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在实验性AMD中,DAPL1通过抑制GRP75介导的线粒体关联的质网膜来抑制RPE PANoptosis

Yan Li¹, Meiyu Jing¹, Wanxiao Wang¹

¹Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China.

Proceedings of the National Academy of Sciences of the United States of America

|February 20, 2026

概括

与死亡相关的蛋白质像1 (DAPL1) 缺乏会通过增加线粒体相关膜 (MAMs) 来导致干燥的与年龄相关的黄斑变性 (AMD). 这导致细胞死亡,但针对MAM形成可能为AMD提供新的治疗策略.

科学领域:

眼科医生眼科眼科
细胞生物学细胞生物学
分子生物学分子生物学

背景情况:

视网膜色素上皮 (RPE) 细胞损伤是与年龄相关的黄斑变性 (AMD) 的核心原因,这是老年人视力丧失的主要原因.
干燥AMD (dAMD) 病原发生的精确机制,特别是与死亡相关蛋白1 (DAPL1) 等敏感基因有关,仍然不完全理解.

研究的目的:

阐明DAPL1在dAMD发病过程中的作用.
研究将DAPL1缺乏与RPE细胞功能障碍和dAMD进展联系在一起的分子机制.
为了确定dAMD的潜在治疗点.

主要方法:

使用了DAPL1缺乏的小鼠模型,表现出干燥的AMD类病理.
研究了线粒体关联的细胞内网膜 (MAMs) 的形成及其对线粒体 (Ca2+) 恒温的影响.
研究了RPE细胞中炎症细胞和RIPK1-介导的PANoptosis的激活.
评估了击倒或过度表达DAPL1,RIPK1和GRP75对dAMD特征的影响.

主要成果:

DAPL1缺乏促进MAM形成,导致RPE细胞中的线粒体Ca2+过载,功能障碍和随后的RIPK1-介导的PANoptosis.
在DAPL1缺乏的小鼠中,对RIPK1或GRP75的抑制改善了RPE细胞PANoptosis和dAMD病理.
DAPL1通过降低GRP75的调节来抑制MAM的形成,破坏了对ER-线粒体合和Ca2+运输至关重要的VDAC-GRP75-IP3R轴.

结论:

DAPL1通过抑制MAM形成和随后的PANoptosis,在RPE细胞中发挥保护作用.
由DAPL1调节的MAMs是RPE细胞死亡和dAMD进展的关键调解者.
向MAM形成,特别是通过调节GRP75来向MAM形成,为dAMD提供了一个有希望的治疗策略.

关键词:

在这个过程中,AMD是AMD.在 GRP75 中,GRP75 是这就是PANoptosis.在 RPE RPE 的情况下,与线粒体相关的ER膜膜.

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