Mitochondrial regulation by MITOL and diseases

• Project/Area Number: 20H03454
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Gakushuin University
• Principal Investigator: Yanagi Shigeru 学習院大学, 理学部, 教授 (60252003)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: ミトコンドリア / ユビキチンリガーゼ / パーキンソン病 / アルツハイマー病 / アミロイドβ

Outline of Research at the Start

アルツハイマー病やパーキンソン病など多くの神経変性疾患の病態において、酸化ストレスによるミトコンドリア機能不全が原因の一つとされていたが、そのメカニズムはよくわかっていなかった。私たちの研究成果は、MITOLを介して神経細胞死を防ぐミトコンドリアの新しい役割を示すと共に、アルツハイマー病やパーキンソン病など、酸化ストレスによって引き起こされる神経疾患の病態解明と治療法開発に新たな視点を提供する。

Outline of Final Research Achievements

Mitochondrial disruption leads to reduced energy production and chronic leakage of reactive oxygen species, triggering age-related pathologies such as neurodegenerative diseases and cardiac disorders. We have previously identified the E3 ubiquitin ligase MITOL, which localizes to the mitochondrial outer membrane, and reported that MITOL regulates mitochondrial dynamics. In the study, we found that MITOL is closely involved in the pathogenesis of Alzheimer's disease, Parkinson's disease and heart failure.

Academic Significance and Societal Importance of the Research Achievements

今回、私たちはアルツハイマー病、パーキンソン病などの神経変性疾患や心不全などの病態にミトコンドリアの機能不全が密接に関与していることを明らかにすることができました。また、MITOLを欠損した様々な老化モデルマウスの作出することができました。これらの老化モデルマウスを解析することにより、今後、老化の分子メカニズムの解明が期待されます。さらに、MITOLやミトコンドリアを標的とした創薬開発が期待されます。

Research Products

• [Journal Article] MITOL regulates phosphatidic acid-binding activity of RMDN3/PTPIP51 (2022)
  • Author(s): Ito Naoki、Takahashi Takara、Shiiba Isshin、Nagashima Shun、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: The Journal of Biochemistry Volume: 171 Issue: 5 Pages: 529-541
  • DOI: 10.1093/jb/mvab153
  • Peer Reviewed / Open Access
• [Journal Article] Protective roles of MITOL against myocardial senescence and ischemic injury partly via Drp1 regulation (2022)
  • Author(s): Tokuyama T、Uosaki H、Sugiura A、Nishitai G、Takeda K、Nagashima S、Shiiba I、Ito N、Amo T、Mohri S、Nishimura A、Nishida M、Konno A、Hirai H、Ishido S、Yoshizawa T、Shindo T、Takada S、Kinugawa S、Inatome R、Yanagi S
  • Journal Title: iScience Volume: 25 Issue: 7 Pages: 104582-104582
  • DOI: 10.1016/j.isci.2022.104582
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitin-mediated mitochondrial regulation by MITOL/MARCHF5 at a glance (2022)
  • Author(s): Nagashima Shun、Ito Naoki、Shiiba Isshin、Shimura Hiroki、Yanagi Shigeru
  • Journal Title: The Journal of Biochemistry Volume: 173 Issue: 1 Pages: 1-11
  • DOI: 10.1093/jb/mvac092
  • Peer Reviewed
• [Journal Article] MITOL promotes cell survival by degrading Parkin during mitophagy (2021)
  • Author(s): Shiiba Isshin、Takeda Keisuke、Nagashima Shun、Ito Naoki、Tokuyama Takeshi、Yamashita Shun‐Ichi、Kanki Tomotake、Komatsu Toru、Urano Yasuteru、Fujikawa Yuuta、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: EMBO reports Volume: 22 Issue: 3
  • DOI: 10.15252/embr.201949097
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation (2021)
  • Author(s): Takeda Keisuke、Uda Aoi、Mitsubori Mikihiro、Nagashima Shun、Iwasaki Hiroko、Ito Naoki、Shiiba Isshin、Ishido Satoshi、Matsuoka Masaaki、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 192-192
  • DOI: 10.1038/s42003-021-01720-2
  • Peer Reviewed / Open Access
• [Journal Article] MITOL dysfunction causes dwarfism with anterior pituitary hypoplasia (2020)
  • Author(s): Matsuno Keigo、Nagashima Shun、Shiiba Isshin、Taniwaka Keito、Takeda Keisuke、Tokuyama Takeshi、Ito Naoki、Matsushita Nobuko、Fukuda Toshifumi、Ishido Satoshi、Inatome Ryoko、Yanagi Shigeru
  • Journal Title: The Journal of Biochemistry Volume: 168 Issue: 3 Pages: 305-312
  • DOI: 10.1093/jb/mvaa050
  • NAID: 40022375443
  • Peer Reviewed