Mechanism of mitochondrial quality defects focusing on the linkage with the cytoskeleton and its application to the treatment of chronic diseases

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07085
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: National Institute for Physiological Sciences (2020-2021); Kyushu University (2019)
• Principal Investigator: Nishimura Akiyuki 生理学研究所, 生体機能調節研究領域, 特任准教授 (00457152)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ミトコンドリア品質 / 慢性疾患 / 心疾患

Outline of Final Research Achievements

Mitochondria, which are responsible for energy production in living organism, maintain their own quality (function) by continuously repeating fission and fusion cycle. Recently, disruption of mitochondrial dynamics (in particular abnormal fission) has been reported in various chronic diseases. We have previously found that mitochondria-cytoskeleton interactions through Drp1-filamin A complex induce abnormal mitochondrial hyperfission. In this study, we investigated whether Drp1-filamin A complex formation is a common molecular mechanism for various chronic disease, and found that Drp1-filamin A complex is involved in the progression of diseases such as cigarette sidestream smoke-induced cardiomyocyte dysfunction, amyotrophic lateral sclerosis and type 1 diabetes mouse models.

Free Research Field

生理科学

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリアダイナミクスの破綻は様々な慢性疾患で共通して確認されることから次世代創薬標的として注目されている。今回我々は、Drp1-filamin A複合体形成を介したミトコンドリア異常分裂を抑制する既承認薬シルニジピンが筋萎縮性側索硬化症や1型糖尿病マウスの症状を改善することを見出した。また、より薬効を高めたシルニジピン誘導体の開発にも着手しており、今後これら誘導体の薬効をマウス疾患モデルで検証していくことでミトコンドリア創薬研究をさらに進めていきたい。