Elucidation of the biological significance and pathophysiological role of the novel mechanisms by which ferroptosis is regulated endogenously

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19325
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Tohoku University
• Principal Investigator: Matsuzawa Atsushi 東北大学, 薬学研究科, 教授 (80345256)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: フェロトーシス / GPX4 / 翻訳後修飾 / 脂質酸化 / プログラム細胞死

Outline of Final Research Achievements

In this study, we sought to elucidate novel regulatory mechanisms of GPX4 expression and activity by a protein kinase and an endogenous factor, respectively, and their roles in ferroptosis.
We identified the phosphorylation site of GPX4 by a stress-responsive protein kinase X. Phosphorylation mimic mutants of the GPX4 showed a marked decrease in its enzyme activity, suggesting that kinase X phosphorylates GPX4 in a stress stimulus-dependent manner to suppress its enzymatic activity, thereby promoting ferroptosis.
In addition, we identified a serum-derived molecule Y that is important for the maintenance of GPX4 protein expression. We found that removing molecule Y from the serum in the medium decreased GPX4 expression, while adding Y increased it.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

フェロトーシスは、生体膜脂質の鉄依存的酸化で誘導される新たな制御性の細胞死で、神経変性疾患や虚血性疾患などの様々な病態増悪との関連から、新規創薬ターゲットとして、近年世界的に注目されている。脂質酸化消去酵素GPX4は、酸化脂質の除去によってフェロトーシス抑制に働く最も重要な制御分子であるが、GPX4の発現・活性制御機構については不明な点が多く残されている。本研究により、GPX4のリン酸化修飾とその責任キナーゼ分子X、発現・活性の制御において重要な役割を担う内因性因子Y同定することができ、関連疾患の発症機序の解明に繋がる、重要な基礎的知見が得られた。