TAZ (Wwtr1) deficiency leads to ER stress and mitochondrial dysfunction in a mouse model of Fuchs' endothelial...

Fuchs' endothelial corneal dystrophy (FECD) impacts over 300 million individuals worldwide with corneal transplantation as the primary treatment. There is a dire need to establish non-surgical alternatives which are dependent on mouse models. Transcriptional co-activator with PDZ-binding motif (TAZ, encoded by Wwtr1) is a mechanotransducer implicated in maintaining homeostasis of corneal endothelial cells (CEnC). Wwtr1 ^-/- (TAZ KO) mice serve as an animal model for late-onset FECD. We combined single-cell transcriptomics, transmission electron microscopy, and immunofluorescence staining to elucidate the mechanisms driving pathogenesis in young (2-month-old) and geriatric (11-month-old) mice. A progressive stress response was observed in TAZ KOs defined by endoplasmic reticulum (ER) stress, mitochondrial structural and functional abnormalities, and impaired Na⁺/K⁺ ATPase localization. These changes were accompanied by an altered expression of genes involved in extracellular matrix (ECM) organization, oxidative phosphorylation, macroautophagy and response to oxidative stress. Additionally, we noted age-related differences in cellular response with young TAZ KO CEnCs upregulating macroautophagy and downregulating ECM organization while geriatric TAZ KO CEnCs downregulated macroautophagy, and ECM organization. Both TAZ KO groups downregulated response to oxidative stress and cell-substrate adhesion. Together, these findings establish a mechanistic link between disrupted mechanotransduction and organelle stress in CEnC degeneration, further elaborating on potential mechanisms driving FECD pathogenesis. This positions TAZ KO mice as a translational platform for evaluating non-surgical therapeutic strategies targeting FECD.