Polysulfur metabolome and regulation of anti-oxidative stress responses

2017 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, 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、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ってきた。本年度は、システイン-tRNA合成酵素（CARS）による翻訳に共役した新規ポリスルフィド生成系について、ポリスルフィド生成の分子メカニズムおよびその生理学的機能についての解析を行った。細菌および哺乳類の各種CARSの解析から、CARSがシステインを基質としてシステインパースルフィドを産生することが分かった。CARSのパースルフィド産生活性は細菌などの原核生物から哺乳類を含めた真核生物まで種横断的に保存されており、パースルフィド合成活性とCARS本来のシステイニルtRNA合成活性とは異なる活性部位が司っていることが明らかになった。さらに、ミトコンドリア型のCARS2のノックアウト細胞の解析から、CARS2が産生するパースルフィドは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っており、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の関与が示唆された。ポリスルフィドによるミトコンドリアのエネルギー産生制御の分子機構について今後さらに詳細な解析を進め、生体内ポリスルフィドの生理機能の解明向けた研究を進めていく。

Current Status of Research Progress

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

Reason

活性イオウ・ポリサルファの生理機能解明に関する当初の研究目的および研究計画に沿って研究を進めることができており、おおむね予定通りの実験・解析の遂行と研究成果を得ることができているため。

Strategy for Future Research Activity

本研究の当初の目的と計画に沿って順調に研究が進展し研究成果が得られており、研究を進める上で問題となるような事項は特にない。今後は、ひきつづき、新しく発見したシステイン-tRNA合成酵素によるポリスルフィド生成系の役割の解明を中心として、当初計画通り、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解明に向けた研究を推進していく。

Research Products

• [Int'l Joint Research] National Institute of Oncology(Hungary)
  • Country Name: Hungary
  • Counterpart Institution: National Institute of Oncology
• [Int'l Joint Research] University of Southampton(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Southampton
• [Int'l Joint Research] Sonoma State University/University of Vermont(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Sonoma State University/University of Vermont
• [Int'l Joint Research] German Cancer Research Center(Germany)
  • Country Name: Germany
  • Counterpart Institution: German Cancer Research Center
• [Journal Article] Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons (2018)
  • Author(s): Masuda K, Tsutsuki H, Kasamatsu S, Ida T, Takata T, Sugiura K, Nishida M, Watanabe Y, Sawa T, Akaike T, Ihara H.
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Pages: 2165～2170
  • DOI: 10.1016/j.bbrc.2017.12.088
  • Peer Reviewed
• [Journal Article] 8-Nitro-cGMP is a promoter of osteoclast differentiation induced by RANKL (2018)
  • Author(s): Kaneko K, Miyamoto Y, Tsukuura R, Sasa K, Akaike T, Fujii S, Yoshimura K, Nagayama K, Hoshino M, Inoue S, Maki K, Baba K, Chikazu D, Kamijo R.
  • Journal Title: Nitric Oxide Volume: 72 Pages: 46～51
  • DOI: 10.1016/j.niox.2017.11.006
  • Peer Reviewed
• [Journal Article] Important role of endothelial caveolin-1 in the protective role of endothelium-dependent hyperpolarization against nitric oxide-mediated nitrative stress in microcirculation in mice (2018)
  • Author(s): Saito H, Godo S, Sato S, Ito A, Ikumi Y, Tanaka S, Ida T, Fujii S, Akaike T, Shimokawa H.
  • Journal Title: J Cardiovasc Pharmacol Volume: 71 Pages: 113～126
  • DOI: 10.1097/FJC.0000000000000552
  • Peer Reviewed
• [Journal Article] 8-Nitro-cGMP attenuates the interaction between SNARE complex and complexin through S-guanylation of SNAP-25 (2018)
  • Author(s): Kishimoto Y, Kunieda K, Kitamura A, Kakihana Y, Akaike T, Ihara H.
  • Journal Title: ACS Chem Neurosci Volume: 9 Pages: 217～223
  • DOI: 10.1021/acschemneuro.7b00363
  • Peer Reviewed
• [Journal Article] Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling? (2018)
  • Author(s): Heppner DE, Hristova M, Ida T, Mijuskovic A, Dustin CM, Bogdandi V, Fukuto JM, Dick TP, Nagy P, Li J, Akaike T, van der Vliet A.
  • Journal Title: Redox Biol Volume: 14 Pages: 379～385
  • DOI: 10.1016/j.redox.2017.10.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persulfide synthases function coupled with translation and mediate sulfur respiration (2018)
  • Author(s): Fujii S, Sawa T, Motohashi H, Akaike T.
  • Journal Title: Br J Pharmacol Volume: - Pages: -
  • Peer Reviewed
• [Journal Article] 概論 レドックス疾患学：レドックス制御の破綻による病態と新たな疾患概念 (2018)
  • Author(s): 本橋ほづみ、赤池孝章、内田浩二、末松 誠.
  • Journal Title: 実験医学増刊「レドックス疾患学」 Volume: 36 Pages: 642-648
• [Journal Article] 活性イオウによる生体防御応答、エネルギー代謝と寿命制御 (2018)
  • Author(s): 澤 智裕、赤池孝章.
  • Journal Title: 実験医学増刊「レドックス疾患学」 Volume: 36 Pages: 649-655
• [Journal Article] 硫黄呼吸の発見：ペルスルフィド産生酵素による新しいエネルギー代謝 (2018)
  • Author(s): 西村 明、赤池孝章.
  • Journal Title: 現代化学 Volume: 565 Pages: 55-59
• [Journal Article] Synthesis of L-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome (2017)
  • Author(s): Ono K, Jung M, Zhang T, Tsutsuki H, Sezaki H, Ihara H, Wei FY, Tomizawa K, Akaike T, Sawa T.
  • Journal Title: Free Radic Biol Med Volume: 106 Pages: 69～79
  • DOI: 10.1016/j.freeradbiomed.2017.02.023
  • Peer Reviewed
• [Journal Article] Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach (2017)
  • Author(s): Ikeda M, Ishima Y, Shibata A, Chuang VTG, Sawa T, Ihara H, Watanabe H, Xian M, Ouchi Y, Shimizu T, Ando H, Ukawa M, Ishida T, Akaike T, Otagiri M, Maruyama T.
  • Journal Title: Anal Chim Acta Volume: 969 Pages: 18～25
  • DOI: 10.1016/j.aca.2017.03.027
  • Peer Reviewed
• [Journal Article] Reactive sulfur species inactivate Ca2+/calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue (2017)
  • Author(s): Takata T, Ihara H, Hatano N, Tsuchiya Y, Akaike T, Watanabe Y.
  • Journal Title: Biochem J Volume: 474 Pages: 2547～2562
  • DOI: 10.1042/BCJ20170092.
  • Peer Reviewed
• [Journal Article] Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells (2017)
  • Author(s): Nishida M, Nishimura A, Matsunaga T, Motohashi H, Kasamatsu S, Akaike T.
  • Journal Title: Free Radic Biol Med Volume: 109 Pages: 132～140
  • DOI: 10.1016/j.freeradbiomed.2017.01.024
  • Peer Reviewed
• [Journal Article] Disruption of the structural and functional features of surfactant protein A by acrolein in cigarette smoke (2017)
  • Author(s): Takamiya R, Uchida K, Shibata T, Maeno T, Kato M, Yamaguchi Y, Ariki S, Hasegawa Y, Saito A, Miwa S, Takahashi H, Akaike T, Kuroki Y, Takahashi M.
  • Journal Title: Sci Rep Volume: 7 Pages: 8304
  • DOI: 10.1038/s41598-017-08588-5
  • Peer Reviewed / Open Access
• [Journal Article] 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage (2017)
  • Author(s): Hoshino M, Kaneko K, Miyamoto Y, Yoshimura K, Suzuki D, Akaike T, Sawa T, Ida T, Fujii S, Ihara H, Tanaka J, Tsukuura R, Chikazu D, Mishima K, Baba K, Kamijo R.
  • Journal Title: Free Radic Biol Med Volume: 110 Pages: 63～71
  • DOI: 10.1016/j.freeradbiomed.2017.05.022
  • Peer Reviewed
• [Journal Article] Exposure to electrophiles impairs reactive persulfide-dependent redox signaling in neuronal cells (2017)
  • Author(s): Ihara H, Kasamatsu S, Kitamura A, Nishimura A, Tsutsuki H, Ida T, Ishizaki K, Toyama T, Yoshida E, Abdul Hamid H, Jung M, Matsunaga T, Fujii S, Sawa T, Nishida M, Kumagai Y, Akaike T.
  • Journal Title: Chem Res Toxicol Volume: 30 Pages: 1673～1684
  • DOI: 10.1021/acs.chemrestox.7b00120
  • Peer Reviewed
• [Journal Article] Chemical biology of hydropersulfides and related species: Possible roles in cellular protection and redox signaling (2017)
  • Author(s): Alvarez L, Bianco CL, Toscano JP, Lin J. Akaike T, Fukuto JM.
  • Journal Title: Antioxid Redox Signal Volume: 27 Pages: 622～633
  • DOI: 10.1089/ars.2017.7081
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diversity and microevolution of CRISPR loci in Helicobacter cinaedi (2017)
  • Author(s): Tomida J, Morita Y, Shibayama K, Kikuchi K, Sawa T, Akaike T, Kawamura Y.
  • Journal Title: PLoS One Volume: 12 Pages: e0186241
  • DOI: 10.1371/journal.pone.0186241
  • Peer Reviewed / Open Access
• [Journal Article] Production of reactive persulfide species in chronic obstructive pulmonary disease (2017)
  • Author(s): Numakura T, Sugiura H, Akaike T, Ida T, Fujii S, Koarai A, Yamada M, Onodera K, Hashimoto Y, Tanaka R, Sato K, Shishikura Y, Hirano T, Yanagisawa S, Fujino N, Okazaki T, Tamada T, Hoshikawa Y, Okada Y, Ichinose M.
  • Journal Title: Thorax Volume: 72 Pages: 1074～1083
  • DOI: 10.1136/thoraxjnl-2016-209359
  • Peer Reviewed
• [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics (2017)
  • Author(s): Akaike T, Ida T, Wei FY, Nishida M, Kumagai Y, Alam MM, Ihara H, Sawa T, Matsunaga T, Kasamatsu S, Nishimura A, Morita M, Tomizawa K, Nishimura A, Watanabe S, Inaba K, Shima H, Tanuma N, Jung M, Fujii S, Watanabe Y, Ohmuraya M, Nagy P, Feelisch M, Fukuto JM, Motohashi H.
  • Journal Title: Nat Commun Volume: 8 Pages: 1177
  • DOI: 10.1038/s41467-017-01311-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ニトロ化環状ヌクレオチドと活性イオウ分子によるレドックスシグナル制御と生理機能 (2017)
  • Author(s): 藤井重元、赤池孝章.
  • Journal Title: 化学療法の領域 Volume: 33 Pages: 2194～2195
• [Journal Article] 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 (2017)
  • Author(s): 西村 明、赤池孝章.
  • Journal Title: 硫酸と工業 Volume: 70 (11) Pages: 1-9
• [Presentation] Sulfur respiration in mammals and its implication for tumor biology (2018)
  • Author(s): Takaaki Akaike, Tomoaki Ida, Md. Morshedul Alam, Akira Nishimura, Masanobu Morita, Tetsuro Matsunaga, Hozumi Motohashi.
  • Organizer: The Cold Spring Harbor Asia Conference on Cancer & Metabolism
  • Int'l Joint Research / Invited
• [Presentation] システインパースルフィド産生酵素（Cysteine Persulfide Synthase, CPERS）の発見 (2017)
  • Author(s): 赤池孝章
  • Organizer: 第17回日本NO学会学術集会
  • Invited
• [Presentation] イオウ呼吸とイオウストレス：ほ乳類における新しいエネルギー代謝とレドックス病態 (2017)
  • Author(s): 赤池孝章、西村 明、井田智章、松永哲郎、守田匡伸、本橋ほづみ.
  • Organizer: 2017年度生理学研究所研究会「オルガネラダイナミクスの新規制御機構とその病態生理」
  • Invited
• [Presentation] イオウ呼吸とイオウストレス：新しいエネルギー代謝とレドックス病態の提案 (2017)
  • Author(s): 赤池孝章、西村 明、井田智章、松永哲郎、守田匡伸、藤井重元、本橋ほづみ.
  • Organizer: 第70回日本酸化ストレス学会学術集会
• [Presentation] Cysteine polysulfidation governed by cysteinyl-tRNA synthetase (CARSs) (2017)
  • Author(s): Takaaki Akaike
  • Organizer: Se2017 - 200 Years of Selenium Research (The 11th International Symposium on Selenium in Biology and Medicine and The 5th International Conference on Selenium in the Environment and Human Health)
  • Int'l Joint Research / Invited
• [Presentation] Cysteinyl-tRNA synthetase (CARS) controls endogenous hydropersulfide production and mediates mitochondrial functions and bioenegetics (2017)
  • Author(s): Takaaki Akaike
  • Organizer: S-Bio 2017 Plant and Human Sulfur Biology Conference 2017
  • Int'l Joint Research / Invited
• [Presentation] Discovery of a novel persulfide synthase that mediates mitochondrial sulfur respiration (2017)
  • Author(s): Takaaki Akaike
  • Organizer: 2nd Karolinska-Tohoku Joint Symposium on Medical Sciences
  • Int'l Joint Research / Invited
• [Presentation] Cysteinyl-tRNA synthetase governs endogenous hydropersulfide production and mediates mitochondrial functions and bioenergetics (2017)
  • Author(s): Takaaki Akaike
  • Organizer: AARS2017: IUBMB Focused Meeting on Aminoacyl-tRNA Synthetase
  • Int'l Joint Research
• [Presentation] Moonlighting functions of cysteinyl-tRNA synthetase: Cysteine hydropersulfide production and regulation of mitochondrial biogenesis and bioenergetics (2017)
  • Author(s): Takaaki Akaike, Akira Nishimura, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hozumi Motohashi.
  • Organizer: SfRBM 2017 - 24th Annual Meeting of the Society for Redox Biology and Medicine
  • Int'l Joint Research
• [Presentation] Cysteinyl-tRNA synthetase (CARS) は活性パースルフィド産生とミトコンドリア機能をコントロールしている (2017)
  • Author(s): 赤池孝章
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Presentation] Cysteine persulfide formation via cysteinyl-tRNA synthetase and its involvement in mitochondrial bioenergetics (2017)
  • Author(s): Takaaki Akaike, Tomoaki Ida, Masanobu Morita, Shigemoto Fujii, Akira Nishimura, Tetsuro Matsunaga, Minkyung Jung, Hozumi Motohashi.
  • Organizer: th Joint Meeting of Society for Free Radical Research Australasia and Japan with International Symposium on Coenzyme Q10,
  • Int'l Joint Research
• [Book] Nitric Oxide: Biology and Pathobiology. 3rd ed. (Ignarro LJ, Freeman BA, eds.) (2017)
  • Author(s): Sawa T, Kumagai Y, Akaike T.
  • Total Pages: 403
  • Publisher: Academic Press
  • ISBN: 978-0-12-804273-1
• [Remarks] 東北大学大学院医学系研究科 環境医学分野教室ホームページ
  • URL: http://www.toxicosci.med.tohoku.ac.jp