Journal article
TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy
Redox biology, Vol.77, 103348
11/2024
DOI: 10.1016/j.redox.2024.103348
PMCID: PMC11470242
PMID: 39332053
Abstract
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 (Fe2+) 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 Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ 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.
Details
- Title: Subtitle
- TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy
- Creators
- Sanjib Saha - University of IowaJessica M. SkeieGregory A. SchmidtTim EgglestonHanna ShevalyeChristopher S. SalesPornpoj Phruttiwanichakun - University of IowaApurva Dusane - University of IowaMatthew G. FieldTommy A. RinkoskiMichael P. Fautsch - Mayo ClinicKeith H. Baratz - Mayo ClinicMadhuparna Roy - Johns Hopkins MedicineAlbert S. Jun - Johns Hopkins MedicineChandler Pendleton - University of Iowa, Dental ResearchAliasger K. Salem - University of IowaMark A. Greiner - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.77, 103348
- DOI
- 10.1016/j.redox.2024.103348
- PMID
- 39332053
- PMCID
- PMC11470242
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- ELSEVIER; AMSTERDAM
- Grant note
- NIH: R21EY034198
The authors cordially thank the Lyle and Sharon Bighley Endowed Chair of Pharmaceutical Sciences, Iowa Lions Eye Bank, the Beulah and Florence Usher Endowed Chair in Cornea/External Disease and Refractive Surgery, the M.D. Wagoner & M.A. Greiner Cornea Excellence Fund, Mr. and Mrs. Robert and Joell Brightfelt, Mr. and Mrs. Lloyd and Betty Schermer, the UIHC Cornea Research Fund for financial support, and the cornea patients, donors, and donor families that made this research possible. MAG, AKS, JMS and SS are supported by the NIH grant R21EY034198.
- Language
- English
- Electronic publication date
- 09/2024
- Date published
- 11/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Ophthalmology and Visual Sciences
- Record Identifier
- 9984701765102771
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