ミトコンドリア透過性遷移孔を制御する蛋白キナーゼ系の解析

• 研究課題/領域番号: 23591086
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 循環器内科学
• 研究機関: 札幌医科大学
• 研究代表者: 三浦 哲嗣 札幌医科大学, 医学部, 教授 (90199951)
• 研究分担者: 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)
• 研究期間 (年度): 2011 – 2013
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 5,330千円 (直接経費: 4,100千円、間接経費: 1,230千円); 2013年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2012年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2011年度: 2,990千円 (直接経費: 2,300千円、間接経費: 690千円)
• キーワード: 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

研究概要

ミトコンドリア透過性遷移孔(mPTP)の構成蛋白とキナーゼの関連を解析し、１）PTP開口閾値がシクロフィリンD(CypD)と無機リン輸送担体(PiC)の結合に規定され、２）細胞質から水ミトコンドリアに移行したGSK-3beta は呼吸鎖複合体IIIと結合し活性酸素産生の亢進によりmPTPを開口させること、３）細胞内シグナルによるGSK-3beta不活化がCypD-PiC相互作用を抑制し、mPTP開口の抑制ばかりでなくmPTP再閉鎖を促進すること、４）GSK-3beta のミトコンドリアへ移行にはVDAC2との結合が重要であることを明らかにした。

研究成果

• [雑誌論文] HASF, a PKC-ε activator with novel features for cardiomyocyte protection. (2014)
  • 著者名/発表者名: Miura T
  • 雑誌名: Journal of Molecular and Cellular Cardiology 巻: 69 ページ: 1-3
  • DOI: 10.1016/j.yjmcc.2014.01.011
  • 査読あり
• [雑誌論文] Pivotal Role of mTORC2 and Involvement of Ribosomal Protein S6 in Cardioprotective Signaling. (2014)
  • 著者名/発表者名: Yano T, Ferlito M, Aponte A, Kuno A, Miura T, Murphy E, Steenbergen C.
  • 雑誌名: Circulation Research 巻: 114 号: 8 ページ: 1268-1280
  • DOI: 10.1161/circresaha.114.303562
  • 査読あり
• [雑誌論文] Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2. (2014)
  • 著者名/発表者名: Sato T, Kobayashi T, Kuno A, Miki T, Tanno M, Kouzu H, Itoh T, Ishikawa S, Kojima T, Miura T, Tohse N.
  • 雑誌名: American Journal of Physiology Heart and Circulatory Physiology 巻: 306 号: 7 ページ: H1054-H1065
  • DOI: 10.1152/ajpheart.00414.2013
  • 査読あり
• [雑誌論文] Diabetic cardiomyopathy: pathophysiology and clinical features. (2013)
  • 著者名/発表者名: Miki T, Yuda S, Kouzu H, Miura T.
  • 雑誌名: Heart Failure Review 巻: 18 号: 2 ページ: 149-166
  • DOI: 10.1007/s10741-012-9313-3
  • 査読あり
• [雑誌論文] Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 Protein-mediated modulation of p300 Protein. (2013)
  • 著者名/発表者名: Kuno A et al.
  • 雑誌名: J. Biol. Chem. 巻: 288 号: 8 ページ: 5963-5972
  • DOI: 10.1074/jbc.m112.392050
  • 査読あり
• [雑誌論文] Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts (2012)
  • 著者名/発表者名: Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Miura T
  • 雑誌名: J Mol Cell Cardiol 巻: 53 号: 6 ページ: 870-9
  • DOI: 10.1016/j.yjmcc.2012.10.001
  • 査読あり
• [雑誌論文] Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes (2012)
  • 著者名/発表者名: Takada A, Miki T, Kuno A, Kouzu H, Sunaga D, Itoh T, Tanno M, Yano T, Sato T, Ishikawa S, Miura T
  • 雑誌名: PLoS One 巻: 7 号: 6 ページ: e39893-e39893
  • DOI: 10.1371/journal.pone.0039893
  • 査読あり
• [雑誌論文] Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. (2012)
  • 著者名/発表者名: Miki T, Itoh T, Sunaga D, Miura T.
  • 雑誌名: Cardiovascular Diabetology 巻: 11 号: 1 ページ: 67-67
  • DOI: 10.1186/1475-2840-11-67
  • 査読あり
• [雑誌論文] Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop (2012)
  • 著者名/発表者名: 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
  • 雑誌名: Basic Res Cardiol 巻: 107 ページ: 300-300
  • 査読あり
• [雑誌論文] Emerging beneficial roles of sirtuins in heart failure. (2012)
  • 著者名/発表者名: Tanno M et al.
  • 雑誌名: Basic Res Cardiol. 巻: 107 号: 4 ページ: 273-273
  • DOI: 10.1007/s00395-012-0273-5
  • 査読あり
• [雑誌論文] Role of connexin-43 in protective PI3K-Akt-GSK-3βsignaling in cardiomyocytes (2012)
  • 著者名/発表者名: Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • 雑誌名: Am J Physiol Heart Circ Physiol 巻: 302 号: 12 ページ: H2536-H2544
  • DOI: 10.1152/ajpheart.00940.2011
  • 査読あり
• [雑誌論文] The mPTP and its regulatory proteins : final common targets of signalling pathways for protection against necrosis (2012)
  • 著者名/発表者名: Miura T, Tanno M
  • 雑誌名: Cardiovasc Res 巻: 94 号: 2 ページ: 181-9
  • DOI: 10.1093/cvr/cvr302
  • 査読あり
• [雑誌論文] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection (2011)
  • 著者名/発表者名: Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K and Miura T
  • 雑誌名: Hypertension 巻: 57 号: 1 ページ: 110-5
  • DOI: 10.1161/hypertensionaha.110.158469
  • 査読あり
• [雑誌論文] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection. (2011)
  • 著者名/発表者名: Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K, Miura T.
  • 雑誌名: Hypertension 巻: 57 ページ: 110-115
  • 査読あり
• [学会発表] Acceleration of mPTP re-closure after oxidant stress by mitochondrial K_<ATP> channel activation is achieved by suppression of residual ROS production (2014)
  • 著者名/発表者名: Ogasawara M, Kuno A, Ishikawa S, Tobisawa T, Kouzu H, Yano T, Miki T, Miura T
  • 学会等名: The 78^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Yokohama, Japan
• [学会発表] Acceleration of mPTP Re-closure after Oxidant Stress by Mitochondrial KATP Channel Activation is Achieved by Suppression of Residual ROS Production (2014)
  • 著者名/発表者名: Ogasawara M, Kuno A, Ishikawa S, Tobisawa T, Kouzu H, Yano T, Miki T, and Miura T.
  • 学会等名: 第78回日本循環器学会学術集会
  • 発表場所: 東京
• [学会発表] Activation of the glucagon-like peptide-1 receptor restores myocardial autophagic flux and reduced mortality after myocardial infarction in diabetic rats (2013)
  • 著者名/発表者名: Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Tobisawa T, Ogasawara M, Ishikawa S, Miura T
  • 学会等名: Scientific Sessions 2013, the American Heart Association
  • 発表場所: Dallas, USA
• [学会発表] The role of mitochondria in organ protection (2013)
  • 著者名/発表者名: Miura T
  • 学会等名: 10^<th> Meeting of Asian Society of Cardiothoracic Anesthesiologists
  • 発表場所: Singapore
• [学会発表] Type 2 diabetes induces ventricular electrical remodeling with a transmural gradient (2013)
  • 著者名/発表者名: Tobisawa T, Sato T, Yuda S, Miki T, Tanno M, Kuno A, Kobayashi T, Akasaka H, Tohse N, Miura T
  • 学会等名: European Society of Cardiology Congress 2013
  • 発表場所: Amsterdam, Netherlands
• [学会発表] 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)
  • 著者名/発表者名: Tanno M, Kuno A, Ishikawa S, Ogasawara M, Tobisawa T, Murase H, Sato T, Kouzu H, Miki T, Miura T
  • 学会等名: American Heart Association BCVS
  • 発表場所: Las Vegas, USA
• [学会発表] Interaction of cyclophilin D with inorganic phosphate carrier during ischemia determines threshold for mPTP opening and reperfusion-induced cell necrosis (2013)
  • 著者名/発表者名: Ito T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Murase H, Ishikawa S, Miura T
  • 学会等名: The 77^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Yokohama, Japan
• [学会発表] Interaction with VDAC2 promotes mitochondrial traslocation of GSK-3beta in a kinase activity-dependent manner and induces cell death (2013)
  • 著者名/発表者名: Tanno M, Miki T, Kuno A, Kouzu H, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura
  • 学会等名: The 77^<th> Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: Yokohama, Japan
• [学会発表] 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)
  • 著者名/発表者名: Sunaga D, Tanno M, Miki T, Kuno A, Kouzu H, Sato T, Ishikawa S, Ogasawara M, Tobisawa T, and Miura T
  • 学会等名: European Society of Cardiology Congress 2013
  • 発表場所: Amsterdam, Netherlands
• [学会発表] 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)
  • 著者名/発表者名: Tanno M, Kuno A, Ishikawa S, Ogasawara M, Tobisawa T, Murase H, Sato T, Kouzu H, Miki T, and Miura T
  • 学会等名: American Heart Association BCVS 2013
  • 発表場所: Las Vegas, Nevada, USA
• [学会発表] Activation of the Glucagon-Like Peptide-1 Receptor Restores Myocardial Autophagic Flux and Reduces Mortality After Myocardial Infarction in Diabetic Rats (2013)
  • 著者名/発表者名: Murase H, Kuno A, Miki T, Tanno M, Yano T, Kouzu H, Tobisawa T, Ogasawara M, Ishikawa S, and Miura T.
  • 学会等名: American Heart Association Scientific Sessions 2013
  • 発表場所: Dallas, Texas, USA
• [学会発表] Interaction of cyclophilin D with inorganic phosphate carrier during ischemia determines threshold for mPTP opening and reperfusion-induced cell necrosis. (2013)
  • 著者名/発表者名: Takahito Ito,Hidemichi Kouzu , Takayuki Miki , Masaya Tanno , Atsushi Kuno , Tatsuya Satoh , Daisuke Sunaga , Hiromichi Murase , Satoko Ishikawa , Tetsuji Miura
  • 学会等名: The 77th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: 横浜
• [学会発表] Interaction with VDAC2 promotes mitochondrial translocation of GSK-3beta in a kinase activity-dependent manner and induces cell death. (2013)
  • 著者名/発表者名: Masaya Tanno,Takayuki Miki, Atsushi Kuno , Hidemichi Kouzu, Takahito Itoh , Tatsuya Satoh, Satoko Ishikawa, Daisuke Sunaga, Tetsuji Miura
  • 学会等名: The 77th Annual Scientific Meeting of the Japanese Circulation Society
  • 発表場所: 横浜
• [学会発表] 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)
  • 著者名/発表者名: Suanga D, Kuno A, Ishikawa S, Miki T, Tanno M, Kouzu H, Itoh T, Sato T, Murase H, Miura T
  • 学会等名: Scientific Sessions 2012, the American Heart Association
  • 発表場所: Los Angeles, USA
• [学会発表] Titin-isoform shift may underlie distinct ventricular responses to pressure and volume overloads in type 2 diabetic heart (2012)
  • 著者名/発表者名: Kouzu H, Kuno A, Miki T, Tanno M, Itoh T, Sato T, Sunaga D, Murase H, Miura T
  • 学会等名: Scientific Sessions 2012, the American Heart Association
  • 発表場所: Los Angeles, USA
• [学会発表] Mitochondria and cardioprotection (2012)
  • 著者名/発表者名: Miura T
  • 学会等名: The 64^<th> Annual Meeting of Korean Physiological Society
  • 発表場所: Busan, Korea
• [学会発表] Mitochondria and cardioprotection (2012)
  • 著者名/発表者名: Tetsuji Miura
  • 学会等名: The 64th Annual Meeting of Korean Physiological Society
  • 発表場所: Busan, Korea
  • 招待講演
• [学会発表] 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)
  • 著者名/発表者名: Daisuke Sunaga, Atsushi Kuno, Satoko Ishikawa, Takayuki Miki, Masaya Tannno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Hiromichi Murase, and Tetsuji Miura
  • 学会等名: Scientific Sessions 2012, the American Heart Assocaition
  • 発表場所: Los Angeles, CA, USA
• [学会発表] Titin-isoform Shift May Underlie Distinct Ventricular Responses to Pressure and Volume Overloads in Type 2 Diabetic Heart (2012)
  • 著者名/発表者名: Hidemichi Kouzu, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, and Tetsuji Miura
  • 学会等名: Scientific Sessions 2012, the American Heart Assocaition
  • 発表場所: Los Angeles, CA, USA
• [学会発表] UPR in endoplasmic reticulum vs. in mitochondria in diabetic myocardium : which is responsible for deficient regulation of mitochondrial permeability transition pores? (2011)
  • 著者名/発表者名: Itoh T, Kouzu H, Miki T, Tanno M, Kuno A, Sato T, Sunaga D, Ishikawa S, Miura
  • 学会等名: Scientific Sessions 2011, the American Heart Association
  • 発表場所: Orlando, USA
• [学会発表] GSK-3beta translocation to mitochodnria by oxidant stress in a kinase activity-dependent manner and contributes to lethal ROS production (2011)
  • 著者名/発表者名: Tanno M, Kuno A, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura T
  • 学会等名: Scientific Sessions 2011, the American Heart Association
  • 発表場所: Orlando, USA
• [学会発表] UPR In Endoplasmic Reticulum vs. UPR In Mitochondria In Diabetic Myocardium: Which Is Responsible For Deficient Regulation Of Mitochondrial Permeability Transition Pores? (2011)
  • 著者名/発表者名: Itoh T, Kouzu H, Miki T, Tanno T, Kuno A, Sato T, Sunaga D, Ishikawa S, Miura T
  • 学会等名: American Heart Association Scientific Sessions 2011
  • 発表場所: Orlando, USA
• [学会発表] GSK-3β Translocates to Mitochondria by Oxidant Stress in a Kinase Activity-Dependent Manner and Contributes to Lethal ROS Production (2011)
  • 著者名/発表者名: Tanno M, Kuno A, Kouzu H, Itoh T, Sato T, Ishikawa S, Sunaga D, Miura T.
  • 学会等名: American Heart Association Scientific Sessions 2011
  • 発表場所: Orlando, USA