Regulatory mechanism of mitochondrial iron contents by mitoMEET in cardiac remodeling

• Project/Area Number: 15H04815
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyushu University (2016-2017); Hokkaido University (2015)
• Principal Investigator: TSUTSUI HIROYUKI 九州大学, 医学研究院, 教授 (70264017)
• Co-Investigator(Kenkyū-buntansha): 絹川 真太郎 北海道大学, 医学研究院, 講師 (60399871) ; 松島 将士 九州大学, 大学病院, 助教 (80552869) ; 井手 友美 九州大学, 医学研究院, 准教授 (90380625)
• Research Collaborator: FURIHATA Takaaki ; IKEDA Masataka
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 心不全 / 心筋リモデリング / ミトコンドリア / 鉄代謝 / 循環器・高血圧 / ミトコンドリア品質管理

Outline of Final Research Achievements

We generated mitoNEET knockout mice and investigated regulatory mechanisms of mitochondrial iron by mitoNEET. Mitochondrial iron contents and ferritin levels in the heart were increased in mitoNEET-KO mice compared with wild-type mice.
We detected adenine nucleotide translocator (ANT) as a novel protein binding to mitoNEET. Administration of cyclosproin A, an inhibitor of mitochondrial permeability transition pore opening, decreased mitochondrial iron contents, indicating that mitoNEET and ANT coordinately regulate mitochondrial iron contents.

Research Products

• [Journal Article] Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation. (2018)
  • Author(s): 3.Tohyama T, Saku K, Kawada T, Kishi T, Yoshida K, Nishikawa T, Mannoji H, Kamada K, Sunagawa K and Tsutsui H
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: e0190830-e0190830
  • DOI: 10.1371/journal.pone.0190830
  • Peer Reviewed
• [Journal Article] Inhibition of Nitric Oxide Synthase Unmasks Vigorous Vasoconstriction in Established Pulmonary Arterial Hypertension. (2017)
  • Author(s): Tanaka M, Abe K, Oka M, Saku K, Yoshida K, Ishikawa T, McMurtry IF, Sunagawa K, Hoka S, Tsutsui H.
  • Journal Title: Physiol Rep Volume: 5 Issue: 23 Pages: 275-276
  • DOI: 10.14814/phy2.13537
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Influence of myopotential interference on the Wavelet discrimination algorithm in implantable cardioverter-defibrillator. (2017)
  • Author(s): Mizukami K, Yokoshiki H, Mitsuyama H, Watanabe M, Tenma T, Kamada R, Takahashi M, Sasaki R, Maeno M, Tsutsui H
  • Journal Title: J Arrhythm Volume: 33 Issue: 3 Pages: 214-219
  • DOI: 10.1016/j.joa.2016.08.005
  • NAID: 120006352209
  • Peer Reviewed
• [Journal Article] Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome (2017)
  • Author(s): Yokota T, Kinugawa S, Hirabayashi K, Suga T, Takada S, Omokawa M, Kadoguchi T, Takahashi M, Fukushima A, Matsushima S, Yamato M, Okita K, Tsutsui H
  • Journal Title: J Diabetes Investig Volume: 印刷中 Issue: 4 Pages: 1-6
  • DOI: 10.1111/jdi.12606
  • NAID: 120006337767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure. (2017)
  • Author(s): Fujii K, Saku K, Kishi T, Oga Y, Tohyama T, Nishikawa T, Sakamoto T, Ikeda M, Ide T, Tsutsui H, Sunagawa K.
  • Journal Title: Am J Hypertens. Volume: 未定 Issue: 8 Pages: 791-798
  • DOI: 10.1093/ajh/hpx062
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes. (2016)
  • Author(s): Mizushima, W., Takahashi , H., Watanabe, M., Kinugawa, S., Matsushima, S., Takada, S., Yokota, T., Furihata, T., Matsumoto, J., Tsuda, M., Chiba, I., Nagashima, S., Yanagi, S., Matsumoto, M., Nakayama, K.I., Tsutsui, H. and Hatakeyama, S.
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 100 Pages: 43-53
  • DOI: 10.1016/j.yjmcc.2016.09.013
  • NAID: 120006360069
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. (2016)
  • Author(s): Matsushima S, Kuroda J, Zhai P, Liu T, Ikeda S, Nagarajan N, Oka S, Yokota T, Kinugawa S, Hsu C, Li H , Tsutsui H, Sadoshima J.
  • Journal Title: Journal of Clinical Investigation Volume: 126 Issue: 9 Pages: 3403-3416
  • DOI: 10.1172/jci85624
  • NAID: 120006809287
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 心筋リモデリング・心不全におけるNKT細胞による炎症制御とそれに基づく新規治療法の開発 (2016)
  • Author(s): 筒井裕之
  • Journal Title: 福岡医学雑誌 Volume: 107 Pages: 177-184
  • NAID: 120005972903
  • Peer Reviewed
• [Journal Article] 期待される新たな心不全治療薬 (2016)
  • Author(s): 筒井裕之
  • Journal Title: Medical Science Digest Volume: 42 Pages: 206-207
• [Journal Article] Angiotensin II can directly induce mitochondrial dysfunction oxdative fiber number and induce atrophy in mouse hindlimb skeletal muscle (2015)
  • Author(s): Kadoguchi T, Kinugawa S, Takada S, Fukushima A, Furihata T, Homma T, Masaki Y, Mizushima W, Nishikawa M, Takahashi M, Yokota T, Matsushima S, Okia K, Tsutsui H
  • Journal Title: Exp Physiol Volume: 100(3) Pages: 312-322
• [Journal Article] Serum brain-derived neurotrophic factor level predicts adverse clinical outcomes in patients with heart failure. (2015)
  • Author(s): Fukushima A, Kinugawa S, Homma T, Masaki Y, Furihata T, Yokota T, Matsushima S, Takada S, Kadoguchi T, Oba K, Okita K, Tsutsui H
  • Journal Title: J Card Fail Volume: 21(4) Pages: 300-306
• [Journal Article] Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats. (2015)
  • Author(s): Mizukami K, Yokoshiki H, Mitsuyama H, Watanabe M, Tenma T, Takada S, Tsutsui H
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 309(6) Pages: 1066-74
• [Journal Article] Sesamin prevents decline in exercise capacity and impairment of skeletal muscle mitochondrial function in mice with high-fat diet-induced diabetes. (2015)
  • Author(s): Takada S, Kinugawa S, Matsushima S, Takemoto D, Furihata T, Mizushima W, Fukushima A, Yokota T, Ono Y, Shibata H, Okita K, Tsutsui H
  • Journal Title: Exp Physiol Volume: 100(11) Pages: 1319-30
• [Presentation] Fyn Regulates Subcellular Redox Signaling in Cardiac Remodeling (2018)
  • Author(s): 2.Matsushima S, Soichiro Ikeda, Kosuke Okabe, Akihito Ishikita, Junichi Sadoshima, Tsutsui H
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] ナチュラルキラー T 細胞活性化による新たな重症心不全治療の実用化 (2018)
  • Author(s): 筒井裕之
  • Organizer: 第82回日本循環器学会学術集会
  • Invited
• [Presentation] CaMK II-NF-kB pathway mediates doxorubicin-induced cardiomyopathy (2017)
  • Author(s): Ikeda S, Matsushima S, Ikeda M, Okabe K, Ishikita A, tadokoro T, Ide T, Tsutsui H:
  • Organizer: Cardiovascular metablic week 2017
• [Presentation] DPP-4-Nox4-HDAC4 axis mediates Angll-induced cardiac hypertrophy (2017)
  • Author(s): Okabe K, Matsushima S, Ikeda M, Ikeda S, Ishikita A, Tadokoro T, Ide T, Tsutsui H
  • Organizer: Cardiovascular metablic week 2017
• [Presentation] 心不全診療の最新動向 (2017)
  • Author(s): 筒井裕之
  • Organizer: 第4回iHFフォーラム
  • Invited
• [Presentation] mitoNEET regulates mitochondrial iron contents in the heart (2016)
  • Author(s): Maekawa S, Furihata T, Takada S, Fukushima A, Tsuda M, Matsumoto J, Yokota T, Kinugawa S
  • Organizer: The 33rd Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 東京コンベンションホール
  • Year and Date: 2016-12-17
• [Presentation] Desruption of mitoNEET, outer mitochondrial membrane protein, increases mitochondrial iron content in the heart (2015)
  • Author(s): Furihata T, Kinugawa S, Takada S, Matsushima S, Mizushima W, Yokota T, Tsutsui H
  • Organizer: The 32nd Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-11
• [Presentation] Disruption of mitoNEET protein increases mitochondrial iron content in the heart (2015)
  • Author(s): 降旗高明，絹川真太郎，松島将士，高田真吾，福島 新，水島 航，門口智泰，正木芳弘，横田 卓，筒井裕之
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府大阪市)
  • Year and Date: 2015-04-24
• [Book] 今日の治療指針 (2017)
  • Author(s): 筒井裕之
  • Total Pages: 4
  • Publisher: 医学書院
• [Book] 循環器疾患最新の治療 (2016)
  • Author(s): 筒井裕之
  • Total Pages: 17
  • Publisher: 南江堂
• [Book] 循環器研修ノート (2016)
  • Author(s): 筒井裕之
  • Total Pages: 10
  • Publisher: 診断と治療社
• [Book] 座談会 わが国発の心不全における利尿薬基礎研究 (2015)
  • Author(s): 筒井裕之，岩永善高，石光俊彦，斎藤能彦
  • Total Pages: 14
  • Publisher: メディカルレビュー社
• [Book] 心筋炎症/酸化ストレス制御による心不全治療 (2015)
  • Author(s): 松島将士，筒井裕之
  • Total Pages: 125
  • Publisher: 科学評論社