{"doi":"10.1038/s42003-024-06773-7","title":"Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration","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.","journal":"Communications Biology","year":2024,"id":426145,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":759566,"name":"Wenjing Wu","orcid":"0000-0001-8437-3370","position":1,"is_corresponding":false},{"id":1070418,"name":"Miwa Hara","orcid":null,"position":2,"is_corresponding":false},{"id":1225531,"name":"Junwen Zhou","orcid":null,"position":3,"is_corresponding":false},{"id":695689,"name":"Carolina Panzarin","orcid":"0000-0003-0903-2343","position":4,"is_corresponding":false},{"id":451311,"name":"Christopher M. Schafer","orcid":"0000-0002-5859-7714","position":5,"is_corresponding":false},{"id":451313,"name":"Courtney T. Griffin","orcid":"0000-0001-8100-3171","position":6,"is_corresponding":false},{"id":1224950,"name":"Jiyang Cai","orcid":"0000-0003-3370-7531","position":7,"is_corresponding":false},{"id":279641,"name":"Jian‐xing Ma","orcid":"0000-0001-8815-1716","position":8,"is_corresponding":false},{"id":471596,"name":"Yusuke Takahashi","orcid":"0000-0002-5436-2942","position":9,"is_corresponding":false},{"id":759565,"name":"Xiang Ma","orcid":"0000-0002-2307-1309","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:58:37.924718Z","pmid":"39223298","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}