Jingqi Huang, Peiyi Jiang, Baoxin Chen, Mi Huang, Jieping Chen, Jiani Wang, Shan Huang, Yizhi Liu
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引用次数: 0
Abstract
Purpose: Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a predominant pathological driver for fibrotic cataracts. This study explores the role and mechanism of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1A), a key mitochondrial regulator, in EMT of LECs.
Methods: RNA-sequencing analysis was applied to reveal biological changes during human lens epithelial fibrosis. Primary rabbit LECs were treated with TGFβ2 to induce EMT. Mitochondrial alterations were evaluated by MitoTracker staining, transmission electron microscopy, mitochondrial membrane potential assay, ATP content assay, and reactive oxygen species (ROS) assay. Loss- and gain-of-function studies were performed to uncover roles and mechanisms of PGC1A in EMT of LECs. Changes of PGC1A, EMT markers, and mitochondrial regulators were analyzed by Western blot, immunofluorescence staining, and RT-qPCR. Cell migration was assessed using the cell scratch assay. Ex vivo whole rat lenses were treated with TGFβ2 to induce fibrotic cataract to evaluate the potential therapeutic effect of PGC1A on lens fibrosis. Lens epithelial fibrosis was examined by hematoxylin and eosin (H&E) and immunofluorescence staining.
Results: PGC1A was decreased with significant mitochondrial dysfunction during TGFβ2-induced EMT of LECs. PGC1A silencing promoted EMT by enhancing TGFβ2-Smad2/3 signaling, accelerating subcapsular fibrotic plaque formation. PGC1A upregulation protected LECs from TGFβ2-induced EMT by restoring mitochondrial health and energy metabolism. Mechanistically, PGC1A inhibition decreased mitochondrial transcription factor (TFAM), which mediated protective effects of PGC1A on mitochondria and LECs. Further, ZLN005, a PGC1A agonist, attenuated fibrotic lens opacity via preventing LECs from EMT.
Conclusions: PGC1A safeguards LECs against EMT by restoring TFAM-mediated mitochondrial energy metabolism under TGFβ2 stress, offering potential targets for the treatment of lens epithelial fibrosis.
期刊介绍：
Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.
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