Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Research
2024
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| _version_ | 1826314560614694912 |
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| author | Ma, X Wu, W Hara, M Zhou, J Panzarin, C Schafer, CM Griffin, CT Cai, J Ma, J Takahashi, Y |
| author_facet | Ma, X Wu, W Hara, M Zhou, J Panzarin, C Schafer, CM Griffin, CT Cai, J Ma, J Takahashi, Y |
| author_sort | Ma, X |
| collection | OXFORD |
| 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, 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. |
| first_indexed | 2024-09-25T04:34:20Z |
| format | Journal article |
| id | oxford-uuid:f928b5a0-f99c-41e0-bd1e-7c2d17053b97 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:34:20Z |
| publishDate | 2024 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:f928b5a0-f99c-41e0-bd1e-7c2d17053b972024-09-11T20:03:49ZDeficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degenerationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f928b5a0-f99c-41e0-bd1e-7c2d17053b97EnglishJisc Publications RouterNature Research2024Ma, XWu, WHara, MZhou, JPanzarin, CSchafer, CMGriffin, CTCai, JMa, JTakahashi, YSubretinal 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. |
| spellingShingle | Ma, X Wu, W Hara, M Zhou, J Panzarin, C Schafer, CM Griffin, CT Cai, J Ma, J Takahashi, Y Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title | Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title_full | Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title_fullStr | Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title_full_unstemmed | Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title_short | Deficient RPE mitochondrial energetics leads to subretinal fibrosis in age-related neovascular macular degeneration |
| title_sort | deficient rpe mitochondrial energetics leads to subretinal fibrosis in age related neovascular macular degeneration |
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