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Article

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

1
Schepens Eye Research Institute of Mass, Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
2
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Monica Fedele
Int. J. Mol. Sci. 2021, 22(9), 4701; https://doi.org/10.3390/ijms22094701
Received: 4 April 2021 / Revised: 24 April 2021 / Accepted: 26 April 2021 / Published: 29 April 2021
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT) 2021)
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. View Full-Text
Keywords: retinal pigment epithelium (RPE); metabolism; mitochondria; transforming growth factor-beta (TGFβ); epithelial-mesenchymal transition (EMT); bioenergetics; PGC-1α; OXPHOS; glycolysis; mitochondrial dynamics retinal pigment epithelium (RPE); metabolism; mitochondria; transforming growth factor-beta (TGFβ); epithelial-mesenchymal transition (EMT); bioenergetics; PGC-1α; OXPHOS; glycolysis; mitochondrial dynamics
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MDPI and ACS Style

Shu, D.Y.; Butcher, E.R.; Saint-Geniez, M. Suppression of PGC-1α Drives Metabolic Dysfunction in TGFβ2-Induced EMT of Retinal Pigment Epithelial Cells. Int. J. Mol. Sci. 2021, 22, 4701. https://doi.org/10.3390/ijms22094701

AMA Style

Shu DY, Butcher ER, Saint-Geniez M. Suppression of PGC-1α Drives Metabolic Dysfunction in TGFβ2-Induced EMT of Retinal Pigment Epithelial Cells. International Journal of Molecular Sciences. 2021; 22(9):4701. https://doi.org/10.3390/ijms22094701

Chicago/Turabian Style

Shu, Daisy Y., Erik R. Butcher, and Magali Saint-Geniez. 2021. "Suppression of PGC-1α Drives Metabolic Dysfunction in TGFβ2-Induced EMT of Retinal Pigment Epithelial Cells" International Journal of Molecular Sciences 22, no. 9: 4701. https://doi.org/10.3390/ijms22094701

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