新しい生体超分子S8環八超硫黄の発見と生理機能解明

• Project/Area Number: 22K19397
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Tohoku University
• Principal Investigator: 赤池 孝章 東北大学, 医学系研究科, 教授 (20231798)
• Co-Investigator(Kenkyū-buntansha): 吉沢 道人 東京工業大学, 科学技術創成研究院, 教授 (70372399)
• Project Period (FY): 2022-06-30 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2023: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 超硫黄分子 / S8硫黄 / 超硫黄分子カプセル

Outline of Research at the Start

驚くべきことに、火山地帯など極限環境に見られる環状化硫黄S8(環八超硫黄)が、ヒト・動物の生体内で積極的に合成され極めて豊富に検出された。これは、無機硫黄分子であるS8環八超硫黄が、生命進化論と生命現象に深く関わることを示す生物学・生命科学における極めて大きな発見である。本研究では、超硫黄分子カプセルを用いて新たに開発した超硫黄解析により、生体内S8の代謝経路その生理機能の全容を解明する。さらに、超硫黄分子カプセルの組織、細胞、オルガネラ(特に、ミトコンドリア)への選択的ターゲットとDDSにより、高等 生物において今回初めて発見されたS8超硫黄の真の生理機能を解明する。

Outline of Annual Research Achievements

驚くべきことに、火山地帯など極限環境に見られる環状八硫黄S8が、ヒト・動物の生体内で積極的に合成され極めて豊富に検出された。これは、無機硫黄分子であるS8が、生命進化論と生命現象に深く関わることを示す生物学・生命科学における極めて大きな発見である。本研究では、超硫黄分子カプセルを用いて新たに開発した超硫黄解析により、生体内S8の代謝経路その生理機能の全容を解明する。当該年度では、超硫黄分子カプセルを用いることにより、各種培養細胞系および動物組織(マウス・ヒト)におけるS8の細胞・生体内検出に成功した。加えて、細胞内に高濃度に生成・蓄積するS8は、ミトコンドリアのエネルギー代謝および脂質過酸化制御に関与していることを明らかにした。すなわち、マウス線維芽細胞MEFを超硫黄ドナーであるグルタチオントリスルフィドGSSSGで処理すると細胞内のS8レベルが顕著に上昇し、さらに、これは超硫黄の酸化代謝酵素であるSQR (sulfide:quione reductase)により代謝維持されていることを見出した。さらに、驚くべきことに、活性酸素産生酵素である NADPH oxidase (NOX)やNO合成酵素(NOS)が、実際は、NADPHの電子・プロトンを優先的に超硫黄GSSSGに渡して超硫黄の伸長反応(catenation, カテネーション)を触媒してS8産生酵素(S8 synthase)として機能していることを明らかにした。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

超硫黄分子カプセルを用いて新たに開発した超硫黄解析を行ったところ、広く自然界に存在する環化八硫黄S8が哺乳類・ヒトの生体内において、当初の想定を超える高濃度で蓄積していること、さらに、ミトコンドリアエネルギー代謝や脂質過酸化制御に関与することを明らかにした。本研究の当初目的である、生体内S8の代謝経路その生理機能の全容解明に関する知見をさらに深めることができ、研究はおおむね順調に進展していると評価できる。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] German Cancer Research Center/Helmholtz(ドイツ)
• [Int'l Joint Research] National Institute of Oncology(ハンガリー)
• [Int'l Joint Research] University of Vermont/Brown University(米国)
• [Int'l Joint Research] Birmingham(英国)
• [Int'l Joint Research] University of Vermont/University of Alabama at Birmingham/Sonoma State University(米国)
• [Int'l Joint Research] University of Southampton/King's College London(英国)
• [Int'l Joint Research] National Institute of Oncology(ハンガリー)
• [Journal Article] 2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels (2024)
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• [Journal Article] Redox regulation of xenobiotics by reactive sulfur and supersulfide species (2024)
  • Author(s): Zhang Tianli、Akaike Takaaki、Sawa Tomohiro
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• [Journal Article] Supersulfide biology and translational medicine for disease control (2023)
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  • Journal Title: Journal of Clinical Investigation Volume: 133 Issue: 17
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• [Journal Article] Persulfide biosynthesis conserved evolutionarily in all organisms (2023)
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  • DOI: 10.1089/ars.2023.0405
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• [Journal Article] Supersulfide catalysis for nitric oxide and aldehyde metabolism (2023)
  • Author(s): Kasamatsu Shingo、Nishimura Akira、Alam Md. Morshedul、Morita Masanobu、Shimoda Kakeru、Matsunaga Tetsuro、Jung Minkyung、Ogata Seiryo、Barayeu Uladzimir、Ida Tomoaki、Nishida Motohiro、Nishimura Akiyuki、Motohashi Hozumi、Akaike Takaaki
  • Journal Title: Science Advances Volume: 9 Issue: 33 Pages: 1-11
  • DOI: 10.1126/sciadv.adg8631
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• [Journal Article] Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop. (2023)
  • Author(s): Takeda H, Murakami S, Liu Z, Sawa T, Takahashi M, Izumi Y, Bamba T, Sato H, Akaike T, Sekine H, Motohashi H*.
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  • DOI: 10.1016/j.redox.2023.102834
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• [Journal Article] Supersulphides provide airway protection in viral and chronic lung diseases (2023)
  • Author(s): Matsunaga Tetsuro、Sano Hirohito、Takita Katsuya、Morita Masanobu、Yamanaka Shun、Ichikawa Tomohiro、Numakura Tadahisa、Ida Tomoaki、Jung Minkyung、Ogata Seiryo、Yoon Sunghyeon、Fujino Naoya、Kyogoku Yorihiko、Akaike Takaaki、et al.
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  • DOI: 10.1038/s41467-023-40182-4
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  • DOI: 10.1038/s41598-023-38696-4
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  • Author(s): Kasamatsu Shingo、Kinno Ayaka、Hishiyama Jun-ichi、Akaike Takaaki、Hideshi IharaIhara Hideshi
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  • DOI: 10.1016/j.foodchem.2023.135610
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• [Journal Article] Presence of <i>Helicobacter cinaedi</i> in Atherosclerotic Abdominal Aortic Aneurysmal Wall (2023)
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  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 261 Issue: 1 Pages: 35-41
  • DOI: 10.1620/tjem.2023.J049
  • ISSN: 0040-8727, 1349-3329
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• [Journal Article] Cystathionine γ-lyase self-inactivates by polysulfidation during cystine metabolism (2023)
  • Author(s): Araki Shoma、Takata Tsuyoshi、Ono Katsuhiko、Sawa Tomohiro、Kasamatsu Shingo、Ihara Hideshi、Kumagai Yoshito、Akaike Takaaki、Watanabe Yasuo、Tsuchiya Yukihiro
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 12 Pages: 9982-9982
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• [Journal Article] Reactive sulfur species omics analysis in the brain tissue of the 5xFAD mouse model of Alzheimer’s disease (2023)
  • Author(s): Kinno Ayaka、Kasamatsu Shingo、Akaike Takaaki、Ihara Hideshi
  • Journal Title: Antioxidants Volume: 12 Issue: 5 Pages: 1105-1105
  • DOI: 10.3390/antiox12051105
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• [Journal Article] Synthesis of sulfides and persulfides is not impeded by disruption of three canonical enzymes in sulfur metabolism (2023)
  • Author(s): Zainol Abidin Qamarul Hafiz、Ida Tomoaki、Morita Masanobu、Matsunaga Tetsuro、Nishimura Akira、Jung Minkyung、Hassan Naim、Takata Tsuyoshi、Ishii Isao、Kruger Warren、Wang Rui、Motohashi Hozumi、Tsutsui Masato、Akaike Takaaki
  • Journal Title: Antioxidants Volume: 12 Issue: 4 Pages: 868-868
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• [Journal Article] Polysulfide metabolizing enzymes influence SqrR-mediated sulfide-induced transcription by impacting intracellular polysulfide dynamics (2023)
  • Author(s): Shimizu Takayuki、Ida Tomoaki、Antelo Giuliano T、Ihara Yuta、Fakhoury Joseph N、Masuda Shinji、Giedroc David P、Akaike Takaaki、Capdevila Daiana A、Masuda Tatsuru
  • Journal Title: PNAS Nexus Volume: 2 Issue: 3 Pages: 1-11
  • DOI: 10.1093/pnasnexus/pgad048
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• [Journal Article] Contribution of NRF2 to sulfur metabolism and mitochondrial activity (2023)
  • Author(s): Alam Md Morshedul、Kishino Akihiro、Sung Eunkyu、Sekine Hiroki、Abe Takaaki、Murakami Shohei、Akaike Takaaki、Motohashi Hozumi
  • Journal Title: Redox Biology Volume: 60 Pages: 102624-102624
  • DOI: 10.1016/j.redox.2023.102624
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• [Journal Article] Echinochrome prevents sulfide catabolism-associated chronic heart failure after myocardial infarction in mice (2023)
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  • Journal Title: Marine Drugs Volume: 21 Issue: 1 Pages: 52-52
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• [Journal Article] Cysteine hydropersulfide reduces lipid peroxidation and protects against myocardial ischaemia-reperfusion injury - Are endogenous persulfides mediators of ischaemic preconditioning? (2023)
  • Author(s): Griffiths Kayleigh、Ida Tomoaki、Morita Masanobu、Lamb Reece J.、Lee Jordan J.、Frenneaux Michael P.、Fukuto Jon M.、Akaike Takaaki、Feelisch Martin、Madhani Melanie
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  • DOI: 10.1016/j.redox.2023.102605
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  • DOI: 10.1016/j.isci.2022.104050
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• [Presentation] Supersulfide redox biology in life science and its translational medicine for disease control (2024)
  • Author(s): Takaaki Akaike
  • Organizer: International Symposium “Signals for Human, Animal and Planetary Health: From Metabolites To Biological Interactions” (Tokyo Univ.)
  • Int'l Joint Research / Invited
• [Presentation] 超硫黄分子のラマン分光イメージングを駆使した定量分析 (2023)
  • Author(s): 赤池 孝章
  • Organizer: CREST「多細胞」領域，第5回領域会議プログラム・連携課題（浜松）（招待講演）
  • Invited
• [Presentation] Supersulfides-mediated cellular protection from lipid oxidation and ferroptosis (2023)
  • Author(s): Takaaki Akaike
  • Organizer: 3rd Annual Meeting of the DFG founded Priority Programme (Heidelberg, Germany)
  • Int'l Joint Research / Invited
• [Presentation] 超硫黄分子の発見と生理機能の解明 (2023)
  • Author(s): 赤池孝章
  • Organizer: 第96回日本生化学会大会・特別講演 (福岡)
  • Invited
• [Presentation] 定量的超硫黄オミックス・イメージング技術の開発と標準化プロトコールの確立 (2023)
  • Author(s): 赤池 孝章
  • Organizer: 学術変革領域研究(A) 「硫黄生物学」第3回領域会議・超硫黄フロンティアシンポジウム2023（熊本）
• [Presentation] Supersulfide biology and translational medicine for disease control (2023)
  • Author(s): Takaaki Akaike
  • Organizer: Chemical Biology/Redox Biology Seminar (Rhode Island, USA)
  • Int'l Joint Research / Invited
• [Presentation] 超硫黄分子によるエネルギー産生と過酸化脂質・カルボニル代謝制御 (2023)
  • Author(s): 赤池孝章
  • Organizer: 名古屋大学大学院生命農学研究科・特別セミナー（名古屋）
  • Invited
• [Presentation] 活性酸素シグナル~酸素生物学~そして硫黄生物学：三つの領域のレドックス生命科学研究から俯瞰される世界 (2023)
  • Author(s): 赤池孝章
  • Organizer: 第96回日本細菌学会総会(姫路)
  • Invited
• [Presentation] Nitric Oxide Synthases, a New Family of NADPH-Dependent Sulfur Oxidoreductases (2023)
  • Author(s): Takaaki Akaike
  • Organizer: Nitric Oxide Gordon Research Conference
  • Int'l Joint Research / Invited
• [Presentation] 空間生体情報メタオミックス解析と呼気医療 (2023)
  • Author(s): 赤池孝章
  • Organizer: JASIS関西2023トピックスセミナー
  • Invited
• [Presentation] 環化超硫黄分子の生体内検出と機能解明 (2023)
  • Author(s): 赤池孝章
  • Organizer: CREST多細胞領域 第4回領域会議プログラム
  • Invited
• [Presentation] Physiological formation and function of new supersulfide, cyclic octa-sulfur in mammals (2023)
  • Author(s): Takaaki Akaike
  • Organizer: 3rd STINT-JSPS Redox Biology Conference
  • Int'l Joint Research / Invited
• [Presentation] The physiological functions of cyclic octa-sulfur (S8) formed endogenously in diverse organisms including mammals (2022)
  • Author(s): Takaaki Akaike
  • Organizer: Redox week in Sendai 2022
  • Int'l Joint Research / Invited
• [Presentation] Sulfur biology and redox signaling in energy metabolism, infection, and immunity (2022)
  • Author(s): Takaaki Akaike
  • Organizer: The 15th Korea-Japan International Symposium on Microbiology
  • Int'l Joint Research / Invited
• [Presentation] 呼気オミックスから空間バイオミックスへの新展開 (2022)
  • Author(s): 赤池孝章
  • Organizer: レドックス R&D 戦略委員会第3回企画シンポジウム
  • Invited
• [Presentation] Cyclo-octasulfur, S8, formed endogenously in mammals: its biosynthesis and physiological functions (2022)
  • Author(s): Takaaki Akaike
  • Organizer: GRC “Thiol-Based Redox Regulation and Signaling: The Chemical Biology of Sulfur”
  • Int'l Joint Research / Invited
• [Presentation] Reactive persulfide regulation of redox signaling and immune response (2022)
  • Author(s): Takaaki Akaike
  • Organizer: 6th World Congress on Hydrogen Sulfide in Biology & Medicine Keynote Lecture, Molecular Mechanisms
  • Int'l Joint Research / Invited
• [Book] 呼吸器疾患最新の治療2025-2026（超硫黄分子による呼吸器疾患制御と呼気オミックス） (2024)
  • Author(s): 緒方星陵, 松永哲郎, 赤池孝章
  • Total Pages: 6
  • Publisher: 南江堂
• [Book] 酸化ストレスの医学 改訂第３版（超硫黄分子の化学と生理機能） (2024)
  • Author(s): 緒方星陵, Uladzimir Barayeu, 赤池孝章
  • Total Pages: 7
  • Publisher: 診断と治療社
• [Book] ［特集］環境化学物質と生体応答 (2023)
  • Author(s): 赤池孝章
  • Total Pages: 56
  • Publisher: Medical Science Digest
• [Book] 環境物質と生命の起源：超硫黄生物学プロローグ (2023)
  • Author(s): 松永哲郎, 赤池孝章
  • Total Pages: 5
  • Publisher: Medical Science Digest
• [Remarks] 東北大学大学院医学系研究科環境医学分野ホームページ
  • URL: http://www.toxicosci.med.tohoku.ac.jp/index.html
• [Remarks] Research Mapマイポータル
  • URL: https://researchmap.jp/AkaikeT
• [Remarks] 「島津製作所×東北大学 超硫黄生命科学共創研究所」を設置
  • URL: https://www.tohoku.ac.jp/japanese/2024/03/press20240313-04-shimazu.html
• [Remarks] 「超硫黄分子」の寿命延長効果を発見 ～新たなサプリメントや健康法の開発に期待～
  • URL: https://www.tohoku.ac.jp/japanese/2024/01/press20240119-01-supersulfides.html
• [Remarks] 東北大学大学院医学系研究科環境医学分野ホームページ
  • URL: http://www.toxicosci.med.tohoku.ac.jp/
• [Remarks] Researchmap マイポータルページ
  • URL: https://researchmap.jp/AkaikeT
• [Remarks] 学術変革領域研究(A) 新興硫黄生物学が拓く生命原理変革(硫黄生物学)ホームページ
  • URL: https://supersulfide-proj.com/
• [Remarks] 咳の流量2倍で約100倍の微小なエアロゾルが発生!?
  • URL: http://www.tohoku.ac.jp/japanese/2022/09/press20220926-03-cough.html
• [Funded Workshop] The 1st International G-ReXS Conference in Sendai (2024)
• [Funded Workshop] Redox week in Sendai 2022 (2022)