Protein kinases regulating the mitochondrial permeability transition pore

2013 Fiscal Year Final Research Report

• 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
• Keywords: ミトコンドリア / 細胞死 / 細胞内情報伝達 / 活性酸素

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-εactivator with novel features for cardiomyocyte protection (2014)
  • Author(s): Miura T
  • Journal Title: J Mol Cell Cardiol 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: Circ Res Volume: 114(8) Pages: 1268-80
  • 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: Am J Physiol Heart Circ Physiol Volume: 306 Pages: H1054-65
  • 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 Fail Rev Volume: 18 Pages: 149-66
  • 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, Hori YS, Hosoda R, Tanno M, Miura T, Shimamoto K, Horio Y
  • Journal Title: J Biol Chem Volume: 288 Pages: 5963-72
  • 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 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 Pages: 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: Cardiovasc Diabetol Volume: 11 Pages: 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
  • DOI: 10.1007%2Fs00395-012-0300-6/fulltext.html
  • Peer Reviewed
• [Journal Article] Emerging beneficial roles of sirtuins in heart failure (2012)
  • Author(s): Tanno M, Kuno A, Horio Y, Miura T
  • Journal Title: Basic Res Cardiol Volume: 107 Pages: 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 Pages: H2536-44
  • 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 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, Miura T
  • Journal Title: Hypertension Volume: 57 Pages: 110-115
  • DOI: 10.1161/HYPERTENSIONAHA.110.158469
  • 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
  • Year and Date: 20140315-17
• [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
  • Year and Date: 20131116-20
• [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
  • Year and Date: 20131003-05
• [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
  • Year and Date: 20130808-0904
• [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
  • Year and Date: 20130722-25
• [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
  • Year and Date: 20130315-17
• [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
  • Year and Date: 20130315-17
• [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
  • Year and Date: 20121103-07
• [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
  • Year and Date: 20121103-07
• [Presentation] Mitochondria and cardioprotection (2012)
  • Author(s): Miura T
  • Organizer: The 64^<th> Annual Meeting of Korean Physiological Society
  • Place of Presentation: Busan, Korea
  • Year and Date: 20121024-26
• [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
  • Year and Date: 20111112-16
• [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
  • Year and Date: 20111112-16