Functional analysis of AIF in the nucleus and mitochondria to understand acute encephalopathy caused by mushroom poisoniing

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K08062
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Kondo Kazunari 国立医薬品食品衛生研究所, 生化学部, 部長 (40270623)
• Research Collaborator: Nakamura Kosuke ; Kato Reiko ; Sakata Kozue
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: スギヒラタケ / 急性脳症 / アポトーシス誘導因子

Outline of Final Research Achievements

To clarify the role of AIF in the nucleus and cytosol, we constructed an AIF mutant, which constantly resides in mitochondria using CRISPR/Cas9. Using the mitochondria resident non-releasable AIF, we examined cell viability, differentiation potential, gene expression profiles. The mutant AIF-carrying cells grew slowly and NGF-derived differentiation was completely blocked. The release of AIF may also be indispensable to cell proliferation and differentiation. DNA microarray analysis revealed that several genes involving in cell proliferation, differentiation, neurite out growth, such as S100 calcium-binding protein A, HSP70, early growth response-1, epidermal growth factor receptor, were significantly down-regulated. To summarize, AIF has a novel function to regulate gene ezpression related to cell proliferation and differentiation. The results also help understand refractory neurological disorders.

Free Research Field

細胞分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、食中毒で急性脳症により19名の死者を出したスギヒラタケきのこの原因物質とその作用メカニズム、急性脳症との関りの解明を目指すものである。これまでに、細胞毒性成分として単離した脂肪酸が新規細胞死経路により細胞を死に至らしめることを明らかにし、その制御分子AIFはこれまで知られていない機構で細胞の維持に関わっていること、および関与する遺伝子群を推定した。本研究の成果は、食中毒原因解明だけではなく、AIFにより多様な遺伝子発現調節機構への関与の結果は今後神経難病の原因を考えるうえでも極めて重要な知見となると考えられる。