Novel therapeutic approach for heart failure by suppression of mitochondrial translocation of GSK-3beta

• Project/Area Number: 26461132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: Tanno Masaya 札幌医科大学, 医学部, 講師 (00398322)
• Co-Investigator(Kenkyū-buntansha): 三木 隆幸 札幌医科大学, 医学部, 准教授 (00336405) ; 三浦 哲嗣 札幌医科大学, 医学部, 教授 (90199951)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ミトコンドリア透過性遷移孔 / 細胞死 / グリコーゲン合成酵素キナーゼ3beta / グリコーゲン合成酵素キナーゼ3β / GSK-3β

Outline of Final Research Achievements

We investigated the molecular mechanisms by which activity of GSK-3beta promotes opening of mitochondrial permeability transition pore (mPTP). The experiments yielded the following results:
(1) Interaction of GSK-3beta with voltage dependent anion channel 2 mediate mitochondrial translocation of GSK-3beta. (2) Lysine 15 at the N terminus of GSK-3beta plays an important role in the function of N-terminal region as a mitochondria targeting signal. (3) ERK and Akt, upstream kinases of GSK-3beta, translocate to the mitochondria and are dephosphorylated in response to oxidative stress. (4) Dusp5 and PHLPP-1, specific phosphatases for ERK and Akt, respectively, also undergo mitochondrial translocation under oxidative stress.

Research Products

• [Journal Article] Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart (2015)
  • Author(s): Hidemichi Kouzu, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, Toshiyuki Tobisawa, Makoto Ogasawara, Satoko Ishikawa, Tetsuji Miura
  • Journal Title: J Mol Cell Cardiol Volume: 80 Pages: 136-145
  • DOI: 10.1016/j.yjmcc.2015.01.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Translocation of glycogen synthase kinase-3β (GSK-3β), a trigger of permeability transition, is kinase activity-dependent and mediated by interaction with voltage-dependent anion channel 2 (VDAC2). (2014)
  • Author(s): Tanno M, Kuno A, Ishikawa S, Miki T, Kouzu H, Yano T, Murase H, Tobisawa T, Ogasawara M, Horio Y, Miura T.
  • Journal Title: J Biol Chem Volume: 289 Issue: 42 Pages: 29285-29296
  • DOI: 10.1074/jbc.m114.563924
  • Peer Reviewed / Open Access
• [Presentation] ROS-induced mitochondrial translocation of phosphatases cancelscell-protective signals activated by phosphorylation of mitochondrial protective kinases (2016)
  • Author(s): Ohwada W, Tanno M, Yano T, Kuno A, Miki T, Ishikawa S, Tatekoshi Y, Abe K, Ohno K, Mizuno M, Nakata K, Miura T.
  • Organizer: 89th Scientific Session of American Heart Association
  • Place of Presentation: New Orleans, U.S.A.
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Excessive ROS production in mitochondria switches off protective mitochondrial kinase signaling. (2016)
  • Author(s): Tanno M, Ohwada W, Yano T, Miki T, Kuno A, Ishikawa S, Tatekoshi Y, Nishizawa K, Mizuno M, Miura T.
  • Organizer: 4th Congress of Frontiers in Cardiovascular Biology
  • Place of Presentation: Florence, Italy
  • Year and Date: 2016-07-08
  • Int'l Joint Research / Invited
• [Presentation] Excessive ROS production in mitochondria switches off protective mitochondrial kinase signaling (2016)
  • Author(s): Owada W, Tanno M, Yano T, Miki T, Kuno A, Ishikawa S, Tatekoshi Y, Nishizawa K, Mizuno M, Miura T.
  • Organizer: 4th Congress of Frontiers in CardioVascular Biology, European Society of Cardiology
  • Place of Presentation: Florence, bItaly
  • Year and Date: 2016-07-08
  • Int'l Joint Research
• [Presentation] Increased activity of AMP deaminase by decreased interaction with PGM1 and depletion of F1,6P: a novel mechanism of diabetic cardiomyopathy (2016)
  • Author(s): Y. Tatekoshi, H. Kouzu, M. Tanno, A. Kuno, S. Ishikawa, T. Yano, T. Miki , M. Ogasawara, T. Tobisawa, K. Ono, S. Muratsubaki, K. Nishizawa, T. Miura
  • Organizer: 22nd Congress of International Society for Heart Research
  • Place of Presentation: Buenos Aires, Argentina
  • Year and Date: 2016-04-18
  • Int'l Joint Research
• [Presentation] Depletion of fructose 1,6-diphosphate but not post-translational modification plays a major role in activation of AMP deaminase in diabetic hearts: a novel mechanism for diabetic cardiomyopathy. (2016)
  • Author(s): Y. Tatekoshi, M. Tanno, A. Kuno, S. Ishikawa, T. Yano, T. Miki, M. Ogasawara, T. Tobisawa, K. Ohno, S. Muratsubaki, K. Nishizawa, T. Miura
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2016-03-18
• [Presentation] Intramolecular inhibition of Ser473 phosphorylation by up-regulated Thr308 phosphorylation in Akt cotributes to enlargement of infarct size by chronic renal failure. (2015)
  • Author(s): T. Tobisawa, T. Yano, T. Miki, M. Tanno, A. Kuno, H. Kouzu, M. Ogasawara, S. Muratsubaki, K. Ohno, K. Nishizawa, M. Mizuno, W. Owada, S. Ishikawa, T. Miura.
  • Organizer: 88th Scientific Session of American Heart Association:
  • Place of Presentation: Orlando, U.S.A.
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Continuous erythropoietin receptor activation reverses increased myocardial susceptibility to ischemia/reperfusion injury in chronic renal failure. (2015)
  • Author(s): K. Nishizawa, T. Yano, T. Miki, M. Tanno, A. Kuno, H. Kouzu, T. Tobisawa, M. Mizuno, H. Sugawara, T. Miura.
  • Organizer: 37th Congress of the European Society of Cardiology
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Mitochondrial translocation of GSK-3β, a trigger of mitochondrial permeability transition, is mediated by its N-terminal domain and promoted by interaction with VDAC2. (2014)
  • Author(s): Tanno M, Ishikawa S, Miki T, Kuno A, Kouzu H, Yano T, Miura T
  • Organizer: Frontiers in Cardiovascular Biology, 3rd meeting of the ESC council on basic cardiovascular science
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-07-04 – 2014-07-06