Lipid radicals in regulation of ferroptosis

• Project/Area Number: 20KK0363
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Tohoku University
• Principal Investigator: Eikan Mishima 東北大学, 医学系研究科, 大学院非常勤講師 (00706939)
• Project Period (FY): 2021 – 2023
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
• Keywords: 細胞死 / フェロトーシス / 酸化ストレス / ビタミンK / 腎臓病 / アポトーシス / FSP1 / GPX4 / 脂質ラジカル / 過酸化脂質 / 急性腎障害 / 脂質酸化 / 虚血再灌流障害

Outline of Research at the Start

フェロトーシス（Ferroptosis）は脂質酸化依存性の制御性細胞死の様式であり、グルタチオンの枯渇や過剰な酸化ストレスなどによって細胞内に酸化脂質が過剰に蓄積することで生じる細胞死である。急性組織障害、神経変性疾患、抗がん剤感受性等の機序への関与が知られておりフェロトーシスの病態関与の解明および薬剤的制御はこれら病態の新規治療法につながる。本研究では個別の脂質酸化種が細胞に与えるin vitro検討とフェロトーシス病態モデルであるGPX4誘導KOマウスによる急性腎不全組織のin vivo検討の統合的脂質解析からフェロトーシス発動に直接的に関与する脂質酸化種の同定を行う。

Outline of Final Research Achievements

I stayed at the Helmholtz Center Munich in Germany (Munich) and conducted international collaborative research. My research was focused on elucidating the regulatory mechanism of ferototic cell death. From this joint research, the following results were obtained: 1) elucidation of the inhibitory effect of vitamin K on ferotosis and its mechanism, 2) development of a versatile new assay for GPX4, a ferotosis inhibitory protein, and 3) development of a new inhibitor for FSP1, a second ferotosis inhibitory protein, and elucidation of its mechanism.

Academic Significance and Societal Importance of the Research Achievements

フェロトーシスは鉄介在性の脂質酸化依存性の細胞死の一種である。近年、腎臓や肝臓の急性臓器障害、アルツハイマー病をはじめとする神経変性疾患、治療抵抗性がん細胞の抗がん薬感受性等の関与することが知られ、これらの病気の治療標的として世界的に注目を浴びている生命事象である。本研究においてフェロトーシスの制御機構やフェロトーシス関連タンパク質を阻害する化合物を開発した。これらの成果はフェロトーシスが関連する病気の治療薬への展開が今後期待される。

Research Products

• [Int'l Joint Research] ヘルムホルツ研究センターミュンヘン(ドイツ) (2021)
  • Year and Date: 2021-04-01
• [Journal Article] A tangible method to assess native ferroptosis suppressor activity (2024)
  • Author(s): Nakamura Toshitaka、Ito Junya、Mourao Andre Santos Dias、Wahida Adam、Nakagawa Kiyotaka、Mishima Eikan、Conrad Marcus
  • Journal Title: Cell Reports Methods Volume: 4 Issue: 3 Pages: 100710-100710
  • DOI: 10.1016/j.crmeth.2024.100710
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Membrane Dynamics and Cation Handling in Ferroptosis (2024)
  • Author(s): Hirata Yusuke、Mishima Eikan
  • Journal Title: Physiology Volume: 39 Issue: 2 Pages: 73-87
  • DOI: 10.1152/physiol.00029.2023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation (2023)
  • Author(s): Nakamura Toshitaka、Mishima Eikan、Yamada Naoya、Mour?o Andr? Santos Dias、Tr?mbach Dietrich、Doll Sebastian、Wanninger Jonas、Lytton Elena、Sennhenn Peter、Nishida Xavier da Silva Thamara、Angeli Jos? Pedro Friedmann、Sattler Michael、Proneth Bettina、Conrad Marcus
  • Journal Title: Nature Structural & Molecular Biology Volume: 30 Issue: 11 Pages: 1806-1815
  • DOI: 10.1038/s41594-023-01136-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition (2023)
  • Author(s): Mishima Eikan、Nakamura Toshitaka、Zheng Jiashuo、Zhang Weijia、Mour?o Andr? Santos Dias、Sennhenn Peter、Conrad Marcus
  • Journal Title: Nature Volume: 619 Issue: 7968 Pages: E9-E18
  • DOI: 10.1038/s41586-023-06269-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phase separation of FSP1 promotes ferroptosis (2023)
  • Author(s): Nakamura Toshitaka、Hipp Clara、Santos Dias Mour?o Andr?、Borggr?fe Jan、Aldrovandi Maceler、Henkelmann Bernhard、Wanninger Jonas、Mishima Eikan、Lytton Elena、Emler David、Proneth Bettina、Sattler Michael、Conrad Marcus
  • Journal Title: Nature Volume: 619 Issue: 7969 Pages: 371-377
  • DOI: 10.1038/s41586-023-06255-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diverse biological functions of vitamin K: from coagulation to ferroptosis (2023)
  • Author(s): Mishima Eikan、Wahida Adam、Seibt Tobias、Conrad Marcus
  • Journal Title: Nature Metabolism Volume: 5 Issue: 6 Pages: 924-932
  • DOI: 10.1038/s42255-023-00821-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 脂質酸化細胞死を抑制するビタミンKとその還元酵素の発見 (2023)
  • Author(s): 伊藤隼哉 三島英換 仲川清隆
  • Journal Title: B＆I Volume: 81 Pages: 100-103
• [Journal Article] 腎障害における細胞死update (2023)
  • Author(s): 三島英換
  • Journal Title: 日腎会誌 Volume: 65 Pages: 17-24
• [Journal Article] A non-canonical vitamin K cycle is a potent ferroptosis suppressor (2022)
  • Author(s): Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, Tonnus W, Nepachalovich P, Eggenhofer E, Aldrovandi M, Henkelmann B, Yamada KI, Wanninger J, Zilka O, Sato E, Feederle R, Hass D, Maida A, Linkermann A, Geissler EK, Conrad M
  • Journal Title: Nature Volume: 608 Issue: 7924 Pages: 778-783
  • DOI: 10.1038/s41586-022-05022-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] What’s New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances (2022)
  • Author(s): Watanabe Kimio、Sato Emiko、Mishima Eikan、Miyazaki Mariko、Tanaka Tetsuhiro
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 1 Pages: 570-570
  • DOI: 10.3390/ijms24010570
  • Peer Reviewed / Open Access
• [Journal Article] Nutritional and Metabolic Control of Ferroptosis (2022)
  • Author(s): Mishima Eikan、Conrad Marcus
  • Journal Title: Annual Review of Nutrition Volume: 42 Issue: 1 Pages: 275-309
  • DOI: 10.1146/annurev-nutr-062320-114541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 腎臓病と腸内細菌叢：最近の話題を中心に (2022)
  • Author(s): 三島英換 菊地晃一 阿部高明
  • Journal Title: 腎臓内科 Volume: 16 Pages: 477-482
• [Journal Article] Gut Microbiota Dynamics and Uremic Toxins (2022)
  • Author(s): Mishima Eikan、Abe Takaaki
  • Journal Title: Toxins Volume: 14 Issue: 2 Pages: 146-146
  • DOI: 10.3390/toxins14020146
  • Peer Reviewed / Open Access
• [Journal Article] Role of the microbiota in hypertension and antihypertensive drug metabolism (2021)
  • Author(s): Mishima Eikan、Abe Takaaki
  • Journal Title: Hypertension Research Volume: 45 Issue: 2 Pages: 246-253
  • DOI: 10.1038/s41440-021-00804-0
  • Peer Reviewed
• [Journal Article] The E2F1-IREB2 axis regulates neuronal ferroptosis in cerebral ischemia (2021)
  • Author(s): Mishima Eikan
  • Journal Title: Hypertension Research Volume: Online ahead of print. Issue: 6 Pages: 1085-1086
  • DOI: 10.1038/s41440-021-00837-5
  • Peer Reviewed
• [Journal Article] SGLT‐1‐specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine‐induced renal failure (2021)
  • Author(s): Ho Hsin‐Jung、Kikuchi Koichi、Oikawa Daiki、Watanabe Shun、Kanemitsu Yoshitomi、Kagawa Yoshiteru、その他19名
  • Journal Title: Physiological Reports Volume: 9 Issue: 24 Pages: 15092-15092
  • DOI: 10.14814/phy2.15092
  • Peer Reviewed / Open Access
• [Journal Article] Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines (2021)
  • Author(s): Zheng Jiashuo、Sato Mami、Mishima Eikan、Sato Hideyo、Proneth Bettina、Conrad Marcus
  • Journal Title: Cell Death & Disease Volume: 12 Issue: 7 Pages: 698-698
  • DOI: 10.1038/s41419-021-03998-w
  • Peer Reviewed / Open Access
• [Presentation] DHODH inhibitors sensitize cancer cells to ferroptosis via FSP1 inhibition (2023)
  • Author(s): Eikan Mishima
  • Organizer: EMBO Workshop
  • Int'l Joint Research
• [Presentation] フェロトーシスと腎臓病 (2023)
  • Author(s): 三島英換
  • Organizer: 第46回日本分子生物学会年会
  • Invited
• [Presentation] ビタミンK のフェロトーシス抑制作用の解明とビタミンK 還元酵素の同定 (2023)
  • Author(s): 三島英換
  • Organizer: ビタミン学会第75回大会
  • Invited
• [Presentation] 急性尿細管障害における細胞死を再考する：アポトーシス？フェロトーシス？ (2023)
  • Author(s): 三島英換
  • Organizer: 第６６回日本腎臓学会学術総会
  • Invited
• [Presentation] Non-canonical vitamin K cycle is a potent ferroptosis suppressor (2022)
  • Author(s): Eikan Mishima
  • Organizer: Redox week 2022
  • Int'l Joint Research / Invited
• [Presentation] Non-canonical vitamin K cycle is a potent ferroptosis suppressor (2022)
  • Author(s): Eikan Mishima
  • Organizer: Cold spring harbor meeting Asia
  • Int'l Joint Research
• [Presentation] Role of Vitamin K on ferroptosis and warfarin toxicity: unexpected link (2022)
  • Author(s): Eikan Mishima
  • Organizer: 第27回心血管内分泌学会 学術集会
  • Invited
• [Presentation] コロナ下でのドイツ留学とフェロトーシス研究 (2022)
  • Author(s): 三島英換
  • Organizer: 第52回日本腎臓学会西部学術大会
  • Invited
• [Presentation] Ferroptosis regulation and kidney disease (2022)
  • Author(s): Eikan Mishima
  • Organizer: 第65回日本腎臓学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] With コロナでの留学は可能か (2021)
  • Author(s): 三島英換
  • Organizer: 第2回 Digital Hypertension Conference発表
• [Presentation] 慢性大動脈解離の偽腔閉塞化による腎動脈狭窄に対してPTRAを施行し腎虚血の改善をDW-MRIで評価しえた1例 (2021)
  • Author(s): 三島英換
  • Organizer: 第9回臨床高血圧フォーラム
• [Remarks] Marcsu Conrad lab
  • URL: https://www.conradlaboratory.com/
• [Remarks] 東北大学病院 腎臓高血圧内科
  • URL: https://www.hosp.tohoku.ac.jp/departments/d1103/
• [Remarks] Conrad Laboratory
  • URL: https://www.conradlaboratory.com/
• [Remarks] 東北大学プレスリリース
  • URL: https://www.tohoku.ac.jp/japanese/2022/08/press20220804-01-vitamink.html
• [Patent(Industrial Property Rights)] フェロトーシス抑制剤 (2022)
  • Inventor(s): 三島英換
  • Industrial Property Rights Holder: 三島英換
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
  • Overseas