Free Radic Biol Med. 2026 Jan 22:S0891-5849(26)00055-9. doi: 10.1016/j.freeradbiomed.2026.01.037. Online ahead of print.
ABSTRACT
Glaucoma remains the leading cause of irreversible blindness worldwide. Trabecular meshwork (TM) dysfunction, particularly fibrosis, is a major driver of elevated intraocular pressure (IOP). Although steroid-induced glaucoma is well established, the impact of chronic stress-related endogenous steroids on TM pathology remains unclear. This study established a corticosterone induced chronic stress mouse model and a cortisol treated human TM cells (HTMCs) model that demonstrated that sustained steroid elevation promotes TM fibrosis and mitochondrial dysfunction. RNA sequencing of HTMCs after cortisol treatment revealed monoamine oxidase A (MAOA) upregulation and enrichment of profibrotic pathways. Cortisol increased mitochondrial elongation factor 1 (MIEF1) and dynamin-related protein 1 (DRP1) phosphorylation at Ser616 (p-DRP1Ser616), driving excessive fission. Knockdown of MAOA or MIEF1 reduced oxidative stress, mitochondrial fragmentation, and extracellular matrix remodeling, whereas overexpression of MAOA and MIEF1 produced the opposite effect. Molecular docking, molecular dynamics simulations, and co-immunoprecipitation confirmed that MAOA interacts with MIEF1 and enhances MIEF1-DRP1 coupling. This study identified the MIEF1-MAOA-DRP1 pathway as a mediator of stress-induced TM fibrosis. It provides new insight into the pathogenesis of glaucoma and identifies MAOA as a potential intervention target for treating glaucoma.
PMID:41579974 | DOI:10.1016/j.freeradbiomed.2026.01.037