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Faculty of Medicine School of Medicine Department of Medical Sciences, Biochemistry and Molecular Biology |
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Related SDGs |
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NISHITOH Hideki
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Research Areas 【 display / non-display 】
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Life Science / Medical biochemistry
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Life Science / Cell biology / オルガネラ
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Life Science / Pathological biochemistry
Education 【 display / non-display 】
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Tokyo Medical and Dental University Graduate School, Division of Dental Research
- 1997.3
Country：Japan
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Tokyo Medical and Dental University Faculty of Dentistry
- 1993.3
Country：Japan
Professional Memberships 【 display / non-display 】
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日本学術振興会
2018.7
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日本神経化学会
2017.9
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日本細胞生物学会
2012.4
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日本薬学会
2011.2
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日本Cell Death学会
2008.4
Papers 【 display / non-display 】
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ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress Reviewed International coauthorship
Shiiba I., Ito N., Oshio H., Ishikawa Y., Nagao T., Shimura H., Oh K.W., Takasaki E., Yamaguchi F., Konagaya R., Kadowaki H., Nishitoh H., Tanzawa T., Nagashima S., Sugiura A., Fujikawa Y., Umezawa K., Tamura Y., Il Lee B., Hirabayashi Y., Okazaki Y., Sawa T., Inatome R., Yanagi S.
Nature Communications 16 ( 1 ) 1508 2025.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications
The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.
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Etomoxir suppresses the expression of PPARgamma2 and inhibits the thermogenic gene induction of brown adipocytes through pathways other than β-oxidation inhibition. Reviewed
Shimura H, Yamamoto S, Shiiba I, Oikawa M, Uchinomiya S, Ojida A, Yanagi S, Kadowaki H, Nishitoh H, Fukuda T, Nagashima S, Yamaguchi T
Journal of biochemistry 177 ( 3 ) 203 - 212 2024.12
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The Derlin-1-Stat5b axis maintains homeostasis of adult hippocampal neurogenesis. Reviewed
Murao N, Matsuda T, Kadowaki H, Matsushita Y, Tanimoto K, Katagiri T, Nakashima K, Nishitoh H
EMBO reports 25 ( 8 ) 3678 - 3706 2024.7
Authorship：Last author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：EMBO Reports
Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.
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Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones. Invited Reviewed
Sugiyama T, Nishitoh H
Journal of biochemistry 176 ( 3 ) 179 - 186 2024.7
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Biochemistry
Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.
DOI： 10.1093/jb/mvae048
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Chemical chaperones ameliorate neurodegenerative disorders in Derlin-1-deficient mice via improvement of cholesterol biosynthesis. Reviewed International journal
Takashi Sugiyama, Naoya Murao, Hisae Kadowaki, Hideki Nishitoh
Scientific reports 12 ( 1 ) 21840 - 21840 2022.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
There are no available therapies targeting the underlying molecular mechanisms of neurodegenerative diseases. Although chaperone therapies that alleviate endoplasmic reticulum (ER) stress recently showed promise in the treatment of neurodegenerative diseases, the detailed mechanisms remain unclear. We previously reported that mice with central nervous system-specific deletion of Derlin-1, which encodes an essential component for ER quality control, are useful as models of neurodegenerative diseases such as spinocerebellar degeneration. Cholesterol biosynthesis is essential for brain development, and its disruption inhibits neurite outgrowth, causing brain atrophy. In this study, we report a novel mechanism by which chemical chaperones ameliorate brain atrophy and motor dysfunction. ER stress was induced in the cerebella of Derlin-1 deficiency mice, whereas the administration of a chemical chaperone did not alleviate ER stress. However, chemical chaperone treatment ameliorated cholesterol biosynthesis impairment through SREBP-2 activation and simultaneously relieved brain atrophy and motor dysfunction. Altogether, these findings demonstrate that ER stress may not be the target of action of chaperone therapies and that chemical chaperone-mediated improvement of brain cholesterol biosynthesis is a promising novel therapeutic strategy for neurodegenerative diseases.
Books 【 display / non-display 】
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疾患研究につながるオルガネラ実験必携プロトコール「概論ー小胞体の機能と品質管理システム」
西頭英起（ Role： Sole author）
羊土社 実験医学別冊 2024.11
Language：Japanese Book type：Scholarly book
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ヒトゲノム辞典
西頭英起、他多数（ Role： Joint author , 小胞体シャペロンと調節因子 15章12 P232-234）
一色出版 2021.11
Language：Japanese Book type：Dictionary, encyclopedia
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ミトコンドリアダイナミクス～機能研究から疾患・老化まで～
西田卓人, 西頭英起（ Role： Sole author , 「ミトコンドリア-小胞体連携ゾーンにおけるストレス応答」第5章2節 ）
NTS 2021.11
Language：Japanese Book type：Textbook, survey, introduction
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脂肪滴と様々なオルガネラとの接触
加藤裕紀, 西頭英起（ Role： Joint author , 脂肪滴と様々なオルガネラとの接触 168:1-5）
同仁化学研究所 2019.3
Language：Japanese
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タンパク質・核酸の分子修飾「NEDD化」
加藤 裕紀, 西頭 英起（ Role： Sole author）
生体の科学 2018.10
Language：Japanese Book type：Scholarly book
MISC 【 display / non-display 】
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褐色脂肪細胞の熱産生とエネルギー代謝
西頭英起
「臨床免疫・アレルギー科」科学評論社 2021.2
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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小胞体から発信されるストレスシグナルによるミトコンドリア制御 Invited
加藤裕紀, 西頭英起
「ミトコンドリアと疾患・老化」実験医学増刊 37 45 - 51 2019.7
Authorship：Corresponding author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
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【タンパク質・核酸の分子修飾】細胞質/オルガネラでの分子修飾 タンパク質機能・品質管理 NEDD化
加藤 裕紀, 西頭 英起
生体の科学 69 ( 5 ) 460 - 461 2018.10
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution) Publisher：(公財)金原一郎記念医学医療振興財団
<文献概要>ユビキチン様タンパク質NEDD8による翻訳後修飾NEDD化は,標的タンパク質の安定化,活性化,局在化などに関与する.加えて,近年NEDD化修飾は,転写,細胞周期制御,クロマチン構成,ストレス顆粒形成などにも重要な役割を果たしている.本稿では,NEDD8修飾システムおよびその機能,がんとの関連性を概説する.
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成体ニューロン新生を介した記憶学習制御における小胞体品質管理機構の役割
村尾直哉, 西頭英起
Pharma Medica 35 ( 12 ) 93 - 93 2017.12
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution) Publisher：(株)メディカルレビュー社
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プロテオスタシス制御の新展開と疾患 ミトコンドリア-小胞体間のオルガネラ連携による細胞機能制御
西頭 英起
生命科学系学会合同年次大会 2017年度 [2AW19 - 5] 2017.12
Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution) Publisher：生命科学系学会合同年次大会運営事務局
Presentations 【 display / non-display 】
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Endoplasmic reticulum quality control system and neurodegenerative diseases resulting from its disruption Invited International conference
Hideki Nishitoh
APPW2025 2025.3.17
Event date： 2025.3.17 - 2025.3.19
Presentation type：Symposium, workshop panel (nominated)
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小胞体品質管理システムとその破綻による脳神経疾患 Invited
西頭英起
日本薬学会九州山口支部コロキウム 2024.10.19
Event date： 2024.10.19
Language：Japanese Presentation type：Symposium, workshop panel (nominated)
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小胞体膜分子によって制御される脳の形態と機能
西頭英起
第17回小胞体ストレス研究会 2024.9.13
Event date： 2024.9.13 - 2024.9.14
Language：Japanese Presentation type：Oral presentation (general)
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小胞体ストレス依存的な翻訳時分解を介したタンパク質品質維持機構
門脇寿枝、西頭英起
第76回日本細胞生物学会大会
Event date： 2024.7.17 - 2024.7.19
Language：Japanese Presentation type：Oral presentation (general)
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小胞体ホメオスタシスと脳疾患 Invited
西頭英起
最先端細胞医科学ｼﾝﾎﾟｼﾞｳﾑ-小胞体ストレスと疾患- 2024.3.7
Event date： 2024.3.7
Language：Japanese Presentation type：Symposium, workshop panel (nominated)
Industrial property rights 【 display / non-display 】
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プローブ、ミトコンドリアの状態判定用キット、ミトコンドリアの状態判定方法及びミトコンドリア機能改善剤のスクリーニング方法
西頭 英起,加藤 裕紀
Applicant：宮崎大学
Application no：2019-205891 Date applied：2019.11.14
Announcement no：特開2020-098199 Date announced：2020.6.25
Patent/Registration no：7353631 Date registered：2023.9.22
Country of applicant：Domestic
Grant-in-Aid for Scientific Research 【 display / non-display 】
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ストレス依存的なタンパク質オルガネラ局在変化を規定する法則の探求
Grant number：24K21975 2024.04 - 2027.03
独立行政法人日本学術振興会 科学研究費基金 挑戦的研究（萌芽）
Authorship：Principal investigator
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病態脳における小胞体プロテオスタシス破綻によるコレステロール合成不全と脳萎縮
Grant number：23K24215 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費基金 基盤研究(B)
Authorship：Principal investigator
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細菌のPUP化を応用した真核細胞のユビキチンリガーゼ基質同定法の確立
Grant number：20K21401 2020.07 - 2022.03
科学研究費補助金 挑戦的研究(萌芽)
Authorship：Principal investigator
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口腔がん幹細胞におけるオルガネラストレス応答の役割の解明
Grant number：18H02973 2018.04 - 2021.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
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小胞体-ミトコンドリア接触場における温度センシング機構の解明
Grant number：18H04699 2018 - 2020.03
科学研究費補助金 新学術領域研究
Authorship：Principal investigator
Joint research activities 【 display / non-display 】
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Identification of the role of ER-mitochondrial crosstalk signaling in lipodystrophy
2018.04 - 2019.03
Identification of the role of ER-mitochondrial crosstalk signaling in lipodystrophy Collaboration in Japan
Authorship：Principal investigator Joint research type：Collaboration in Japan
Other research activities 【 display / non-display 】
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第18回臨床ストレス応答学会大会
2024.11
学会主催
Available Technology 【 display / non-display 】
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細胞の機能をナノレベルで理解する
メタボリックシンドロームに関する研究
脳神経疾患に関する研究Related fields where technical consultation is available：化合物や機能性食品抽出物などのライブラリースクリーニング
Message：化合物や生体物質で、疾患に応用できるかもしれないものがございましたら、ご相談ください。生体や細胞への活性を調べるお手伝いをいたします。