Suppression of PGC-1α Drives Metabolic Dysfunction in TGFß2-Induced EMT of Retinal Pigment Epithelial Cells.
Int J Mol Sci
; 22(9)2021 Apr 29.
Article
em En
| MEDLINE
| ID: mdl-33946753
ABSTRACT
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 (TGFß2) suppressed PGC-1α expression. Correspondingly, TGFß2 induced defects in mitochondrial network integrity with increased sphericity and fragmentation. TGFß2 reduced expression of genes regulating mitochondrial dynamics, reduced citrate synthase activity and intracellular ATP content. High-resolution respirometry showed that TGFß2 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 TGFß2-induced upregulation of mesenchymal genes (αSMA, Snai1, CTGF, COL1A1) and TGFß2-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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MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta2
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Epitélio Pigmentado da Retina
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Transição Epitelial-Mesenquimal
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Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article