TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy
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Le résumé fourni par la source
Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe 2+ ) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe 2+ , basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe 2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy
- Date Crossref
- 01/11/2024
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Iowa pays non établi dans la noticeUniversité ou école supérieure
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Minnesota Lions Eye Bank pays non établi dans la noticeInstitution
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Mayo Clinic Department of Ophthalmology pays non établi dans la noticeÉtablissement de santé
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WinnMed pays non établi dans la noticeOrganisation à but non lucratif
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Johns Hopkins University pays non établi dans la noticeUniversité ou école supérieure
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College of Pharmacy Department of Pharmaceutical Sciences and Experimental Therapeutics pays non établi dans la noticeUniversité ou école supérieure
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Carver College of Medicine Department of Ophthalmology & Visual Sciences pays non établi dans la noticeUniversité ou école supérieure
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Iowa Lions Eye Bank pays non établi dans la noticeInstitution
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Wilmer Eye Institute pays non établi dans la noticeStructure de recherche
University of Iowa, Minnesota Lions Eye Bank et Department of Ophthalmology — Mayo Clinic, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.