| Experiment Id | GSE221952 | Name | Impaired RPE Mitochondrial Energetics Leads Subretinal Fibrosis in Neovascular Age-related Macular Degeneration |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2025-01-30 |
| description | Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr-/- mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGF2 induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGF receptor I/II complex by interacting with unglycosylated TGF receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGF2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis. The RPE-choroid tissues of WT mice and Vldlr-/- mice at the age of 1 month and 2 months were used for scRNA seq. |
