Protein kinases regulating the mitochondrial permeability transition pore

• Project/Area Number: 23591086
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Sapporo Medical University
• Principal Investigator: TETSUJI Miura 札幌医科大学, 医学部, 教授 (90199951)
• Co-Investigator(Kenkyū-buntansha): MIKI Takayuki 札幌医科大学, 医学部, 准教授 (00336405) ; TANNO Masaya 札幌医科大学, 医学部, 講師 (00398322)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: ミトコンドリア / 細胞死 / 細胞内情報伝達 / 活性酸素 / 透過性遷移孔

Research Abstract

The aim of this study was to characterize roles of protein kinases in regulation of mitochondrial permeability transition pore (mPTP) opening. We found that interaction of cyclophilin D (CypD) and inorganic phosphate carrier (PiC) determines the threshold for mPTP opening and that translocation of GSK-3beta via its interaction with VDAC2 and subsequent interaction with complex III promotes mPTP opening by enhanced production of reactive oxygen species. Inactivation of GSK-3beta by PI3K-Akt signaling or by activation of the mitochondrial KATP channel was found to increase threshold for mPTP opening and also to accelerate re-closure of opened mPTP, leading to protection from cell necrosis.

Research Products

• [Journal Article] HASF, a PKC-ε activator with novel features for cardiomyocyte protection. (2014)
  • Author(s): Miura T
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 69 Pages: 1-3
  • DOI: 10.1016/j.yjmcc.2014.01.011
  • Peer Reviewed
• [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] Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2. (2014)
  • Author(s): Sato T, Kobayashi T, Kuno A, Miki T, Tanno M, Kouzu H, Itoh T, Ishikawa S, Kojima T, Miura T, Tohse N.
  • Journal Title: American Journal of Physiology Heart and Circulatory Physiology Volume: 306 Issue: 7 Pages: H1054-H1065
  • DOI: 10.1152/ajpheart.00414.2013
  • Peer Reviewed
• [Journal Article] Diabetic cardiomyopathy: pathophysiology and clinical features. (2013)
  • Author(s): Miki T, Yuda S, Kouzu H, Miura T.
  • Journal Title: Heart Failure Review Volume: 18 Issue: 2 Pages: 149-166
  • DOI: 10.1007/s10741-012-9313-3
  • Peer Reviewed
• [Journal Article] Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 Protein-mediated modulation of p300 Protein. (2013)
  • Author(s): Kuno A et al.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 8 Pages: 5963-5972
  • DOI: 10.1074/jbc.m112.392050
  • Peer Reviewed
• [Journal Article] Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts (2012)
  • Author(s): Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Miura T
  • Journal Title: J Mol Cell Cardiol Volume: 53 Issue: 6 Pages: 870-9
  • DOI: 10.1016/j.yjmcc.2012.10.001
  • Peer Reviewed
• [Journal Article] Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes (2012)
  • Author(s): Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T, Tanno M, Yano T, Sato T, Ishikawa S, Miura T
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: e39893-e39893
  • DOI: 10.1371/journal.pone.0039893
  • Peer Reviewed
• [Journal Article] Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. (2012)
  • Author(s): Miki T, Itoh T, Sunaga D, Miura T.
  • Journal Title: Cardiovascular Diabetology Volume: 11 Issue: 1 Pages: 67-67
  • DOI: 10.1186/1475-2840-11-67
  • Peer Reviewed
• [Journal Article] Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop (2012)
  • Author(s): Bell R, Beeuwkes R, Bøtker HE, Davidson S, Downey J, Garcia-Dorado D, Hausenloy DJ, Heusch G, Ibanez B, Kitakaze M, Lecour S, Mentzer R, Miura T, Opie L, Ovize M, Ruiz-Meana M, Schulz R, Shannon R, Walker M, Vinten-Johansen J, Yellon D
  • Journal Title: Basic Res Cardiol Volume: 107 Pages: 300-300
  • Peer Reviewed
• [Journal Article] Emerging beneficial roles of sirtuins in heart failure. (2012)
  • Author(s): Tanno M et al.
  • Journal Title: Basic Res Cardiol. Volume: 107 Issue: 4 Pages: 273-273
  • DOI: 10.1007/s00395-012-0273-5
  • Peer Reviewed
• [Journal Article] Role of connexin-43 in protective PI3K-Akt-GSK-3βsignaling in cardiomyocytes (2012)
  • Author(s): Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 302 Issue: 12 Pages: H2536-H2544
  • DOI: 10.1152/ajpheart.00940.2011
  • Peer Reviewed
• [Journal Article] The mPTP and its regulatory proteins : final common targets of signalling pathways for protection against necrosis (2012)
  • Author(s): Miura T, Tanno M
  • Journal Title: Cardiovasc Res Volume: 94 Issue: 2 Pages: 181-9
  • DOI: 10.1093/cvr/cvr302
  • Peer Reviewed
• [Journal Article] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection (2011)
  • Author(s): Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K and Miura T
  • Journal Title: Hypertension Volume: 57 Issue: 1 Pages: 110-5
  • DOI: 10.1161/hypertensionaha.110.158469
  • Peer Reviewed
• [Journal Article] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection. (2011)
  • Author(s): Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K, Miura T.
  • Journal Title: Hypertension Volume: 57 Pages: 110-115
  • Peer Reviewed
• [Presentation] Acceleration of mPTP re-closure after oxidant stress by mitochondrial K_<ATP> channel activation is achieved by suppression of residual ROS production (2014)
  • Author(s): Ogasawara M, Kuno A, Ishikawa S, Tobisawa T, Kouzu H, Yano T, Miki T, Miura T
  • Organizer: The 78^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Yokohama, Japan
• [Presentation] Acceleration of mPTP Re-closure after Oxidant Stress by Mitochondrial KATP Channel Activation is Achieved by Suppression of Residual ROS Production (2014)
  • Author(s): Ogasawara M, Kuno A, Ishikawa S, Tobisawa T, Kouzu H, Yano T, Miki T, and Miura T.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Activation of the glucagon-like peptide-1 receptor restores myocardial autophagic flux and reduced mortality after myocardial infarction in diabetic rats (2013)
  • Author(s): Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Tobisawa T, Ogasawara M, Ishikawa S, Miura T
  • Organizer: Scientific Sessions 2013, the American Heart Association
  • Place of Presentation: Dallas, USA
• [Presentation] The role of mitochondria in organ protection (2013)
  • Author(s): Miura T
  • Organizer: 10^<th> Meeting of Asian Society of Cardiothoracic Anesthesiologists
  • Place of Presentation: Singapore
• [Presentation] Type 2 diabetes induces ventricular electrical remodeling with a transmural gradient (2013)
  • Author(s): Tobisawa T, Sato T, Yuda S, Miki T, Tanno M, Kuno A, Kobayashi T, Akasaka H, Tohse N, Miura T
  • Organizer: European Society of Cardiology Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Mechanisms underlying mitochondrial translocation of GSK-3beta, a crucial induces of mitochondrial permeability transition : GSK-3beta activity, interaction with VDAC2 and a mitochondrial targeting sequence (2013)
  • Author(s): Tanno M, Kuno A, Ishikawa S, Ogasawara M, Tobisawa T, Murase H, Sato T, Kouzu H, Miki T, Miura T
  • Organizer: American Heart Association BCVS
  • Place of Presentation: Las Vegas, USA
• [Presentation] Interaction of cyclophilin D with inorganic phosphate carrier during ischemia determines threshold for mPTP opening and reperfusion-induced cell necrosis (2013)
  • Author(s): Ito T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Ishikawa S, Miura T
  • Organizer: The 77^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Yokohama, Japan
• [Presentation] Interaction with VDAC2 promotes mitochondrial traslocation of GSK-3beta in a kinase activity-dependent manner and induces cell death (2013)
  • Author(s): Tanno M, Miki T, Kuno A, Kouzu H, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura
  • Organizer: The 77^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Yokohama, Japan
• [Presentation] Activation of the mitochondrial ATP-sensitive potassium channel achieves cell protection by promoting re-closure of the mPTP via suppression of GSK-3beta - complex III interaction (2013)
  • Author(s): Sunaga D, Tanno M, Miki T, Kuno A, Kouzu H, Sato T, Ishikawa S, Ogasawara M, Tobisawa T, and Miura T
  • Organizer: European Society of Cardiology Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Mechanisms Underlying Mitochondrial Translocation Of GSK-3β, A Crucial Inducer Of Mitochondrial Permeability Transition: GSK-3β Activity, Interaction With VDAC2 And A Mitochondrial Targeting Sequence. (2013)
  • Author(s): Tanno M, Kuno A, Ishikawa S, Ogasawara M, Tobisawa T, Murase H, Sato T, Kouzu H, Miki T, and Miura T
  • Organizer: American Heart Association BCVS 2013
  • Place of Presentation: Las Vegas, Nevada, USA
• [Presentation] Activation of the Glucagon-Like Peptide-1 Receptor Restores Myocardial Autophagic Flux and Reduces Mortality After Myocardial Infarction in Diabetic Rats (2013)
  • Author(s): Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Tobisawa T, Ogasawara M, Ishikawa S, and Miura T.
  • Organizer: American Heart Association Scientific Sessions 2013
  • Place of Presentation: Dallas, Texas, USA
• [Presentation] Interaction of cyclophilin D with inorganic phosphate carrier during ischemia determines threshold for mPTP opening and reperfusion-induced cell necrosis. (2013)
  • Author(s): Takahito Ito,Hidemichi Kouzu , Takayuki Miki , Masaya Tanno , Atsushi Kuno , Tatsuya Satoh , Daisuke Sunaga , Hiromichi Murase , Satoko Ishikawa , Tetsuji Miura
  • Organizer: The 77th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
• [Presentation] Interaction with VDAC2 promotes mitochondrial translocation of GSK-3beta in a kinase activity-dependent manner and induces cell death. (2013)
  • Author(s): Masaya Tanno,Takayuki Miki, Atsushi Kuno , Hidemichi Kouzu, Takahito Itoh , Tatsuya Satoh, Satoko Ishikawa, Daisuke Sunaga, Tetsuji Miura
  • Organizer: The 77th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 横浜
• [Presentation] Facilitated re-closure of the mitochondrial permeability transition pore underlies protection of cardiomyocytes from ROS-induced necrosis by activation of the mitochondrial ATP-sensitive K^+ channel (2012)
  • Author(s): Suanga D, Kuno A, Ishikawa S, Miki T, Tanno M, Kouzu H, Itoh T, Sato T, Murase H, Miura T
  • Organizer: Scientific Sessions 2012, the American Heart Association
  • Place of Presentation: Los Angeles, USA
• [Presentation] Titin-isoform shift may underlie distinct ventricular responses to pressure and volume overloads in type 2 diabetic heart (2012)
  • Author(s): Kouzu H, Kuno A, Miki T, Tanno M, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • Organizer: Scientific Sessions 2012, the American Heart Association
  • Place of Presentation: Los Angeles, USA
• [Presentation] Mitochondria and cardioprotection (2012)
  • Author(s): Miura T
  • Organizer: The 64^<th> Annual Meeting of Korean Physiological Society
  • Place of Presentation: Busan, Korea
• [Presentation] Mitochondria and cardioprotection (2012)
  • Author(s): Tetsuji Miura
  • Organizer: The 64th Annual Meeting of Korean Physiological Society
  • Place of Presentation: Busan, Korea
  • Invited
• [Presentation] Facilitated Re-Closure of the Mitochondrial Permeability Transition Pore Underlies Protection of Cardiomyocytes from ROS-Induced Necrosis by Activation of the Mitochondrial ATP-Sensitive K+ Channel (2012)
  • Author(s): Daisuke Sunaga, Atsushi Kuno, Satoko Ishikawa, Takayuki Miki, Masaya Tannno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Hiromichi Murase, and Tetsuji Miura
  • Organizer: Scientific Sessions 2012, the American Heart Assocaition
  • Place of Presentation: Los Angeles, CA, USA
• [Presentation] Titin-isoform Shift May Underlie Distinct Ventricular Responses to Pressure and Volume Overloads in Type 2 Diabetic Heart (2012)
  • Author(s): Hidemichi Kouzu, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, and Tetsuji Miura
  • Organizer: Scientific Sessions 2012, the American Heart Assocaition
  • Place of Presentation: Los Angeles, CA, USA
• [Presentation] UPR in endoplasmic reticulum vs. in mitochondria in diabetic myocardium : which is responsible for deficient regulation of mitochondrial permeability transition pores? (2011)
  • Author(s): Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Ishikawa S, Miura
  • Organizer: Scientific Sessions 2011, the American Heart Association
  • Place of Presentation: Orlando, USA
• [Presentation] GSK-3beta translocation to mitochodnria by oxidant stress in a kinase activity-dependent manner and contributes to lethal ROS production (2011)
  • Author(s): Tanno M, Kuno A, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura T
  • Organizer: Scientific Sessions 2011, the American Heart Association
  • Place of Presentation: Orlando, USA
• [Presentation] UPR In Endoplasmic Reticulum vs. UPR In Mitochondria In Diabetic Myocardium: Which Is Responsible For Deficient Regulation Of Mitochondrial Permeability Transition Pores? (2011)
  • Author(s): Itoh T, Kouzu H, Miki T, Tanno T, Kuno A, Sato T, Sunaga D, Ishikawa S, Miura T
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orlando, USA
• [Presentation] GSK-3β Translocates to Mitochondria by Oxidant Stress in a Kinase Activity-Dependent Manner and Contributes to Lethal ROS Production (2011)
  • Author(s): Tanno M, Kuno A, Kouzu H, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura T.
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orlando, USA