2019 Fiscal Year Final Research Report

Therapeutic development of immune deficiency with mitochondrial dysfunction using CoQ10

Research Project

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Project/Area Number	17K12900
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Eating habits
Research Institution	Prefectural University of Kumamoto (2018-2019) The University of Tokushima (2017)
Principal Investigator	Ayako Tanimura 熊本県立大学, 環境共生学部, 助教 (10610199)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	ミトコンドリア / エネルギー代謝 / 細網異型性症 / 免疫不全 / 好中球分化 / フルクトース / CoQ10
Outline of Final Research Achievements	I established a model cell line of reticular dysgenesis which presents similar phenotypes to promyelocytic cells of patients by mutating causative gene AK2 using genome-editing system. One of symptoms in reticular dysgenesis is differentiation arrest of neutrophil differentiation that is thought to be caused by decreased ATP production and/or increased ROS due to impairment of mitochondrial energy production. I tried to improve the impairment of neutrophil differentiation with fructose or MitoQ, a mitochondria-targeted CoQ10 to increase ATP production or decrease ROS respectively. As a results, neutrophil differentiation rate was improved to similar level of that of WT cells by fructose in a model cell line. In addition, I revealed that lower ATP level suppress unfolded protein response (UPR) and then increasing ER stress inhibited neutrophil differentiation. According to this, it was thought that energy metabolism and ER stress/UPR play a critical role on neutrophil differentiation.
Free Research Field	栄養学
Academic Significance and Societal Importance of the Research Achievements	ミトコンドリア機能異常による希少難病であり、免疫不全により出生直後から重篤な感染症を引き起こしうる細網異形成症において、発症機序の一端を明らかにし、それを基に乳児での新規治療法につながりうる候補栄養素を見出した。この成果は、栄養素による免疫機能のコントロールやミトコンドリア異常疾患に対する栄養療法の可能性についても強く期待できるものである。また、最も数が多い免疫細胞である好中球において、その分化がエネルギー代謝と小胞体ストレスによって調節されていることを明らかにした。このことは好中球の賦活方法の開発や他の免疫細胞の分化機構解明などの一助になりうると考えられる。