老化に伴い発症するミトコンドリア関連性疾患の機能解析と予防治療
キーワード：ミトコンドリア リソソーム 老化
2021.04～2023.03.
| 八木 美佳子（やぎ みかこ） | データ更新日：2023.12.06 |
主な研究テーマ
ミトコンドリアがオートファジーを制御する新機構と老化随伴疾患代謝物の探索
キーワード：ミトコンドリア オートファジー
2018.04～2021.03.
従事しているプロジェクト研究
老化に伴い発症するミトコンドリア関連性疾患の機能解析と予防治療
2021.07～2023.03, 代表者：八木美佳子, 保健学部門検査技術科学分野.
2021.07～2023.03, 代表者：八木美佳子, 保健学部門検査技術科学分野.
ミトコンドリアがオートファジーを制御する新機構と老化随伴疾患代謝物の探索
2019.04～2021.03, 代表者：八木美佳子, 保健学部門検査技術科学分野
老化に伴う多くの疾患はミトコンドリア機能、オートファジー機能, 血中NAD量低下が関与すると考えられているがその詳細な分子機構は明らかでない。我々が作成した、ミトコンドリア機能不全マウスの解析から心筋特異的ノックアウトマウスでは拡張型心筋症を早期に呈することを見出し、寿命は約500日に減少することを突き止めた。このマウスの心臓を用いて様々な解析を行った結果、オートファジー機能低下、NAD合成酵素発現量低下、を発見し新たなメカニズムの構築を果たした。.
2019.04～2021.03, 代表者：八木美佳子, 保健学部門検査技術科学分野
老化に伴う多くの疾患はミトコンドリア機能、オートファジー機能, 血中NAD量低下が関与すると考えられているがその詳細な分子機構は明らかでない。我々が作成した、ミトコンドリア機能不全マウスの解析から心筋特異的ノックアウトマウスでは拡張型心筋症を早期に呈することを見出し、寿命は約500日に減少することを突き止めた。このマウスの心臓を用いて様々な解析を行った結果、オートファジー機能低下、NAD合成酵素発現量低下、を発見し新たなメカニズムの構築を果たした。.
研究業績
主要原著論文
| 1. | Saori Ueda, Mikako Yagi, Ena Tomoda, Shinya Matsumoto, Yasushi Ueyanagi, Yura Do, Daiki Setoyama, Yuichi Matsushima, Asuteka Nagao, Tsutomu Suzuki, Tomomi Ide, Yusuke Mori, Noriko Oyama, Dongchon Kang, Takeshi Uchiumi, Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation, Nucleic acids research, doi.org/10.1093/nar/gkad591, 2023.07. |
| 2. | Masakazu Fujii, Daiki Setoyama, Kazuhito Gotoh, Yushi Dozono, Mikako Yagi, Masataka Ikeda, Tomomi Ide, Takeshi Uchiumi, Dongchon Kang, TFAM expression in brown adipocytes confers obesity resistance by secreting extracellular vesicles that promote self-activation, ISCIENCE, 10.1016/j.isci.2022.104889, 25, 9, 2022.09. |
| 3. | Mikako Yagi, Takahiro Toshima, Rie Amamoto, Yura Do, Haruka Hirai, Daiki Setoyama, Dongchon Kang, Takeshi Uchiumi, Mitochondrial translation deficiency impairs NAD(+)-mediated lysosomal acidification, EMBO JOURNAL, 10.15252/embj.2020105268, 40, 8, 2021.04, Mitochondrial translation dysfunction is associated with neurodegenerative and cardiovascular diseases. Cells eliminate defective mitochondria by the lysosomal machinery via autophagy. The relationship between mitochondrial translation and lysosomal function is unknown. In this study, mitochondrial translation-deficient hearts from p32-knockout mice were found to exhibit enlarged lysosomes containing lipofuscin, suggesting impaired lysosome and autolysosome function. These mice also displayed autophagic abnormalities, such as p62 accumulation and LC3 localization around broken mitochondria. The expression of genes encoding for nicotinamide adenine dinucleotide (NAD+) biosynthetic enzymes—Nmnat3 and Nampt—and NAD+ levels were decreased, suggesting that NAD+ is essential for maintaining lysosomal acidification. Conversely, nicotinamide mononucleotide (NMN) administration or Nmnat3 overexpression rescued lysosomal acidification. Nmnat3 gene expression is suppressed by HIF1α, a transcription factor that is stabilized by mitochondrial translation dysfunction, suggesting that HIF1α-Nmnat3-mediated NAD+ production is important for lysosomal function. The glycolytic enzymes GAPDH and PGK1 were found associated with lysosomal vesicles, and NAD+ was required for ATP production around lysosomal vesicles. Thus, we conclude that NAD+ content affected by mitochondrial dysfunction is essential for lysosomal maintenance.. |
| 4. | Mikako Yagi, Takeshi Uchiumi, Noriaki Sagata, Daiki Setoyama, Rie Amamoto, Yuichi Matsushima, Dongchon Kang, Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration, Scientific reports, 10.1038/s41598-017-15414-5, 7, 1, 2017.12, [URL], Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy.. |
| 5. | Toshiro Saito, Takeshi Uchiumi, Mikako Yagi, Rie Amamoto, Daiki Setoyama, Yuichi Matsushima, Dongchon Kang, Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses, Cardiovascular research, 10.1093/cvr/cvx095, 113, 10, 1173-1185, 2017.08, [URL], Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial p32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of p32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic p32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial p32/C1qbp in the heart. Methods and results We investigated the role of p32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against p32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of p32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by p32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific p32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the p32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in p32-deficient compared with control myocytes, AMPKI' was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the p32-deficient hearts. Conclusion These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.. |
| 6. | Mikako Yagi, Takeshi Uchiumi, Shinya Takazaki, Bungo Okuno, Masatoshi Nomura, Shin Ichi Yoshida, Tomotake Kanki, Dongchon Kang, p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability, NUCLEIC ACIDS RESEARCH, 10.1093/nar/gks774, 40, 19, 9717-9737, 2012.10, p32 is an evolutionarily conserved and ubiquitously expressed multifunctional protein. Although p32 exists at diverse intra and extracellular sites, it is predominantly localized to the mitochondrial matrix near the nucleoid associated with mitochondrial transcription factor A. Nonetheless, its function in the matrix is poorly understood. Here, we determined p32 function via generation of p32-knockout mice. p32-deficient mice exhibited midgestation lethality associated with a severe developmental defect of the embryo. Primary embryonic fibroblasts isolated from p32-knockout embryos showed severe dysfunction of the mitochondrial respiratory chain, because of severely impaired mitochondrial protein synthesis. Recombinant p32 binds RNA, not DNA, and endogenous p32 interacts with all mitochondrial messenger RNA species in vivo. The RNA-binding ability of p32 is well correlated with the mitochondrial translation. Coimmunoprecipitation revealed the close association of p32 with the mitoribosome. We propose that p32 is required for functional mitoribosome formation to synthesize proteins within mitochondria.. |
| 7. | Amamoto, R., Yagi, M., Song, Y. H., Oda, Y., Tsuneyoshi, M., Naito, S., Yokomizo, A., Kuroiwa, K., Tokunaga, S., Kato, S., Hiura, H., Samori, T., Kang, D. & Uchiumi, T.,, Mitochondrial p32/C1QBP is highly expressed in prostate cancer and is associated with shorter prostate-specific antigen relapse time after radical prostatectomy, CANCER SCIENCE, 10.1111/j.1349-7006.2010.01828.x, 102, 3, 639-647, 2011.03. |
| 8. | Takayuki Ohnuma, Mikako Yagi, Takeshi Yamagami, Toki Taira, Yoichi Aso, Masatsune Ishiguro, Molecular cloning, functional expression, and mutagenesis of cDNA encoding rye (Secale cereale) seed chitinase-c, BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 66, 2, 277-284, 2002.02, We cloned a complete cDNA encoding rye seed chitinase-c, designated RSC-c, by rapid amplification of cDNA end and PCR procedures. The cDNA of RSC-c consists of 1,018 nucleotides and includes an open reading frame encoding a polypeptide of 266 amino acid residues. A recombinant RSC-c was produced by expression in Escherichia coli Origami(DE3) and purified. rRSC-c had almost the same chitinase activity toward glycolchitin and antifungal activity against Trichoderma sp. as the authentic RSC-c did. RSC-c mutants were subsequently constructed and characterized with respect to their chitinase and antifungal activities. Mutation of Glu67 to Gln completely abolished the chitinase activity and diminished the antifungal activity. Considerable decreases in both activities were observed in the mutations of Trp72 and Ser120 to Ala, and Glu89 to Gln. The roles of these residues in the catalytic event of RSC-c are discussed.. |
学会活動
学会大会・会議・シンポジウム等における役割
2022.11.09～2022.11.11, 日本生化学会, シンポジウム応募、開催.
2020.09.15～2020.09.15, 生化学会, シンポジウム発表.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2021年度～2023年度, 基盤研究(C), 代表, 老化に伴い発症するミトコンドリア関連性疾患の機能解析と予防治療.
2018年度～2020年度, 若手研究, 代表, ミトコンドリアがオートファジーを制御する新機構と老化随伴疾患代謝物の探索.
2014年度～2016年度, 若手研究(B), 代表, 大脳白質脳症疾患モデルマウスの病態解析と病因関連代謝物の探索.
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