Role of mitochondrial permeability transition in necroptosis of the cardiomyocyte

• Project/Area Number: 26461133
• 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: Miura Tetsuji 札幌医科大学, 医学部, 教授 (90199951)
• Co-Investigator(Kenkyū-buntansha): 三木 隆幸 札幌医科大学, 医学部, 准教授 (00336405) ; 丹野 雅也 札幌医科大学, 医学部, 講師 (00398322)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: mitochondria / cell death / necroptosis / autophagy / signal transduction / ネクロプトーシス / オートファジー / 細胞内情報伝達 / ミトコンドリア

Outline of Final Research Achievements

This study showed that, in contrast to its role in necrosis, mitochondrial permeability transition (MPT) does not directly trigger cell death in necroptosis of cardiomyocytes and that necroptotic signals significantly inhibit autophagy, which is potentially modulated by MPT, leading to exaggeration of necroptotic cardiomyocyte death. Sequestration of p62 from p62-LC3-II interaction by increased p62-RIP1 interaction and inhibition of fusion of autophagosomes with lysosomes were proposed to be mechanisms by which necroptotic signals inhibits autophagy.

Research Products

• [Journal Article] Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55alpha contributes to enlargement of infarct size by chronic kidney disease. (2017)
  • Author(s): Toshiyuki Tobisawa*, Toshiyuki Yano*, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida, Tetsuji Miura
  • Journal Title: Basic Research in Cardiology Volume: 112 Issue: 3 Pages: 31-31
  • DOI: 10.1007/s00395-017-0621-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size. (2016)
  • Author(s): Nishizawa K, Yano T, Tanno M, Miki T, Kuno A, Tobisawa T, Ogasawara M, Muratsubaki S, Ohno K, Ishikawa S, Miura T.
  • Journal Title: Hypertension Volume: 68 Issue: 3 Pages: 697-706
  • DOI: 10.1161/hypertensionaha.116.07480
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research". (2016)
  • Author(s): Cabrera-Fuentes HA, Aragones J, Bernhagen J, Miura T, et al.
  • Journal Title: Basic Research in Cardiology Volume: 111 Issue: 6 Pages: 69-69
  • DOI: 10.1007/s00395-016-0586-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. (2016)
  • Author(s): Hausenloy DJ, Barrabes JA, Davidson SM, Di Lisa F, Downey J, Miura T, et al.
  • Journal Title: Basic Research in Cardiology Volume: 111 Issue: 6 Pages: 70-70
  • DOI: 10.1007/s00395-016-0588-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy. (2016)
  • Author(s): Yano T, Shimoshige S, Miki T, Tanno M, Mochizuki A, Fujito T, Yuda S, Muranaka A, Ogasawara M, Hashimoto A, Tsuchihashi K, Miura T
  • Journal Title: J Mol Cell Cardiol Volume: 91 Pages: 6-9
  • DOI: 10.1016/j.yjmcc.2015.12.022
  • Peer Reviewed
• [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] Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats. (2015)
  • Author(s): Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Ishikawa S, Tobisawa T, Ogasawara M, Nishizawa K, Miura T.
  • Journal Title: Cardiovasc Diabetol Volume: 14 Issue: 1 Pages: 103-118
  • DOI: 10.1186/s12933-015-0264-6
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal Role of mTORC2 and Involvement of Ribosomal Protein S6 in Cardioprotective Signaling. (2014)
  • Author(s): Yano T, Ferlito M, Aponte A, Kuno A, Miura T, Murphy E, Steenbergen C.
  • Journal Title: Circulation Research Volume: 114 Issue: 8 Pages: 1268-1280
  • DOI: 10.1161/circresaha.114.303562
  • Peer Reviewed
• [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
• [Journal Article] Accelerated recovery of mitochondrial membrane potential by GSK-3β inactivation affords cardiomyocytes protection from oxidant-induced necrosis. (2014)
  • Author(s): Sunaga D, Tanno M, Kuno A, Ishikawa S, Ogasawara M, Yano T, Miki T, Miura T
  • Journal Title: PLoS One Volume: 12 Issue: 11 Pages: e112529-e112529
  • DOI: 10.1371/journal.pone.0112529
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Sequestration of p62 by RIP1 promotes necroptosis through suppression of autophagic flux in cardiomyocytes; a novel cross-talk between autophagy and necroptosis (2016)
  • Author(s): Yano T, Ogasawara M, Miki T, Tanno M, Kuno A, Ohno K, Nishizawa K, Owada W, Mizuno M, Suwawara H, Tatekoshi Y, Nakata K, Ishikawa S, Miura T
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Diabetes and Cardioprotection. (2016)
  • Author(s): Miura T
  • Organizer: Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery,
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-05-12
  • Int'l Joint Research / Invited
• [Presentation] Role of mitochondria in cell death. The mPTP and its regulatory kinases in cardioprotection. (2016)
  • Author(s): Miura T
  • Organizer: 2016 XXII ISHR World Congress
  • Place of Presentation: Buenos Aires, Argentina
  • Year and Date: 2016-04-18
  • Int'l Joint Research / Invited
• [Presentation] Suppression of Autophagic Flux by Sequestration of p62 Promotes RIP1-mediated Necroptosis in Cardiomyocytes (2015)
  • Author(s): Makoto Ogasawara; Toshiyuki Yano; Takayuki Miki; Masaya Tanno; Atsushi Kuno; Hidemichi Kouzu; Toshiyuki Tobisawa; Shingo Muratsubaki; Kohei Ohno; Keitaro Nishizawa; Satoko Ishikawa; Tetsuji Miura
  • Organizer: Scientific Sessions of the American Heart Association 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Role of mitochondrial GSK-3beta in myocardial ischemia/reperfusion injury (2014)
  • Author(s): Miura T
  • Organizer: ESC 2nd International Symposium on “Frontiers in Cardio-vascular Research
  • Place of Presentation: Huatulco-Oaxaca, Mexico
  • Year and Date: 2014-11-23 – 2014-11-25
  • Invited
• [Presentation] Accumulation of p62 by dysregulation of autophagy induces RIP1-dependent necroptosis in cardiomyocytes: a novel interplay between autophagy and necroptosis. (2014)
  • Author(s): Ogasawara M, Yano T, Miki T, Tanno M, Kuno A, Kouzu H, Murase H, Tobisawa T, Muratsubaki S, Nishizawa K, Mizuno M, Ishikawa S, Miura T.
  • Organizer: American Heart Association, Scientific Sessions 2014
  • Place of Presentation: Chicago, Illinois, USA
  • Year and Date: 2014-11-15 – 2014-11-19