2019 Fiscal Year Final Research Report
metabomic analysis of mitochondria-ralted diseases
Project/Area Number |
17H01550
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Laboratory medicine
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Research Institution | Kyushu University |
Principal Investigator |
Kang Dongchon 九州大学, 医学研究院, 教授 (80214716)
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Co-Investigator(Kenkyū-buntansha) |
内海 健 九州大学, 医学研究院, 教授 (80253798)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Keywords | ミトコンドリア / p32 / IL6 / 免疫樹状細胞 / 心不全 / 拡張性心筋症 / NAD+ / リソソーム |
Outline of Final Research Achievements |
(1) Intra-mitochondria specific metabolomics analysis: the systems were made for metabolomics assay for more than 1000 metabolites and rapid isolation of intact mitochondria. (2) Prevention and treatment of mitochondria-related disease: (i) p32 is a mitochondria localized protein and critical for mitochondrial ATP production. We have found p32 adequately regulates LPS-induced IL6 production via AT4-intgarated stress response axis and maintains immune dendritic cell function by keeping citrate dehydrogenase active. (ii) Cardiomyocyte-specific KO of p32 gene induced dilated cardiomyopathy and cardiac failure. Its mechanism is not a general decline of cellular ATP level but a decrease in ATP production localized on lysosome membranes caused by reduced mitochondrial NAD+ production, which leads to less acidification of intra-lysosomes and impairs autophagic quality control of mitochondria. These results suggest a new mechanism for cardiac myopathy and raise a new target for its treatment.
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Free Research Field |
臨床検査医学
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Academic Significance and Societal Importance of the Research Achievements |
今回の研究はミトコンドリア翻訳に極めて重要なタンパク質であるp32遺伝子のKOマウスの研究を通じて、ミトコンドリアによる自然免疫および獲得免疫機能の新しい制御機序を明らかにした。社会的に大きな問題となっている免疫異常による様々な疾患に対する新しい予防治療標的を提供するものである。また、心筋特異的p32遺伝子KOによる拡張性心筋症と引き続く心不全の発症機序に細胞内全体のATPではなくリソソーム膜上に限定したATP産生が重要であるという予想外の新しい視点を提供するとともに、NAD+と言う新しい治療標的を提示した。
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