Polysulfur metabolome and regulation of anti-oxidative stress responses

2018 Fiscal Year Annual Research Report

• Project Area: Oxygen biology: a new criterion for integrated understanding of life
• Project/Area Number: 26111008
• 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): 渡辺 泰男 昭和薬科大学, 薬学部, 教授 (10273228) ; 澤 智裕 熊本大学, 大学院生命科学研究部(医), 教授 (30284756) ; 朽津 和幸 東京理科大学, 理工学部応用生物科学科, 教授 (50211884)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 活性酸素 / 代謝 / ケミカルバイオロジー / メタボローム / 抗酸化

Outline of Annual Research Achievements

本研究では、システインのイオウ付加体であるシステインパースルフィドをはじめとする活性ポリスルフィドの生理機能に注目し、メタボローム解析手法（ポリサルファメタボローム）を駆使して、動物および植物における活性イオウ・ポリサルファ系のユニークな抗酸化制御システムの全貌を解明することを目的としている。昨年度までの研究において活性ポリスルフィドを網羅的かつ定量的に測定するメタボローム解析系を確立して、生体内に存在する様々な活性イオウ分子種の検出と動態解析、代謝経路と生理機能解析を行い、システイン-tRNA合成酵素（CARS）によるタンパク質翻訳に共役した新規ポリスルフィド生成系を同定し、ミトコンドリア型のCARS2が生成するパースルフィドがミトコンドリアの酸素消費速度や膜電位形成の制御に深く関わることが示された。本年度は、ポリスルフィド生成の生理学的機能についての詳細な解析を行った。ミトコンドリア型CARS2のノックアウト細胞の解析から、CARS2由来パースルフィドはミトコンドリア形態形成にも関わっており、哺乳類細胞においてミトコンドリアの分裂に中心的な役割を果たすDrp1 (dynamin-related protein 1)の酵素活性がタンパク質ポリスルフィド化によって制御されていることが分かった。また、CARS2によるイオウ代謝プロファイルを詳細に解析した結果、CARS2により生成されるパースルフィドは電子伝達系から電子を授受し、硫化水素(H2S)へと代謝・還元することが示唆された。さらに、イオウ代謝産物であるH2Sの代謝経路としてSQR (sulfide:quinone oxidoreductase)によるプロトン供与を介したミトコンドリア膜電位形成が認められ、ミトコンドリアの電子伝達およびエネルギー産生における活性ポリスルフィドおよびイオウ代謝経路の関与が示唆された。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] National Institute of Oncology(ハンガリー)
  • Country Name: HUNGARY
  • Counterpart Institution: National Institute of Oncology
• [Int'l Joint Research] Sonoma State University/University of Vermont/University of Alabama at Birmingham(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Sonoma State University/University of Vermont/University of Alabama at Birmingham
• [Int'l Joint Research] University of Southampton/King's College London(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Southampton/King's College London
• [Journal Article] Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension. (2019)
  • Author(s): Rudyk O, Rowan A, Prysyazhna O, Krasemann S, Hartmann K, Zhang M, Shah MA, Ruppert C, Weiss A, Schermuly RT, Ida T, Akaike T, Zhao L, Eaton P.
  • Journal Title: Proc Natl Acad Sci USA Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock. (2019)
  • Author(s): Zhang T, Ono K, Tsutsuki H, Ihara H, Islam W, Akaike T, Sawa T.
  • Journal Title: Cell Chem Biol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.chembiol.2019.02.003.
  • Peer Reviewed
• [Journal Article] The active-site cysteine residue of Ca2+/calmodulin-dependent protein kinase I is protected from irreversible modification via generation of polysulfidation. (2019)
  • Author(s): Takata T, Tsukuda A, Tsuchiya Y, Akaike T, Watanabe Y.
  • Journal Title: Nitric Oxide Volume: 86 Pages: 68-75
  • DOI: 10.1016/j.niox.2019.02.008.
  • Peer Reviewed
• [Journal Article] 8-Nitro-cGMP attenuates context-dependent fear memory in mice. (2019)
  • Author(s): Kishimoto Y, Kasamatsu S, Yanai S, Endo S, Akaike T, Ihara H.
  • Journal Title: Biochem Biophys Res Commun Volume: 511 Pages: 141-147
  • DOI: 10.1016/j.bbrc.2019.01.138.
  • Peer Reviewed
• [Journal Article] The Uptake and Release of Polysulfur Cysteine Species by Cells: Physiological and Toxicological Implications. (2019)
  • Author(s): Lin J, Akiyama M, Bica I, Long FT, Henderson CF, Goddu RN, Suarez V, Baker B, Ida T, Shinkai Y, Nagy P, Akaike T, Fukuto JM, Kumagai Y.
  • Journal Title: Chem Res Toxicol Volume: 32 Pages: 447-455
  • DOI: 10.1021/acs.chemrestox.8b00340.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis. (2019)
  • Author(s): Hamid HA, Tanaka A, Ida T, Nishimura A, Matsunaga T, Fujii S, Morita M, Sawa T, Fukuto JM, Nagy P, Tsutsumi R, Motohashi H, Ihara H, Akaike T.
  • Journal Title: Redox Biol Volume: 21 Pages: 101096
  • DOI: 10.1016/j.redox.2019.101096.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Production of 8-nitro-cGMP in osteocytic cells and its upregulation by parathyroid hormone and prostaglandin E2. (2019)
  • Author(s): Nagayama K, Miyamoto Y, Kaneko K, Yoshimura K, Sasa K, Akaike T, Fujii S, Izumida E, Uyama R, Chikazu D, Maki K, Kamijo R.
  • Journal Title: In Vitro Cell Dev Biol Anim Volume: 55 Pages: 45-51
  • DOI: 10.1007/s11626-018-0304-0.
  • Peer Reviewed
• [Journal Article] SNAP-25 S-Guanylation and SNARE Complex Formation. (2019)
  • Author(s): Kishimoto Y, Akaike T, Ihara H.
  • Journal Title: Methods Mol Biol Volume: 1860 Pages: 163-173
  • DOI: 10.1007/978-1-4939-8760-3_9.
  • Peer Reviewed
• [Journal Article] Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell? (2019)
  • Author(s): Bogdandi V, Ida T, Sutton TR, Bianco C, Ditroi T, Koster G, Henthorn HA, Minnion M, Toscano JP, van der Vliet A, Pluth MD, Feelisch M, Fukuto JM, Akaike T, Nagy P.
  • Journal Title: Br J Pharmacol Volume: 176 Pages: 646-670
  • DOI: 10.1111/bph.14394.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems. (2019)
  • Author(s): Bianco CL, Akaike T, Ida T, Nagy P, Bogdandi V, Toscano JP, Kumagai Y, Henderson CF, Goddu RN, Lin J, Fukuto JM.
  • Journal Title: Br J Pharmacol Volume: 176 Pages: 671-683
  • DOI: 10.1111/bph.14372.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells. (2019)
  • Author(s): Fujii S, Sawa T, Motohashi H, Akaike T.
  • Journal Title: Br J Pharmacol Volume: 176 Pages: 607-615
  • DOI: 10.1111/bph.14356.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. (2018)
  • Author(s): Nishimura A, Shimauchi T, Tanaka T, Shimoda K, Toyama T, Kitajima N, Ishikawa T, Shindo N, Numaga-Tomita T, Yasuda S, Sato Y, Kuwahara K, Kumagai Y, Akaike T, Ide T, Ojida A, Mori Y, Nishida M.
  • Journal Title: Sci Signal Volume: 11 Pages: eaat5185
  • DOI: 10.1126/scisignal.aat5185.
  • Peer Reviewed
• [Journal Article] Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling. (2018)
  • Author(s): Khan S, Fujii S, Matsunaga T, Nishimura A, Ono K, Ida T, Ahmed KA, Okamoto T, Tsutsuki H, Sawa T, Akaike T.
  • Journal Title: Cell Chem Biol Volume: 25 Pages: 1403-1413.e4.
  • DOI: 10.1016/j.chembiol.2018.08.007.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biological hydropersulfides and related polysulfides - a new concept and perspective in redox biology. (2018)
  • Author(s): Fukuto JM, Ignarro LJ, Nagy P, Wink DA, Kevil CG, Feelisch M, Cortese-Krott MM, Bianco CL, Kumagai Y, Hobbs AJ, Lin J, Ida T, Akaike T.
  • Journal Title: FEBS Lett Volume: 592 Pages: 2140-2152
  • DOI: 10.1002/1873-3468.13090.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Reactive sulfur species (RSS) mediate sulfur respiration in mitochondria and redox signaling (2019)
  • Author(s): Akaike T.
  • Organizer: 第 7 回 IRG(Inflammation and ReGeneration)Meeting（東京）
  • Invited
• [Presentation] Cysteine persulfide synthases mediate sulfur respiration and energy metabolism (2019)
  • Author(s): Akaike T.
  • Organizer: The Kick-off Symposium of Advanced Graduate Program for Future Medicine and Health Care（仙台）
  • Int'l Joint Research / Invited
• [Presentation] Chemical biology of reactive sulfur species and its metabolome analysis (2018)
  • Author(s): Akaike T.
  • Organizer: 2018 Annual Medical Technology Conference 3rd Annual Conference New Frontiers in Mass Spectrometry Clinical and Biomedical Applications（タイ）
  • Int'l Joint Research / Invited
• [Presentation] ミトコンドリアのイオウ呼吸とイオウストレス (2018)
  • Author(s): 赤池孝章
  • Organizer: 山形分子生物研究会（山形）
  • Invited
• [Presentation] 新しいエネルギー代謝機構：イオウ呼吸の発見と生理機能解明 (2018)
  • Author(s): 赤池孝章
  • Organizer: 平成30年度東北大学医学系病理同窓会特別公演（仙台）
  • Invited
• [Presentation] Translation-coupled persulfide synthases (PERSs) involved critically in sulfur respiration and energy metabolism (2018)
  • Author(s): Akaike T.
  • Organizer: 10th Internatinal Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide（イギリス）
  • Int'l Joint Research / Invited
• [Presentation] Persulfide synthase coupled with translation mediates sulfur respiration in mammals (2018)
  • Author(s): Akaike T.
  • Organizer: KCL Redox Biology & Medicine Symposium（イギリス）
  • Int'l Joint Research / Invited
• [Presentation] Sulfur respiration as a target for mitochondrial disease (2018)
  • Author(s): 赤池孝章
  • Organizer: 7 SEAS PROJECT Research meeting 2018（東京）
  • Invited
• [Presentation] イオウ呼吸：レドックス研究の新たなパラダイム (2018)
  • Author(s): 赤池孝章
  • Organizer: Free Radical Summer School 2018（群馬）
  • Invited
• [Presentation] Cysteine persulfide synthases coupled with translation mediate sulfur respiration and redox signaling (2018)
  • Author(s): Akaike T.
  • Organizer: The 43rd FEBS Congress（トルコ）
  • Int'l Joint Research / Invited
• [Presentation] Cysteinyl-tRNA synthetase (CARS) controls endogenous hydropersulfide production and mitochondrial respiration （ (2018)
  • Author(s): Akaike T.
  • Organizer: The 19th biennial meeting for the Society for Free Radical Research International (SFRRI)（ポルトガル）
  • Int'l Joint Research / Invited
• [Book] 活性イオウ分子によるエネルギー代謝制御 (2019)
  • Author(s): 西村 明、本橋ほづみ、赤池孝章
  • Total Pages: 6 (Vol. 43, 7-12)
  • Publisher: 基礎老化研究
• [Book] 活性イオウ分子：システインパースルフィドの新規生合成経路の発見とその生理機能 (2018)
  • Author(s): 西村 明、赤池孝章
  • Total Pages: 2 (Vol.56 No.8, 518-519)
  • Publisher: 化学と生物
• [Book] ポリスルフィド化 (2018)
  • Author(s): 西村 明、井田智章、赤池孝章
  • Total Pages: 2 (Vol.69 No.5, 448-449)
  • Publisher: 生体の科学
• [Book] SH(ポリスルフィド)の酸化 (2018)
  • Author(s): 西村 明、井田智章、赤池孝章
  • Total Pages: 2 (Vol.69 No.5, 446-447)
  • Publisher: 生体の科学
• [Book] 哺乳類におけるイオウ呼吸の発見 (2018)
  • Author(s): 西村 明、赤池孝章
  • Total Pages: 2 (Vol.267 No.7, 532-533)
  • Publisher: 医学のあゆみ
• [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/