scholarly journals Quercetin inhibits transforming growth factor β1-induced epithelial–mesenchymal transition in human retinal pigment epithelial cells via the Smad pathway

2018 ◽  
Vol Volume 12 ◽  
pp. 4149-4161 ◽  
Author(s):  
Wenting Cai ◽  
Donghui Yu ◽  
Jiaqi Fan ◽  
Xiuwei Liang ◽  
Huizi Jin ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Retinal Pigment Epithelial ◽  
Transforming Growth Factor ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Pigment Epithelial ◽  
Growth Factor Beta ◽  
Pigment Epithelial Cells

scholarly journals Suppression of PGC-1α Drives Metabolic Dysfunction in TGFβ2-Induced EMT of Retinal Pigment Epithelial Cells

2021 ◽  
Vol 22 (9) ◽  
pp. 4701
Author(s):  
Daisy Y. Shu ◽  
Erik R. Butcher ◽  
Magali Saint-Geniez
Keyword(s):  
Epithelial Cells ◽  
Retinal Pigment Epithelial ◽  
Transforming Growth Factor ◽  
Citrate Synthase ◽  
Mitochondrial Dynamics ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Mesenchymal Transition ◽  
Pigment Epithelial ◽  
Pigment Epithelial Cells

PGC-1α, a key orchestrator of mitochondrial metabolism, plays a crucial role in governing the energetically demanding needs of retinal pigment epithelial cells (RPE). We previously showed that silencing PGC-1α induced RPE to undergo an epithelial-mesenchymal-transition (EMT). Here, we show that induction of EMT in RPE using transforming growth factor-beta 2 (TGFβ2) suppressed PGC-1α expression. Correspondingly, TGFβ2 induced defects in mitochondrial network integrity with increased sphericity and fragmentation. TGFβ2 reduced expression of genes regulating mitochondrial dynamics, reduced citrate synthase activity and intracellular ATP content. High-resolution respirometry showed that TGFβ2 reduced mitochondrial OXPHOS levels consistent with reduced expression of NDUFB5. The reduced mitochondrial respiration was associated with a compensatory increase in glycolytic reserve, glucose uptake and gene expression of glycolytic enzymes (PFKFB3, PKM2, LDHA). Treatment with ZLN005, a selective small molecule activator of PGC-1α, 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 metabolic shift towards reduced OXPHOS and increased glycolysis that may be driven by PGC-1α suppression. ZLN005 effectively blocks EMT in RPE and thus serves as a novel therapeutic avenue for treatment of subretinal fibrosis.

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