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CGI1746的目标是 σ₁R 通过线粒体关联膜调节铁亡

Zili Zhang¹, Hong Zhou¹, Wenjia Gu^2,3

¹Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Nature chemical biology

|January 11, 2024

概括

线粒体相关膜 (MAMs) 调节铁,一种依赖铁的细胞死亡. 针对MAMs上的sigma-1受体 (σ1R) 抑制铁亡并防止损伤.

科学领域:

细胞生物学细胞生物学
生物化学生物化学
病理学病理学病理学

背景情况:

铁亡是一种受调节的细胞死亡形式,依赖于铁和多不和脂肪酸 (PUFA).
虽然铁平衡和脂质合成是已知的调节剂,但其他可能参与铁亡的细胞过程仍然未被探索.

研究的目的:

在铁代谢和脂质合成之外,研究铁灭的新型调节剂.
识别可以抑制铁灭的小分子并探索它们的作用机制.

主要方法:

激酶抑制剂图书馆选以确定铁灭抑制剂.
鉴定出抑制剂的作用机制的表征,包括西格玛-1受体 (σ1R) 相互作用.
在小鼠中对西斯普拉丁诱导的急性损伤 (AKI) 模型中的铁亡的评估.
对 (Ca2+) 转移,线粒体反应性氧物种 (ROS) 生产和脂质积累的分析.

主要成果:

鉴定出一种名为CGI1746的小分子,能够有效抑制铁灭.
CGI1746通过位于线粒体关联膜 (MAMs) 的sigma-1受体 (σ1R) 起作用.
σ1R抑制或MAM干扰会损害Ca2+转移,增加线粒体ROS,并改变PUFA-三糖醇的积累,从而抑制铁灭.
抑制 σ1R 受保护的小鼠从西斯胺诱导的 AKI.

结论:

线粒体相关膜 (MAMs) 在铁灭的执行中起着至关重要的作用.
在MAMs中的sigma-1受体 (σ1R) 是铁亡的关键调解者.
向MAMs和s1R代表了治疗ferroptosis相关疾病的潜在治疗策略,例如急性损伤.

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