Identification of oxidized lipid metabolites in which involves lipid oxidation dependent novel cell death using deuterium-labeled phospholipids

• Project/Area Number: 18K14906
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kitasato University
• Principal Investigator: SAKAMOTO TARO 北里大学, 薬学部, 講師 (10383655)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 酸化脂質 / フラクソーム解析 / 重水素型リン脂質 / 細胞死 / 脂質代謝 / リン脂質ヒドロペルオキシド / LC-MS / 重水素

Outline of Final Research Achievements

Glutathione peroxidase 4 (GPx4) is a unique antioxidant enzyme that directly reduces the phospholipid hydroperoxides generated in biomembranes. We have demonstrated that the disruption of GPx4 leads to phospholipid hydroperoxide dependent novel cell death. In this study, by the fluxome analysis using deuterium labelled-phospholipid, we attempted to generate the whole aspect of metabolic map for phospholipid hydroperoxides. We found the phospholipase activity was elevated in the GPx4-depleted cells as compared with that of control cells. In addition, reacylation of lysophospholipids was decreased in the GPx4-depleted cells. These data indicate that the lysophospholipids were metabolized to unknown compounds in the GPx4-depleted cells.

Academic Significance and Societal Importance of the Research Achievements

GPx4欠損による新規細胞死は、GPx4ノックアウトマウスの胚致死を誘導するだけでなく、心不全性突然死、雄性不妊、COPDなどにも関わることを研究代表者らは明らかにしている。本研究では、GPx4欠損時にリゾリン脂質からリン脂質への再アシル化活性が低下し、代わりに未知の物質へと代謝される可能性を見出している。今後、実際にどういった代謝物に変化するのかが明らかとなれば、上記のような疾患のバイオマーカーへ利用できる可能性が高い。

Research Products

• [Journal Article] Inhibition of lipid peroxidation during the reproductive period extends the lifespan of <i>Caenorhabditis elegans</i> (2020)
  • Author(s): Taro Sakamoto, Kana Maebayashi, Yuka Tsunoda, Hirotaka Imai
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 66 Issue: 2 Pages: 116-123
  • DOI: 10.3164/jcbn.19-51
  • NAID: 130007804523
  • ISSN: 0912-0009, 1880-5086
  • Year and Date: 2020-03-01
  • Peer Reviewed
• [Journal Article] Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis (2019)
  • Author(s): Tsubouchi K、Araya J、Yoshida M、Sakamoto T、Koumura T、Minagawa S、Hara H、Hosaka Y、Ichikawa A、Saito N、Kadota T、Kurita Y、Kobayashi K、Ito S、Fujita Y、Utsumi H、Hashimoto M、Wakui H、Numata T、Kaneko Y、Mori S、Asano Hi、Matsudaira H、Ohtsuka T、Nakayama K、Nakanishi Y、Imai H、Kuwano K
  • Journal Title: The Journal of Immunology Volume: 203 Issue: 8 Pages: 2076-2087
  • DOI: 10.4049/jimmunol.1801232
  • Peer Reviewed
• [Journal Article] Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. (2019)
  • Author(s): Yoshida M, Minagawa S, Araya J, Sakamoto T, Hara H, Tsubouchi K, Hosaka Y, Ichikawa A, Saito N, Kadota T, Sato N, Kurita Y, Kobayashi K, Ito S, Utsumi H, Wakui H, Numata T, Kaneko Y, Mori S, Asano H, Yamashita M, Odaka M, Morikawa T, Nakayama K, Iwamoto T, Imai H, Kuwano K.
  • Journal Title: Nat Commun. Volume: 10 Issue: 1 Pages: 3145-3145
  • DOI: 10.1038/s41467-019-10991-7
  • Peer Reviewed / Open Access
• [Presentation] フラクソーム解析を介したリン脂質ヒドロぺルオキシドの新規代謝機構の解明 (2019)
  • Author(s): 坂本太郎、品川尚久、馬場直道、今井浩孝
  • Organizer: 第61回日本脂質生化学会
• [Presentation] Involvement of GPx4-mediated ferroptosis in COPD pathogensis (2018)
  • Author(s): Masahiro Yoshida, Shunsuke Minagawa, Taro Sakamoto, Jun Araya, Hirotaka Imai and Kazuyoshi Kuwano
  • Organizer: The 7th International Selenium Conference Se2018 Selenium in Biology, Chemistry and Medicine
  • Int'l Joint Research
• [Presentation] Lipid peroxideation dependent cell death by GPx4 depletion involves different cell death pathway from ferroptosis (2018)
  • Author(s): Hirotaka Imai, Kahori Oka, Tomoko Koumura, Takeshi Kumagai, Taro Sakamoto and Masaki Matsuoka
  • Organizer: The 7th International Selenium Conference Se2018 Selenium in Biology, Chemistry and Medicine
  • Int'l Joint Research
• [Presentation] 新規重水素型リン脂質ヒドロペルオキシドの合成と脂質酸化依存的新規細胞死におけるフラクソーム解析への応用 (2018)
  • Author(s): 今井浩孝、品川尚久、馬場直道、坂本太郎
  • Organizer: 日本過酸化脂質・抗酸化物質学会 第26回年会
• [Presentation] SMS2によるGPx4欠損による新規細胞死抑制機構の解析 (2018)
  • Author(s): 熊谷 剛、平澤星蘭、大矢梨里香、坂本太郎、今井浩孝
  • Organizer: 日本過酸化脂質・抗酸化物質学会 第26回年会
• [Presentation] GPx４欠損新規細胞死実行因子lipo-3の機能解析 (2018)
  • Author(s): 今井浩孝、岡佳保里、坂本太郎、松岡正城
  • Organizer: 第４回日本セレン研究会
• [Presentation] SMS２による脂質酸化依存的新規細胞死抑制機構の解析 (2018)
  • Author(s): 今井浩孝、大矢梨里香、平澤星蘭、坂本太郎、熊谷 剛
  • Organizer: 日本ビタミン学会 第70回大会
• [Presentation] フラクソーム解析を用いたリン脂質ヒドロペルオキシドの新規代謝機構の解明 (2018)
  • Author(s): 品川尚久、坂本太郎、平澤星蘭、熊谷 剛、馬場直道、今井浩孝
  • Organizer: 第60回日本脂質生化学会