Membrane-less organelles and control of metabolic pathways

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19412
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: National Cancer Center Japan
• 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)
• Project Period (FY): 2022-06-30 – 2024-03-31
• 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 / 酵素反応 / 代謝連続反応 / p53

Outline of Final Research Achievements

Biomolecular condensates (BCs) are formed by proteins with intrinsically disordered regions (IDRs) via liquid-liquid phase separation.Here, we report that Mieap is an IDR-containing protein that drives formation of BCs involved in cardiolipin metabolism. Mieap BCs specifically phase separate the mitochondrial phospholipid, cardiolipin. Mieap directly binds to cardiolipin in vitro. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions in cardiolipin biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap BCs. Mieap-deficient cells exhibit altered crista structure, leading to decreased respiration activity and ATP production in mitochondria. These results suggest that Mieap may form membrane-less organelles to compartmentalize and facilitate cardiolipin metabolism, thus potentially contributing to mitochondrial quality control.

Free Research Field

腫瘍生物学

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液滴による代謝制御という全く新しい概念で解明することが可能になると期待される。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生物活性として説明可能になると期待される。Mieap液滴を応用することで、カルジオリピン代謝制御を介した全く新しいミトコンドリア健常性維持の手段を提供し、がん・認知症・老化などの予防や治療が可能になると期待され、広く人類の健康福祉に大きく貢献する可能性がある。