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Molecular mechanism of mitochondrial selection by mitophagy machinery

Research Project

Project/Area Number 17H03671
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionNiigata University

Principal Investigator

Tomotake Kanki  新潟大学, 医歯学系, 教授 (50398088)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywordsオートファジー / ミトコンドリア / マイトファジー / 生体分子
Outline of Final Research Achievements

Mitophagy plays an important role in mitochondrial quality control. We identified that the PP2A (protein phosphatase 2A)-like protein phosphatase Ppg1 was essential for dephosphorylation of mitophagy receptor Atg32 and thus inhibited mitophagy in yeast. We identified the Far complex consisting of Far3-7-8-9-10-11 proteins as Ppg1-binding proteins and Far proteins also essential for dephosphorylation of Atg32. From these findings, we concluded that Ppg1 and the Far complex cooperatively dephosphorylate Atg32 to prevent excessive mitophagy.
Using mammalian culture cells, we found that the anticancer drug gemcitabine induces mitophagy. Notably, the PINK1 and MUL1, but not Parkin have important role in mitophagy induced by gemcitabine. We also identified that Glaucoma-mutant OPTN proteins retain their normal properties as mitophagy receptors, suggesting that mutations in the OPTN gene cause glaucoma through a mechanism independent of mitophagy defects.

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリアは、細胞の活動に必要なATPの大部分を産生するオルガネラであり、その量や機能の維持は生命活動に非常に重要である。マイトファジーは、細胞内の不要な、もしくは余剰なミトコンドリアを適切に分解することにより、ミトコンドリア恒常性維持を行う重要な機構であるが、その分子機構は不明な点が多い。本研究では、出芽酵母、哺乳類と複数の生物種を用いてマイトファジーの研究を行い、その分子機構の一端を解明した。これらの研究成果は、将来、ミトコンドリア機能低下が関わる種々の疾患や老化現象の治療法、予防法の開発に結びつくと考えられ、学術的にも社会的にも重要である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (14 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (4 results) (of which Invited: 3 results) Remarks (1 results)

  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1.2020

    • Author(s)
      Igarashi R, Yamashita SI, Yamashita T, Inoue K, Fukuda T, Fukuchi T, Kanki T.
    • Journal Title

      Sci Rep.

      Volume: 10(1) Issue: 1 Pages: 1465-1465

    • DOI

      10.1038/s41598-020-58315-w

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] FKBP8 LIRL‐dependent mitochondrial fragmentation facilitates mitophagy under stress conditions2020

    • Author(s)
      Yoo Seung‐Min、Yamashita Shun‐ichi、Kim Hyunjoo、Na DoHyeong、Lee Haneul、Kim Seo Jin、Cho Dong‐Hyung、Kanki Tomotake、Jung Yong‐Keun
    • Journal Title

      The FASEB Journal

      Volume: 34 Issue: 2 Pages: 2944-2957

    • DOI

      10.1096/fj.201901735r

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Regulatory mechanisms of mitochondrial autophagy: Lessons from yeast2019

    • Author(s)
      Kentaro Furukawa, Aleksei Innokentev, Tomotake Kanki
    • Journal Title

      Frontiers in Plant Science

      Volume: 10 Pages: 1479-1479

    • DOI

      10.3389/fpls.2019.01479

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glaucoma-Associated Mutations in the Optineurin Gene Have Limited Impact on Parkin-Dependent Mitophagy.2019

    • Author(s)
      Chernyshova K, Inoue K, Yamashita SI, Fukuchi T, Kanki T.
    • Journal Title

      Invest Ophthalmol Vis Sci.

      Volume: 60(10) Issue: 10 Pages: 3625-3635

    • DOI

      10.1167/iovs.19-27184

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PP2A-like protein phosphatase Ppg1: an emerging negative regulator of mitophagy in yeast.2018

    • Author(s)
      Furukawa K, Kanki T.
    • Journal Title

      Autophagy

      Volume: 14(12) Issue: 12 Pages: 2171-2172

    • DOI

      10.1080/15548627.2018.1511505

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The PP2A-like protein phosphatase Ppg1 and the Far complex cooperatively counteract CK2-mediated phosphorylation of Atg32 to inhibit mitophagy.2018

    • Author(s)
      Furukawa K, Fukuda T, Yamashita SI, Saigusa T, Kurihara Y, Yoshida Y, Kirisako H, Nakatogawa H, Kanki T.
    • Journal Title

      Cell Reports

      Volume: 23(12) Issue: 12 Pages: 3579-3590

    • DOI

      10.1016/j.celrep.2018.05.064

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanisms and Physiological Roles of Mitophagy in Yeast.2018

    • Author(s)
      Fukuda T, Kanki T.
    • Journal Title

      Mol Cells.

      Volume: 41 Pages: 35-44

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] How autophagy eats large mitochondria; autophagosome formation coupled with mitochondrial fragmentation2017

    • Author(s)
      Shun-ichi Yamashita and Tomotake Kanki
    • Journal Title

      Autophagy

      Volume: 印刷中 Issue: 5 Pages: 980-981

    • DOI

      10.1080/15548627.2017.1291113

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] 脂肪組織におけるミトコンドリアオートファジーの生理的意義2019

    • Author(s)
      神吉智丈
    • Organizer
      第66回日本実験動物学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 環境温度変化に応答した脂肪組織におけるミトコンドリア分解2018

    • Author(s)
      山下 俊一、神吉 智丈
    • Organizer
      BIOTHERMOLOGY WORKSHOP
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 出芽酵母におけるミトコンドリア オートファジーの分子機構2017

    • Author(s)
      神吉智丈
    • Organizer
      日本植物学会第81回大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ミトコンドリア分解を制御するリン酸化2017

    • Author(s)
      神吉智丈
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Remarks] 機能制御学分野

    • URL

      https://www.med.niigata-u.ac.jp/mit/

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report 2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-12-28  

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