氧化应激会诱导溶酶体膜透和胺在视网膜色素上皮细胞中的积累
Kevin R Zhang1, Connor S R Jankowski2,3, Rayna Marshall1
1F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Disease models & mechanisms
|July 4, 2023
概括
铁过载会损害视网膜色素上皮质 (RPE) 细胞,这是与年龄相关的黄斑退化的一个关键因素. 这项研究表明,铁会损害 lysosomal 功能,导致细胞死亡和潜在的失明.
科学领域:
- 眼科医生 眼科 眼科
- 细胞生物学 细胞生物学
- 毒理学 毒理学 毒理学
背景情况:
- 氧化应激有助于与年龄相关的黄斑变性 (AMD) 病变.
- 视网膜色素上皮质 (RPE) 细胞在AMD发育中至关重要.
- 铁过载可以加剧RPE细胞中的氧化应激.
研究的目的:
- 在铁过载条件下研究RPE细胞中氧化应激的细胞毒性机制.
- 阐明铁在RPE细胞功能障碍和死亡中的作用.
主要方法:
- 利用诱导多能干细胞衍生的RPE细胞和系统性铁过载的小鼠模型 (肝脏特异性Hepc淘汰赛).
- 进行了细胞培养实验,蛋白质和脂质组分析.
- 评估了 lysosomal 功能,酶活性和细胞活力.
主要成果:
- 在RPE细胞中的铁负载增加了 lysosomal 丰度,蛋白质分解受损,并降低了 lysosomal 酶活性 (LIPA,SMPD1).
- 铁过载小鼠中的RPE细胞显示脂质过氧化,溶酶体积累,过度缩小和细胞死亡.
- 受到影响的cathepsin D成熟和加勒-3阳性溶解体的增加表明细胞毒性溶解体膜透性.
结论:
- 铁过载会导致RPE细胞的溶酶体积累和功能障碍.
- 铁诱导的脂质过氧化物可能会抑制溶酶酶,导致RPE细胞死亡.
- 这些发现突显了与铁毒性相关的AMD病原发生的新型机制.
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