Exploring the mitochondrial landscape in trabecular meshwork of primary open-angle glaucoma for novel therapeutic targets

Abstract Glaucoma ranks among the primary contributors to irreversible vision loss globally, with its pathogenesis closely associated with mitochondrial function. This study aims to identify candidate hub genes associated with mitochondrial impairment in the trabecular meshwork (TM) of individuals with primary open-angle glaucoma (POAG) and to develop a corresponding diagnostic model. We extracted mitochondrial-related differentially expressed genes (MRDEGs) from the GSE27276 dataset, utilizing the MitoCarta3.0 database. Functional analysis of MRDEGs was conducted via receiver operating characteristic curve, gene ontology, and kyoto encyclopedia of genes and genomes. A mitochondrial-related diagnostic model was constructed using support vector machine and least absolute shrinkage and selection operator regression, followed by internal validation and external validation using a combined dataset from GSE138125 and GSE4316. The model genes underwent Friends analysis, correlation analysis, and the construction of a transcription factor and miRNA regulatory network. POAG samples from the GSE27276 dataset were categorized into high-risk and low-risk groups, followed by gene set enrichment analysis. A total of 25 MRDEGs were identified, primarily associated with mitochondrial respiration and energy metabolism. Among these, 8 genes emerged as potential hub genes, with ALAS2 and MAOA exhibiting the highest diagnostic specificity, while MGARP was suggested as playing an important role among the hub genes. Validation of the diagnostic model, both internally and externally, demonstrated high accuracy and discrimination ability. In addition to oxidative phosphorylation and TCA cycle, the wnt signaling pathway and neutrophil degranulation were also suggested to be associated with the high-risk state. This study explored mitochondrial-related hub genes in the TM of patients with POAG and establishes a novel diagnostic model, providing potential new directions for research on the pathogenesis and drug targets of POAG.