Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration

Journal article

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, TGFβ2 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 TGFβ receptor I/II complex by interacting with unglycosylated TGFβ receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFβ2-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.

Authors: Ma, X; Wu, W; Hara, M; Zhou, J; Panzarin, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Biology
• Volume: 7
• Issue: 1
• Article number: 1075
• Publication date: 2024-09-02
• Acceptance date: 2024-08-22
• DOI: 10.1038/s42003-024-06773-7
• EISSN: 2399-3642
• ISSN: 2399-3642
• Language: English