Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells |
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| Affiliation: | 1. Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia;2. Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway;3. Center of Excellence CIPKeBiP, Jamova 39, 1000 Ljubljana, Slovenia;4. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia;1. Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Hunan 410083, PR China;2. Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Hunan 410083, PR China;3. Institute of Clinical Medicine, Hunan Provincial People''s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan 410005, PR China;1. Department of Ophthalmology, Peking University Third Hospital, Beijing, China;2. Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital, Beijing, China;3. Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China;4. Department of Ophthalmology, Shandong University Qilu Hospital, Shandong, China |
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| Abstract: | Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells. |
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| Keywords: | AMD Retinal pigment epithelium ROS Ferroptosis Degeneration Macula |
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