Mechanisms of pH-dependent cellular responses mediated by membrane phospholipids

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K05983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42030:Animal life science-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: SAKO KEISUKE 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (50786291)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: pH / PIP2 / ゼブラフィッシュ / 初期発生

Outline of Final Research Achievements

Cells survive by responding and adapting to diverse external environments, including mechanical stimuli, temperature, and oxygen. A crucial external factor is the proton concentration in an external fluid pH, for instance, in interstitial fluid and blood. However, the mechanisms of cellular adaptation to pH are not well understood yet. In this study, we focused on the plasma membrane, which is directly exposed to changes in external fluid pH, and discovered a novel adaptation mechanism wherein membrane phospholipids, which constitute the plasma membrane, translocate from the inner to the outer leaflet. Zebrafish embryos without the membrane protein that regulates this mechanism exhibit abnormal development, indicating that an appropriate pH response is vital for proper development.

Free Research Field

発生生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で見出した、膜リン脂質のトポロジカルな変化を介した、新規pH応答機構を欠損する個体では、発育不全や胎生致死など様々な表現型を呈することが明らかになってきた。これらの結果は、体の中では常にpHの変動が起きており、うまく対処できない場合には、個体に異常をきたし、最悪死に至る可能性があることを示唆している。今後、例えばpH変動が起きると言われる虚血性心疾患や炎症反応時、またがん組織においてpH応答機構を調べることで、新たな病態の原因解明や新規治療法の確立につながることが期待できる。