The interplay between metabolic reprogramming, mitochondrial impairment, and steroid response in proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a major cause of rhegmatogenous retinal detachment repair failure. Despite many attempts to find therapeutics for PVR, no pharmacotherapy has been proven effective. Steroids, as the epitome, show uncertain clinical effectiveness, which lacks an explanation and hints at unappreciated mechanisms of PVR. In this study, we investigated the involvement of metabolic reprogramming, mitochondrial impairment, and their association with steroid effectiveness in PVR using dexamethasone (Dex) as an example. Proteomics of vitreous samples from PVR patients demonstrated an upregulation in the glycolysis pathway. Transcriptomics of PVR tissues (dataset GSE179603) revealed downregulations in oxidative phosphorylation (OXPHOS), mitochondrial respiration, and mitochondrial quality control-related pathways. Transcriptomics of TGFβ and TNFα (TNT)-induced retinal pigment epithelial (RPE) cell model (GSE176513) confirmed the changes in glycolysis, OXPHOS, and mitochondria and also revealed downregulation of Dex response pathway with increased duration of TNT exposure. Transcriptomics of mouse RPE/choroid following Dex intravitreal injections (GSE49872) showed that glycolysis decreased at 1-week postinjection but increased at 1-month postinjection; OXPHOS increased but gradually decreased with treatment duration. The dispase-induced mouse PVR model revealed that a simultaneous Dex injection could alleviate PVR severity rather than an injection 5 days after the PVR induction. The TGFβ2-induced RPE cell model demonstrated the enhancement of EMT, oxidative stress, and mitochondrial impairment, which could be alleviated by Dex: Cellular ROS were accumulated; the mRNA expressions of antioxidases (GPX, SOD1 and TXN2) were decreased; mitochondrial morphology and dynamics were impaired, exhibiting decreases in mitochondrial heterogeneity, mitochondrial length and MFN2 expression; Mitochondrial membrane potential showed an elevation; and mitophagy was decreased, related to reduced Parkin recruitment. These results demonstrate the essential roles of metabolic reprogramming and mitochondrial dysfunction in PVR pathology, which is associated with the therapeutic effect of steroids. Steroid intervention might benefit the treatment of PVR in the early rather than late stages.