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Identification of mitochondrial aconitase as a critical enzyme sensitive to microgravity stress

Publicly Offered Research

Project Area"LIVING IN SPACE" - Integral Understanding of life-regulation mechanism from "SPACE"
Project/Area Number 16H01645
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Complex systems
Research InstitutionThe University of Tokushima

Principal Investigator

二川 健  徳島大学, 大学院医歯薬学研究部(医学系), 教授 (20263824)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Keywords無重力センサー / 酸化ストレス / ミトコンドリア / アコニターゼ / 筋萎縮 / 無重力環境 / メカニカルストレス / メタボローム解析
Outline of Annual Research Achievements

筋萎縮などメカニカルストレスの応答異常による疾患(いわゆる無重力病)は代謝疾患である。つまり、メカニカルストレスに対する臓器・細胞の応答異常は、遺伝子異常を伴わない。研究代表者は、究極のメカニカルストレスである、無重力環境に対する生体の応答を、網羅的な代謝レベルの解析(メタボローム解析)を基盤に研究してきた。本研究では、無重力ストレスに対する筋細胞の初期応答(シグナル・トランスダクション)を明らかにした。具体的には、
1.「酸化ストレスによるミトコンドリア機能異常」:もう一つは、酸化ストレスがミトコンドリア・アコニターゼ活性を不活化し、ミトコンドリアの機能障害を引き起こす経路である。宇宙空間で培養したL6細胞において、TCAサイクル上の中間生成物であるcisアコニット酸の蓄積が見られていたため、これらを触媒する酵素であり、酸化ストレス感受性を持つアコニターゼに注目した。そこで、3D-Clinorotationを行い、アコニターゼ活性について調べたところ、活性の有意な低下が見られた。
2.「アコニターゼノックダウンの筋管細胞への影響」:アコニターゼノックダウンは筋管細胞の好気的解糖系を障害し、嫌気的解糖系を高めた。その結果、ATP産生量は減少した。さらに、アコニターゼノックダウンはERK1/2とDrp1の活性化を介してミトコンドリアの断片化を誘導し、遅筋型のミオシン重鎖の分解を引き起こした。
3.萎縮筋の見られた酸化ストレスの亢進は、ERK1/2-Egr-Cbl-bの発現経路を介して筋量の減少を、Aconitase活性低下-Mitochondrial dysfunctionを介して筋質(遅筋から速筋へ)の変化を誘導していることがわかった。また、抗酸化剤はクリノスタットによるERK1/2の活性化を抑制した。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (33 results)

All 2018 2017 2016 2015

All Journal Article (19 results) (of which Int'l Joint Research: 13 results,  Peer Reviewed: 17 results,  Open Access: 11 results,  Acknowledgement Compliant: 2 results) Presentation (12 results) (of which Int'l Joint Research: 4 results,  Invited: 7 results) Book (2 results)

  • [Journal Article] VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells2018

    • Author(s)
      Tomida Chisato、Yamagishi Naoko、Nagano Hikaru、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
    • Journal Title

      International Journal of Oncology

      Volume: 52 Pages: 1350-1362

    • DOI

      10.3892/ijo.2018.4291

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct Gene Expression Profile Distinguishes Increased Metabolic Activity in Spontaneously Hyperactive Rats While Sedentary from That Induced by Exercise2018

    • Author(s)
      Abe Manami、Matsuo Yuki、Harada-Sukeno Akiko、Uchida Takayuki、Kitahata Kanako、Tomida Chisato、Hirasaka Katsuya、Teshima-Kondo Shigetada、Harada Nagakatsu、Nakaya Yutaka、Sakaue Hiroshi、Nakao Reiko、Nikawa Takeshi
    • Journal Title

      Advances in Biological Chemistry

      Volume: 08 Issue: 01 Pages: 1-14

    • DOI

      10.4236/abc.2018.81001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reactive oxygen species up-regulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells.2018

    • Author(s)
      Uchida T, Sakashita Y, Kitahata K, Yamashita Y, Tomida C, Kimori Y, Komatsu A, Hirasaka K, Ohno A, Nakao R, Higashitani A, Higashibata A, Ishioka N, Shimazu T, Kobayashi T, Okumura Y, Choi I, Oarada M, Mills EM, Teshima-Kondo S, Takeda S, Tanaka E, Tanaka K, Sokabe M, Nikawa T.
    • Journal Title

      Am J Physiol Cell Physiol

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size2017

    • Author(s)
      BAYARSAIKHAN Od、KAWAI Nobuhiko、MORI Hiroyo、KINOUCHI Nao、NIKAWA Takeshi、TANAKA Eiji
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 63 Issue: 4 Pages: 244-248

    • DOI

      10.3177/jnsv.63.244

    • NAID

      130007314434

    • ISSN
      0301-4800, 1881-7742
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Update on recent progress in vitamin D research. Vitamin D and muscle tissues2017

    • Author(s)
      Kaneko I, Miyamoto KI, Nikawa T
    • Journal Title

      Clin Calcium

      Volume: 27 Pages: 1571-1578

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor2017

    • Author(s)
      Tomida Chisato、Nagano Hikaru、Yamagishi Naoko、Uchida Takayuki、Ohno Ayako、Hirasaka Katsuya、Nikawa Takeshi、Teshima-Kondo Shigetada
    • Journal Title

      The Journal of Medical Investigation

      Volume: 64 Issue: 3.4 Pages: 262-265

    • DOI

      10.2152/jmi.64.262

    • NAID

      130006105177

    • ISSN
      1343-1420, 1349-6867
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells2017

    • Author(s)
      Chisato Tomida, Naoko Yamagishi, Hikaru Nagano, Takayuki Uchida, Ayako Ohno, Katsuya Hirasaka, Takeshi Nikawa, Shigetada Teshima-Kondo
    • Journal Title

      The Journal of Medical Investigation

      Volume: 64 Issue: 3.4 Pages: 250-254

    • DOI

      10.2152/jmi.64.250

    • NAID

      130006105181

    • ISSN
      1343-1420, 1349-6867
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct effects of dietary whey peptide and soy protein on denervation-mediated muscle atrophy.2017

    • Author(s)
      Takagi M, Uchida T, Takatsu E, Kishimoto H, Ida K, Ishida Y, Ono-Ohmachi A, Morita Y, Kato K, Ochi A, Ohno-Maita A, Oarada M, Abe T, Teshima-Kondo S, Nakao R, Hirasaka K, Nikawa T*.
    • Journal Title

      J Nutr Food Sci

      Volume: 印刷中

    • Related Report
      2016 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Modulation of cutaneous extracellular collagen contraction by phosphorylation status of p130Cas2017

    • Author(s)
      Takeya M, Okumura Y, Nikawa T*
    • Journal Title

      J Physiol Sci

      Volume: 印刷中

    • NAID

      40021302104

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolic Suppression by 3-Iodothyronamine Induced Muscle Cell Atrophy <i>via</i> Activation of FoxO–Proteasome Signaling and Downregulation of Akt1–S6K Signaling2017

    • Author(s)
      Ju H, Kim T, Chung CM, Park J, Nikawa T, Park K, Choi I*
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 5 Pages: 576-582

    • DOI

      10.1248/bpb.b16-00653

    • NAID

      130005631971

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development and performance evaluation of a three-dimensional clinostat synchronized heavy-ion irradiation system2017

    • Author(s)
      Ikeda H, Hidema J and Takahashi A et al.
    • Journal Title

      Life Sci Space Res

      Volume: 12 Pages: 51-60

    • DOI

      10.1016/j.lssr.2017.01.003

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Nutritional counseling regulates interdialytic weight gain and blood pressure in outpatients receiving maintenance hemodialysis2017

    • Author(s)
      Sakai A, Hamada H, Hara K, Mori K, Uchida T, Mizuguchi T, Minaguchi J, Shima K, Kawashima S, Hamada Y, Nikawa T*.
    • Journal Title

      J Med Invest

      Volume: 64 Pages: 129-135

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance.2017

    • Author(s)
      Abe T, Hirasaka K, Nikawa T.
    • Journal Title

      World J Diabetes.

      Volume: 8 Issue: 3 Pages: 97-103

    • DOI

      10.4239/wjd.v8.i3.97

    • NAID

      120006937652

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] UCP3 is associated with Hax-1 in mitochondria in the presence of calcium ion2016

    • Author(s)
      Hirasaka K, Mills EM, Haruna M, Bando A, Ikeda C, Abe T, Kohno S, Nowinski SM, Lago CU, Akagi K, Tochio H, Ohno A, Teshima-Kondo S, Okumura Y, Nikawa T
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 472 Issue: 1 Pages: 108-113

    • DOI

      10.1016/j.bbrc.2016.02.075

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Capric Acid Up-Regulates UCP3 Expression without PDK4 Induction in Mouse C2C12 Myotubes2016

    • Author(s)
      Abe T, Hirasaka K, Kohno S, Tomida C, Haruna M, Uchida T, Ohno A, Oarada M, Teshima-Kondo S, Okumura Y, Choi I, Aoyama T, Terao J, Nikawa T*.
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 62 Issue: 1 Pages: 32-39

    • DOI

      10.3177/jnsv.62.32

    • NAID

      130005148603

    • ISSN
      0301-4800, 1881-7742
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Preventive effect of dietary quercetin on disuse muscle atrophy by targeting mitochondria in denervated mice2016

    • Author(s)
      Mukai R, Matsui N, Fujikura Y, Matsumoto N, Hou DX, Kanzaki N, Shibata H, Horikawa M, Iwasa K, Hirasaka K, Nikawa T, Terao J
    • Journal Title

      J Nutr Biochem

      Volume: 31 Pages: 67-76

    • DOI

      10.1016/j.jnutbio.2016.02.001

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice2016

    • Author(s)
      Hirasaka K*, Saito S, Yamaguchi S, Miyazaki R, Wang Y, Haruna M, Taniyama S, Higashitani A, Terao J, Nikawa T, Tachibana K
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 62 Issue: 3 Pages: 178-184

    • DOI

      10.3177/jnsv.62.178

    • NAID

      130005253104

    • ISSN
      0301-4800, 1881-7742
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 8-Prenylnaringenin promotes recovery from immobilization-induced disuse muscle atrophy through activation of the Akt phosphorylation pathway in mice2016

    • Author(s)
      Mukai R, Horikawa H, Lin PY, Tsukumo N, Nikawa T, Kawamura T, Nemoto H, Terao J*
    • Journal Title

      Am J Physiol Regul Integr Comp Physiol

      Volume: 311 Issue: 6 Pages: 1022-1031

    • DOI

      10.1152/ajpregu.00521.2015

    • NAID

      120006535072

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The malignant progression effects of regorafenib in human colon cancer cells2015

    • Author(s)
      Tomida C, Aibara K, Yamagishi N, Yano C, Nagano H, Abe T, Ohno A, Hirasaka K, Nikawa T, Teshima-Kondo S
    • Journal Title

      The Journal of Medical Investigation

      Volume: 62 Issue: 3.4 Pages: 195-198

    • DOI

      10.2152/jmi.62.195

    • NAID

      130005099146

    • ISSN
      1343-1420, 1349-6867
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Molecular mechanism and nutritional approach for unloading-mediated muscle atrophy2018

    • Author(s)
      Takeshi Nikawa, Takayuki Uchida, Ayako Miata (Ohno), Reiko Nakao
    • Organizer
      2018 International Conference on Functional Food for improving Sarcopenia, Cachexia and Frailty
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 骨格筋蛋白質代謝と骨格筋量調節2017

    • Author(s)
      二川健
    • Organizer
      第20回日本病態栄養学会年次学術集会
    • Place of Presentation
      京都国際会議場(京都府・京都市)
    • Year and Date
      2017-01-15
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Unloading induces reactive oxygen species associated signal transduction toward atrophy in skeletal muscle cells2017

    • Author(s)
      Takeshi Nikawa
    • Organizer
      3rd Internation Symposium on Mechanobiology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 無重力ストレスに対する初期応答酵素(アコニターゼ)の筋萎縮における役割2017

    • Author(s)
      二川健
    • Organizer
      2017年度生命科学系学会合同年次大会第40回日本分子生物学会年会、第90回日本生化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Molecular mechanism of microgravity-induced muscle atrophy2017

    • Author(s)
      二川健
    • Organizer
      第65回国際歯科研究学会日本部会総会・学術大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Unloading induces reactive oxygen species associated signal transduction toward atrophy in skeletal muscle cells2017

    • Author(s)
      Takeshi Nikawa
    • Organizer
      14th Japan-Korea Joint Seminar on Space Environment Utilization Research
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 無重力ストレスによる筋萎縮における酸化ストレスの重要性2017

    • Author(s)
      内田貴之、真板綾子、中尾玲子、小林剛、東谷篤志、石原直忠、武田伸一、曽我部正博、二川健
    • Organizer
      日本筋学会第3回学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 無重力による酸化ストレス産生を介した筋細胞内シグナル・トランスダクション2017

    • Author(s)
      内田貴之、木森有希、二宮みゆき、坂下禎宏、安倍知紀、真板綾子、中尾玲子、平坂勝也、東谷篤志、小林剛、曽我部正博、武田伸一、二川健
    • Organizer
      第71回日本栄養・食糧学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Effects of dietary soy protein on unloading mediated muscle atrophy2016

    • Author(s)
      Takeshi Nikawa, Rie Hashimoto, Katsuya Hirasaka, Chiaki Yano, Kana Aibara, Takayuki Uchida, Tomoki Abe, Ayako Ohno(Maita), Kazuhito Akama
    • Organizer
      11th Asian Microgravity Symposium
    • Place of Presentation
      北海道大学(北海道・札幌市)
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 廃用性筋萎縮とユビキチンリガーゼ2016

    • Author(s)
      二川健
    • Organizer
      第21回日本病態プロテアーゼ学会学術集会
    • Place of Presentation
      千里ライフサイエンスセンター(大阪府・豊中市)
    • Year and Date
      2016-08-05
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 筋萎縮における細胞内シグナルとその制御による筋萎縮治療2016

    • Author(s)
      二川健
    • Organizer
      第70回日本栄養・食糧学会大会
    • Place of Presentation
      武庫川女子大学(兵庫県・西宮市)
    • Year and Date
      2016-05-13
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Unloading環境による筋萎縮とその栄養学的治療法2016

    • Author(s)
      二川健
    • Organizer
      第23回アミノ酸セミナー:基礎と臨床を結ぶ会
    • Place of Presentation
      東京国際フォーラム(東京都・千代田区)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Book] 食品サイエンス2017

    • Author(s)
      井田くるみ、内田貴之、赤間一仁、二川健
    • Publisher
      羊土社
    • Related Report
      2016 Annual Research Report
  • [Book] 「季刊 腎と骨代謝」特集 スペースサイエンス2017

    • Author(s)
      二川健
    • Publisher
      日本メディカルセンター
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-26   Modified: 2018-12-17  

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