Hsiao Yu-Ting, Hsiao Chang-Chun, Lee Jong-Jer
Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Ophthalmology, Kaohsiung Municipal Feng Shan Hospital-Under the Management of Chang Gung Medical Foundation, Kaohsiung, Taiwan.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Biomed J. 2025 Aug;48(4):100875. doi: 10.1016/j.bj.2025.100875. Epub 2025 Jun 2.
Given the role of polyunsaturated fatty acid (PUFA) overload and mitochondrial dysfunction in retinal pigment epithelium (RPE) cells in causing retinal degeneration in Bietti crystalline dystrophy (BCD), we aimed to identify the pathways responsible for intracellular oxidative stress and mitochondrial damage in CYP4V2-deficient RPE cells.
Proteomic analysis of control and CYP4V2-knockdown (KD) ARPE-19 cells revealed that endoplasmic reticulum (ER) stress was the most enriched pathway. The effects of CYP4V2 deficiency on intracellular reactive oxygen species, mitochondrial integrity, and ATP production were assessed.
Inositol-requiring enzyme 1 α (IRE1α) inhibitors suppressed upregulation of endoplasmic reticulum oxidoreductase 1 alpha (ERO1-Lα) protein expression, which contributed to ER-associated oxidative stress. Loss of mitochondrial transmembrane potential and reduced ATP production were mitigated with IRE1α inhibitor in CYP4V2-KD ARPE-19 cells.
Our findings reveal a novel regulatory mechanism involving potential reduction in PUFA utilization, IRE1α signaling mediated ER oxidative stress, and mitochondrial dysfunction in BCD, potentially offering future therapeutic avenues.
鉴于多不饱和脂肪酸（PUFA）过载和视网膜色素上皮（RPE）细胞中的线粒体功能障碍在贝蒂结晶性视网膜病变（BCD）中导致视网膜变性的作用，我们旨在确定CYP4V2缺陷型RPE细胞中细胞内氧化应激和线粒体损伤的相关途径。
对对照和CYP4V2基因敲低（KD）的ARPE-19细胞进行蛋白质组学分析，结果显示内质网（ER）应激是最富集的途径。评估了CYP4V2缺乏对细胞内活性氧、线粒体完整性和ATP生成的影响。
肌醇需求酶1α（IRE1α）抑制剂抑制了内质网氧化还原酶1α（ERO1-Lα）蛋白表达的上调，这导致了内质网相关的氧化应激。在CYP4V2-KD ARPE-19细胞中，IRE1α抑制剂减轻了线粒体跨膜电位的丧失和ATP生成的减少。
我们的研究结果揭示了一种新的调节机制，涉及BCD中PUFA利用可能减少、IRE1α信号介导的内质网氧化应激和线粒体功能障碍，这可能为未来的治疗提供途径。
