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Uncovering the role of ferroptosis in Bietti crystalline dystrophy and potential therapeutic strategies.
- Source :
-
Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jul 11; Vol. 22 (1), pp. 359. Date of Electronic Publication: 2024 Jul 11. - Publication Year :
- 2024
-
Abstract
- Purpose: Bietti crystalline dystrophy (BCD) is an inherited retinal degeneration disease caused by mutations in the CYP4V2 gene. Currently, there is no clinical therapy approach available for BCD patients. Previous research has suggested that polyunsaturated fatty acids (PUFAs) may play a significant role in the development of BCD, implicating the involvement of ferroptosis in disease pathogenesis. In this work, we aimed to investigate the interplay between ferroptosis and BCD and to detect potential therapeutic strategies for the disease.<br />Methods: Genetic-edited RPE cell line was first established in this study by CRISPR-Cas9 technology. Cyp4v3 (the homologous gene of human CYP4V2) knock out (KO) mice have also been used. Lipid profiling and transcriptome analysis of retinal pigment epithelium (RPE) cells from Cyp4v3 KO mice have been conducted. Ferroptosis phenotypes have been first investigated in BCD models in vitro and in vivo, including lipid peroxidation, mitochondrial changes, elevated levels of reactive oxygen species (ROS), and altered gene expression. Additionally, an iron chelator, deferiprone (DFP), has been tested in vitro and in vivo to determine its efficacy in suppressing ferroptosis and restoring the BCD phenotype.<br />Results: Cyp4v3 KO mice exhibited progressive retinal degeneration and lipid accumulation, similar to the BCD phenotype, which was exacerbated by a high-fat diet (HFD). Increased levels of PUFAs, such as EPA (C22:5) and AA (C20:4), were observed in the RPE of Cyp4v3 KO mice. Transcriptome analysis of RPE in Cyp4v3 KO mice revealed changes in genes involved in iron homeostasis, particularly an upregulation of NCOA4, which was confirmed by immunofluorescence. Ferroptosis-related characteristics, including mitochondrial defects, lipid peroxidation, ROS accumulation, and upregulation of related genes, were detected in the RPE both in vitro and in vivo. Abnormal accumulation of ferrous iron was also detected. DFP, an iron chelator administration suppressed ferroptosis phenotype in CYP4V2 mutated RPE. Oral administration of DFP also restored the retinal function and morphology in Cyp4v3 KO mice.<br />Conclusion: This study represented the first evidence of the substantial role of ferroptosis in the development of BCD. PUFAs resulting from CYP4V2 mutation may serve as substrates for ferroptosis, potentially working in conjunction with NCOA4-regulated iron accumulation, ultimately leading to RPE degeneration. DFP administration, which chelates iron, has demonstrated its ability to reverse BCD phenotype both in vitro and in vivo, suggesting a promising therapeutic approach in the future.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Humans
Mice
Reactive Oxygen Species metabolism
Retinal Diseases genetics
Retinal Diseases pathology
Retinal Diseases metabolism
Retinal Diseases drug therapy
Cytochrome P450 Family 4 genetics
Mice, Inbred C57BL
Cell Line
Lipid Peroxidation drug effects
Ferroptosis genetics
Ferroptosis drug effects
Corneal Dystrophies, Hereditary genetics
Corneal Dystrophies, Hereditary pathology
Corneal Dystrophies, Hereditary metabolism
Corneal Dystrophies, Hereditary drug therapy
Retinal Pigment Epithelium metabolism
Retinal Pigment Epithelium pathology
Retinal Pigment Epithelium drug effects
Mice, Knockout
Subjects
Details
- Language :
- English
- ISSN :
- 1478-811X
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell communication and signaling : CCS
- Publication Type :
- Academic Journal
- Accession number :
- 38992691
- Full Text :
- https://doi.org/10.1186/s12964-024-01710-x