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Adaptation to Environmental stress and quality control of myocardial mitochondria by reactive sulfur species

Research Project

Project/Area Number 17K15464
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Pharmacology in pharmacy
Research InstitutionKyushu University (2018)
National Institute for Physiological Sciences (2017)

Principal Investigator

Nishimura Akiyuki  九州大学, 薬学研究院, 講師 (00457152)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsレドックス / 心臓リモデリング / ミトコンドリア品質 / 活性イオウ / 親電子物質 / 心臓 / ストレス適応 / 環境化学物質 / ミトコンドリア / 心疾患 / 環境ストレス
Outline of Final Research Achievements

We found that abnormal quality control (hyperfission) of cardiac mitochondria triggered the disruption of cardiac homeostasis. We identified that filamin A act as a guanine nucleotide exchange factor for Drp1, mitochondrial fission-accelerating factor. Pathological interaction of Drp1-filamin-actin at mitochondrial fission induced mitochondrial hyperfission-associated myocardial senescence, resulting in cardiac dysfunctions. Reactive sulfur-dependent polysulfidation of Drp1 negatively regulated the interaction with filamin A, and environmental electrophiles such as a methylmercury promoted depolysulfidation and activation of Drp1. Depolysulfidation of Drp1 by electrophiles increased cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.

Academic Significance and Societal Importance of the Research Achievements

心疾患による死亡者数は年間約20万に上がり、これはがんに次ぐ死因となっている。心不全患者の5年生存率は未だ50%であり、新しいコンセプトに基づいた薬の開発が必要とされている。我々は心筋ミトコンドリアの品質異常が心機能低下の引き金になることを見出し、ミトコンドリアの品質を改善する既承認薬シルニジピンを同定した。さらに、シルニジピンは環境化学物質曝露による心疾患リスク上昇に対しても改善効果を示すことをマウス動物実験モデルから明らかにした。これらの成果はミトコンドリア機能保護という新しいコンセプトに基づいた心不全治療薬開発に貢献すると期待される。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (29 results)

All 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (13 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 13 results,  Open Access: 12 results) Presentation (11 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Int'l Joint Research] Mahidol University(タイ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Universiti Malaysia Sabah(マレーシア)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Universiti Malaysia Sabah(Malaysia)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Mahidol University(Thailand)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Mitochondrial dynamics in exercise physiology.2019

    • Author(s)
      Tanaka T, Nishimura A, Nishiyama K, Goto T, Numaga-Tomita T, Nishida M.
    • Journal Title

      Pflugers Archiv European Journal of Physiology

      Volume: 印刷中 Issue: 2 Pages: 1-17

    • DOI

      10.1007/s00424-019-02258-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence.2018

    • Author(s)
      Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-Tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T, Ide T, Ojida A, Mori Y, Nishida M.
    • Journal Title

      Sci Signal

      Volume: 11 Issue: 556 Pages: 5185-5195

    • DOI

      10.1126/scisignal.aat5185

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolonged stimulation of β2-adrenergic receptor with β2-agonists impairs insulin actions in H9c2 cells2018

    • Author(s)
      Parichatikanond Warisara、Nishimura Akiyuki、Nishida Motohiro、Mangmool Supachoke
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 138 Issue: 3 Pages: 184-191

    • DOI

      10.1016/j.jphs.2018.09.007

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy.2018

    • Author(s)
      Sunggip C, Shimoda K, Oda S, Tanaka T, Nishiyama K, Mangmool S, Nishimura A, Numaga-Tomita T and Nishida M
    • Journal Title

      Front. Pharmacol.

      Volume: 9 Pages: 523-523

    • DOI

      10.3389/fphar.2018.00523

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPC5-eNOS axis negatively regulates ATP-induced cardiomyocyte hypertrophy2018

    • Author(s)
      Sunggip C., Shimoda K., Oda S., Tanaka T., Nishiyama K., Mangmool S., Nishimura A., Numaga-Tomita T. and Nishida M.
    • Journal Title

      Frontiers in Pharmacology

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics2017

    • Author(s)
      Akaike Takaaki、、、Nishida Motohiro(4)、、、、、、Fujii Shigemoto(20)、、、Motohashi Hozumi(26)
    • Journal Title

      Nature Communications

      Volume: 8 Issue: 1 Pages: 1177-1177

    • DOI

      10.1038/s41467-017-01311-y

    • NAID

      120007134656

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice2017

    • Author(s)
      Oda Sayaka、Numaga-Tomita Takuro、Kitajima Naoyuki、Toyama Takashi、Harada Eri、Shimauchi Tsukasa、Nishimura Akiyuki、Ishikawa Tatsuya、Kumagai Yoshito、Birnbaumer Lutz、Nishida Motohiro
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 7511-7511

    • DOI

      10.1038/s41598-017-07903-4

    • NAID

      120007128849

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy2017

    • Author(s)
      Shimauchi Tsukasa、Numaga-Tomita Takuro、Ito Tomoya、Nishimura Akiyuki、Matsukane Ryosuke、Oda Sayaka、Hoka Sumio、Ide Tomomi、Koitabashi Norimichi、Uchida Koji、Sumimoto Hideki、Mori Yasuo、Nishida Motohiro
    • Journal Title

      The JCI insight

      Volume: 2 Issue: 15 Pages: 93358-93358

    • DOI

      10.1172/jci.insight.93358

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stimulation of Adenosine A2B Receptor Inhibits Endothelin-1-Induced Cardiac Fibroblast Proliferation and α-Smooth Muscle Actin Synthesis Through the cAMP/Epac/PI3K/Akt-Signaling Pathway2017

    • Author(s)
      Phosri Sarawuth、Arieyawong Ajaree、Bunrukchai Kwanchai、Parichatikanond Warisara、Nishimura Akiyuki、Nishida Motohiro、Mangmool Supachoke
    • Journal Title

      Frontiers in Pharmacology

      Volume: 8 Pages: 428-428

    • DOI

      10.3389/fphar.2017.00428

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPC3 Channels in Cardiac Fibrosis2017

    • Author(s)
      Numaga-Tomita Takuro、Oda Sayaka、Shimauchi Tsukasa、Nishimura Akiyuki、Mangmool Supachoke、Nishida Motohiro
    • Journal Title

      Frontiers in Cardiovasc Med

      Volume: 4 Pages: 56-56

    • DOI

      10.3389/fcvm.2017.00056

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells2017

    • Author(s)
      Nishida M, Nishimura A, Matsunaga T, Motohashi H, Kasamatsu S, Akaike T.
    • Journal Title

      Free Radic Biol Med.

      Volume: 印刷中 Pages: 30033-3

    • DOI

      10.1016/j.freeradbiomed.2017.01.024

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases2017

    • Author(s)
      Nishimura Akiyuki、Sunggip Caroline、Oda Sayaka、Numaga-Tomita Takuro、Tsuda Makoto、Nishida Motohiro
    • Journal Title

      Pharmacology & Therapeutics

      Volume: 180 Pages: 113-128

    • DOI

      10.1016/j.pharmthera.2017.06.010

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Purinergic P2Y6 receptors: a new therapeutic target of age-dependent hypertension2017

    • Author(s)
      Sunggip C, Nishimura A, Shimoda K, Numaga-Tomita T, Tsuda M, and Nishida M. M
    • Journal Title

      Pharmacological Research

      Volume: 120 Pages: 51-59

    • DOI

      10.1016/j.phrs.2017.03.013

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Age-dependent dimer formation of AT1R and P2Y6R promotes angiotensin II-induced hypertension2018

    • Author(s)
      Akiyuki Nishimura, Caroline Sunggip, Takuro Numaga-Tomita, Motohiro Nishida
    • Organizer
      FAOPS2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drp1-Filamin A複合体によるミトコンドリア過剰分裂を介した心筋細胞の早期老化機構2018

    • Author(s)
      西村明幸、田中智弘、下田翔、冨田拓郎、西田基宏
    • Organizer
      第35回日本薬学会九州支部大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メチル水銀による心毒性と活性イオウ分子種による制御2018

    • Author(s)
      西村明幸、西山和宏、田中 智弘、冨田拓郎、西田基宏
    • Organizer
      メタルバイオサイエンス研究会2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] ミトコンドリア-アクチン細胞骨格連携による心筋細胞の早期老化機構2018

    • Author(s)
      西村明幸、島内司、田中智弘、下田翔、冨田 拓郎、西田基宏
    • Organizer
      心血管膜輸送研究会2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] 親電子物質と活性イオウによる心筋ミトコンドリアの品質管理2018

    • Author(s)
      西村明幸、田中智弘、冨田拓郎、西田基宏
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Drp1-Filamin A相互作用による心筋ミトコンドリアの品質管理機構2018

    • Author(s)
      西村明幸、島内司、田中智弘、冨田拓郎、西田基宏
    • Organizer
      第71回日本酸化ストレス学会/第18回日本NO学会合同学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メチル水銀による心毒性と活性イオウ分子種による制御2018

    • Author(s)
      西村明幸、田中智弘、冨田拓郎、西田基宏
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性イオウによるミトコンドリア品質管理2018

    • Author(s)
      西村明幸、田中智弘、西山和宏、西田基宏
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性イオウによるミトコンドリア品質管理2018

    • Author(s)
      西村明幸、田中智弘、西山和宏、西田基宏
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] メチル水銀による心毒性と活性イオウ分子種による制御2018

    • Author(s)
      西村明幸、田中智弘、冨田拓郎、西田基宏
    • Organizer
      日本薬学会 第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 加齢に伴うAT1R-P2Y6R複合体形成によるアンジオテンシンII誘発性高血圧の制御2017

    • Author(s)
      西村明幸、Caroline Sunggip、冨田拓郎、西田基宏
    • Organizer
      Conbio2017
    • Related Report
      2017 Research-status Report
  • [Remarks] ミトコンドリアの品質を維持する既承認薬を発見 ー慢性心不全や難治性疾患への適応拡大に希望ー

    • URL

      http://www.phar.kyushu-u.ac.jp/bbs/view2.php?S_Publ_Year=2018&word=&page=1&B_Code=436

    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2020-03-30  

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