Ferroptosis drives photoreceptor degeneration in mice with defects in all-trans-retinal clearance
| Autor: | Yan Wang, Yalin Wu, Zuguo Liu, Jingmeng Chen, Chao Chen |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Retinal degeneration STEAP3 six-transmembrane epithelial antigen of prostate 3 genetic structures STGD1 autosomal recessive Stargardt disease TFRC transferrin receptor ONL outer nuclear layer Mitochondrion medicine.disease_cause Biochemistry Photoreceptor cell Mice DMT1 Divalent metal transporter 1 GSH glutathione Stargardt Disease oxidative stress iron metabolism AMD age-related macular degeneration IREB2 Iron-responsive element binding protein 2 POS photoreceptor outer segments chemistry.chemical_classification Deferoxamine mesylate LDH lactate dehydrogenase Chemistry TEM transmission electron microscope lipid peroxidation LED light emitting diode Cell biology medicine.anatomical_structure cell death Retinaldehyde Photoreceptor Cells Vertebrate Research Article Programmed cell death macular degeneration 03 medical and health sciences ROS reactive oxygen species medicine Animals Ferroptosis Molecular Biology Reactive oxygen species Retina 030102 biochemistry & molecular biology Cell Biology medicine.disease all-trans-retinal photoreceptor eye diseases TF transferrin Mice Inbred C57BL 030104 developmental biology CP ceruloplasmin atRAL all-trans-retinal H&E hematoxylin and eosin sense organs FPN Ferroportin Reactive Oxygen Species Oxidative stress |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | The death of photoreceptor cells in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1) is closely associated with disruption in all-trans-retinal (atRAL) clearance in neural retina. In this study, we reveal that the overload of atRAL leads to photoreceptor degeneration through activating ferroptosis, a nonapoptotic form of cell death. Ferroptosis of photoreceptor cells induced by atRAL resulted from increased ferrous ion (Fe2+), elevated ACSL4 expression, system Xc- inhibition, and mitochondrial destruction. Fe2+ overload, tripeptide glutathione (GSH) depletion, and damaged mitochondria in photoreceptor cells exposed to atRAL provoked reactive oxygen species (ROS) production, which, together with ACSL4 activation, promoted lipid peroxidation and thereby evoked ferroptotic cell death. Moreover, exposure of photoreceptor cells to atRAL activated COX2, a well-accepted biomarker for ferroptosis onset. In addition to GSH supplement, inhibiting either Fe2+ by deferoxamine mesylate salt (DFO) or lipid peroxidation with ferrostatin-1 (Fer-1) protected photoreceptor cells from ferroptosis caused by atRAL. Abca4-/-Rdh8-/- mice exhibiting defects in atRAL clearance is an animal model for dry AMD and STGD1. We observed that ferroptosis was indeed present in neural retina of Abca4-/-Rdh8-/- mice after light exposure. More importantly, photoreceptor atrophy and ferroptosis in light-exposed Abca4-/-Rdh8-/- mice were effectively alleviated by intraperitoneally injected Fer-1, a selective inhibitor of ferroptosis. Our study suggests that ferroptosis is one of the important pathways of photoreceptor cell death in retinopathies arising from excess atRAL accumulation and should be pursued as a novel target for protection against dry AMD and STGD1. |
| Databáze: | OpenAIRE |
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