Journal Article

Deficiency of 2‐Oxoglutarate Carrier (Slc25a11) Drives RPE Epithelial‐to‐Mesenchymal Transition and Exacerbates Subretinal Fibrosis in Neovascular Age‐Related Macular Degeneration

Tang, Wenyi, Sreekumar, Parameswaran G., Lei, Boya, Gao, Feng‐Juan, Xu, Gezhi, Ma, Jun, Sadda, Srinivas R., Kannan, Ram, Wang, Mo, Hu, Fangyuan

2025

Overview

Subretinal fibrosis significantly contributes to vision loss in neovascular age‐related macular degeneration (nAMD). Epithelial‐to‐mesenchymal transition (EMT) in RPE cells is a key early step in subretinal fibrosis. While mitochondrial dysfunction in RPE is involved, the metabolic and molecular connections between EMT and mitochondria are not well understood. This study explores the role of oxoglutarate carrier (OGC; Slc25a11) on EMT and investigates the molecular mechanisms, focusing on its role in mitochondrial metabolism and GSH transport. OGC‐silenced or overexpressed ARPE‐19 cells were treated with TGF‐β2 (10 ng/mL) for 48 h. EMT markers, cell migration, mtGSH, and mitochondrial bioenergetics and signaling pathways were assessed. In vivo, subretinal fibrosis was induced in wild‐type and OGC+/− mice via laser photocoagulation. Fibrosis volume was measured using optical coherence tomography and immunostaining in RPE‐choroid flat mounts. OGC silencing aggravated EMT, while overexpression attenuated TGF‐β2‐induced EMT, cell proliferation, and migration. OGC knockdown significantly enhanced RPE EMT, as evidenced by upregulated expression of α‐SMA, fibronectin, collagen type I, and Slug, while E‐cadherin was downregulated. OGC overexpression improved mitochondrial bioenergetics, whereas its inhibition reduced mitochondrial respiration, which was further aggravated by co‐treatment with TGF‐β2. Loss of OGC promoted cell proliferation and migration through Slug‐mediated EMT. OGC depletion stimulated EMT via pSmad2/3 upregulation, dependent on the PI3K/AKT signaling pathway activation. In vivo studies further demonstrate that subretinal fibrosis was significantly augmented in OGC+/− mice via TGF‐β2‐dependent PI3K signaling. In conclusion, modulating OGC expression in RPE affects EMT and mitochondrial function, making OGC a potential therapeutic target for subretinal fibrosis in nAMD. The diagram shows that OGC deficiency leads to mitochondrial dysfunction, which activates the PI3K/AKT/Slug pathway and triggers epithelial‐mesenchymal transition (EMT) in retinal pigment epithelial cells. This process promotes myofibroblast accumulation and subretinal fibrosis in laser‐induced CNV, contributing to the progression of AMD.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Animals / Bioenergetics / Blood vessels / Cell migration / Cell proliferation / Collagen (type I) / Epithelial-Mesenchymal Transition - genetics / Fibroblasts / Fibronectin / Fibrosis / Glutathione / Humans / Laboratory animals / Lasers / Macular degeneration / Macular Degeneration - genetics / Macular Degeneration - metabolism / Macular Degeneration - pathology / Medical imaging / Metabolism / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria - metabolism / mitochondrial dysfunction / Molecular modelling / neovascular AMD / OGC / Pathogenesis / Retinal Pigment Epithelium - metabolism / Retinal Pigment Epithelium - pathology / RPE‐EMT / Signal Transduction / Smooth muscle / subretinal fibrosis / Therapeutic targets / Tomography / Vascular endothelial growth factor