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Metabolic Reprogramming of the Retinal Pigment Epithelium Drives TGFβ2‐Induced Epithelial‐Mesenchymal Transition
Author(s) -
Shu Daisy,
Butcher Erik,
Cai Siwei,
Senthilkumar Ilakya,
Frank Scott,
Gollapalli Deviprasad,
SaintGeniez Magali
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03272
Subject(s) - epithelial–mesenchymal transition , microbiology and biotechnology , snai1 , biology , retinal pigment epithelium , anaerobic glycolysis , oxidative phosphorylation , glycolysis , chemistry , downregulation and upregulation , retinal , biochemistry , gene , enzyme
Transforming growth factor‐beta 2 (TGFβ2) is a key orchestrator of retinal wound healing through induction of epithelial‐mesenchymal‐transition (EMT) in retinal pigment epithelial cells (RPE). Here we describe a previously unrecognized function of TGFβ2 in modulating mitochondrial morphology and metabolic function in human RPE cells. Treating ARPE‐19 (human RPE cell line) with TGFβ2 (10 ng/ml) induced defects in mitochondrial network integrity with increased sphericity and fragmentation. Correspondingly, TGFβ2 reduced expression of genes regulating mitochondrial dynamics, reduced citrate synthase activity and intracellular ATP content. High‐resolution respirometry showed that TGFβ2 reduced mitochondrial oxidative phosphorylation (OXPHOS) levels consistent with reduced expression of NDUFB5, a key gene of Complex I of the electron transport chain. The reduced mitochondrial respiration was associated with a compensatory increase in gene expression of glycolytic enzymes (PFKFB3, PKM2, LDHA) and glycolytic reserve. TGFβ2 induced a severe suppression of PGC‐1α gene expression and treatment with the selective small molecule activator of PGC‐1α, ZLN005, blocked TGFβ2‐induced upregulation of mesenchymal genes (αSMA, Snai1, CTGF, COL1A1) and TGFβ2‐induced migration using the scratch wound assay. Our data show that EMT is accompanied by mitochondrial dysfunction and a profound metabolic shift towards reduced OXPHOS and increased glycolysis that may be driven by PGC‐1α suppression. The PGC‐1α promoter, ZLN005, effectively blocks EMT in RPE and thus serves as a novel therapeutic avenue for treatment for subretinal fibrosis.