place of Presentation: Ritz Carlton Hotel, Berlin, Germany
  • Year and Date: 2014-10-30
• [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: ホテルニューオータニ、東京
  • Year and Date: 2014-05-30
• [Presentation] The hepatitis C virus core protein suppresses mitophagy by affecting Parkin
  • Author(s): Yuichi Hara, Izumi Yanatori , Masanori Ikeda, Sohji Nishina, Yasuyuki Tomiyama, Fumio Kishi, Kazunori Toida, Nobuyuki Kato, Kazuaki Chayama , Keisuke Hino
  • Organizer: Cell Sumposium Mitochondria:from Signaling to Disease
  • Place of Presentation: Sheraton Lisbosa, Lisbon, Portugal
• [Presentation] Fibroblast Activation Protein (FAP) Expression of Cancer-Associated Fibroblast Predicts Poor Prognosis in Patients With Pancreatic Adenocarcinoma
  • Author(s): Tomoya Kawase, Koji Yoshida, Keisuke Hino
  • Organizer: DDW2013(American Gastroenterological Association)
  • Place of Presentation: orange Country Convention Center, Orland FL, USA
• [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
  • Author(s): 原裕一，仁科惣治，日野啓輔
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル、東京
• [Presentation] HCVタンパクはエストロゲン欠乏起因性酸化ストレスに対する抗酸化機構を抑制する
  • Author(s): 富山恭行，小山展子，佐々木恭，仁科惣治，吉岡奈穂子，原 裕一，日野啓輔
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル、東京
• [Presentation] Splenectomy causes hepatic inflammation and oxidative stress through activation of Kupffer cells in iron-overloaded mice
  • Author(s): Sohji Nishina, Yuichi Hara, Yasuyuki Tomiyama, Keisuke Hino
  • Organizer: 17th International Symposium on Cells of the Hepatic Sinusoid
  • Place of Presentation: Osaka International Convention Center, osaka, Japan
• [Presentation] Splenectomy causes hepatic inflammation and oxidative stress through activation of Kupffer cells in iron-overloaded mice
  • Author(s): Sohji Nishina, Yuichi Hara, Yasuyuki Tomiyama, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Waltere Washington Convention Center, Washington DC, USA
• [Presentation] Ovariectomized transgenic mice expressing hepatitis C virus polyprotein develop hepatic steatosis through suppression of AMPK/PGC1a signaling
  • Author(s): Yasuyuki Tomiyama, Sohji Nishina , Yuichi Hara, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Waltere Washington Convention Center, Washington DC, USA
• [Presentation] Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin
  • Author(s): Yuhichi Hara, Izumi Yanatori, EmiKiyokage, Sohji Nishina, Yasuyuki Tomiyama, Kazunori Toida, Masanori Ikeda, Fumio Kishi, Nobuyuki Kato, Keisuke Hino
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Waltere Washington Convention Center, Washington DC, USA
• [Book] HEPATOLOGY PRACTICE（第３巻） (2014)
  • Author(s): 原裕一, 日野啓輔
  • Total Pages: 321
  • Publisher: 文光堂
• [Book] 酸化ストレスの医学 (2014)
  • Author(s): 原裕一, 日野啓輔
  • Total Pages: 444
  • Publisher: 診断と治療社
• [Book] 診断と治療 ウイルス肝炎の新展開 (2013)
  • Author(s): 原 裕一、日野啓輔
  • Total Pages: 190
  • Publisher: 診断と治療社