ME3 (malic enzyme 3) is a mitochondrial NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of (S)-malate to pyruvate, contributing to both pyruvate biosynthesis and malate metabolism [7818469]. The enzyme localizes to the mitochondrial matrix and can reverse this reaction with significantly lower efficiency, functioning primarily in the forward direction under physiological conditions [7818469]. ME3 has been identified as a genetic risk factor for primary open-angle glaucoma (POAG) through genome-wide association studies. In a large cross-sectional study of 2,617 POAG patients and 2,634 controls, higher ME3 genetic risk scores were associated with specific disease phenotypes, including greater prevalence of paracentral visual field loss and higher maximum treated intraocular pressure [36813040]. SNP effect sizes in the ME3 locus strongly correlated with reduced ME3 expression levels, suggesting that altered mitochondrial metabolic capacity may contribute to glaucoma pathogenesis [36813040]. ME3 variants also associate with other complex traits including age-related macular degeneration and various systemic conditions, though the mechanistic basis for these associations remains unclear. Functional studies exploring how ME3 variants impact mitochondrial function and oxidative metabolism in disease contexts are warranted to better understand the clinical relevance of these associations.