Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration
Xiang Ma, Wenjing Wu, Miwa Hara, Junwen Zhou, Carolina Panzarin, Christopher M. Schafer, Courtney T. Griffin, Jiyang Cai, Jian‐xing Ma, Yusuke Takahashi
Abstract
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. Targeting mitochondrial lipid transporter CPT1A in the retinal pigment epithelium to rebalance the disturbed metabolism and suppress subretinal fibrosis in age-related macular degeneration.