2021 Fiscal Year Final Research Report
Discovery of non-canonical mitophagy and its role in mitochondrial quality control
| Project/Area Number |
20K20305
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| Project/Area Number (Other) |
17H06267 (2017-2019)
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| Research Category |
Grant-in-Aid for Challenging Research (Pioneering)
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| Allocation Type | Multi-year Fund (2020)
Single-year Grants (2017-2019) |
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| Research Field |
Tumor biology and related fields
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| Research Institution | National Cancer Center Japan |
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Principal Investigator |
Arakawa Hirofumi 国立研究開発法人国立がん研究センター, 研究所, 分野長 (70313088)
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| Project Period (FY) |
2017-06-30 – 2022-03-31
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| Keywords | 相分離 / 液滴 / 非膜オルガネラ / ミトコンドリア / カルジオリピン / 代謝反応 / p53 / がん抑制 |
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| Outline of Final Research Achievements |
Liquid droplets function as membrane-less organelles that compartmentalize and facilitate efficient biological reactions. Here, we report that Mieap is a protein that drives formation of liquid droplets in mitochondria. Mieap liquid droplets (Mi-LDs) specifically phase separate the mitochondrial phospholipid, cardiolipin. Lipidomic analysis suggests that Mieap promotes enzymatic reactions involved in cardiolipin metabolism, including biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mi-LDs. Mieap-deficient mice exhibit altered crista structure in mitochondria of various tissues, including brown fat, and tend to become obese. These results suggest that Mieap drives formation of membrane-less organelles to compartmentalize and promote cardiolipin metabolism at the inner mitochondrial membrane, thus potentially contributing to mitochondrial quality control.
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| Free Research Field |
腫瘍生物学
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| Academic Significance and Societal Importance of the Research Achievements |
古典的概念ではこれまで説明が難しかった代謝連続反応のメカニズムを、本研究課題が明らかにした全く新しい概念で説明できるようになる（パラダイムシフト）。細胞内の様々な生物活性の反応様式が、単なる教科書の図ではなく、リアリティーのある時空間的に動的な生物活性として理解できるようになる。Mieap液滴を応用することで、カルジオリピン代謝促進によるミトコンドリア健常性維持の新しい手段を得ることが出来る。それによって、がん・認知症・老化などのミトコンドリア異常を背景とした病態の克服に貢献し、人類の健康長寿を実現できる。
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