Coordinated retinal metabolic remodeling reveals mitochondrial stress and redox vulnerability in experimental myopia.

Form-deprivation myopia (FDM) was initiated by retinal responses to abnormal visual input, but how retinal metabolism was coordinated with mitochondrial and redox homeostasis remains incompletely understood. We integrated transcriptomics, proteomics, untargeted and targeted metabolomics, U-13C6-glucose tracing, extracellular flux analysis, molecular validation, and transmission electron microscopy in a guinea pig FDM model. FDM retinas showed accumulation of glycolytic intermediates and lactate, increased glucose-derived carbon contribution to lactate, and upregulation of GLUT1, HK2, PFKFB3, PKM, and LDHA. Although oxidative-phosphorylation-related proteins were reduced and mitochondrial cristae were disrupted, basal, maximal, and ATP-linked oxygen consumption were not significantly decreased, indicating early mitochondrial stress rather than global respiratory failure. Glutathione abundance was reduced, whereas cystathionine, γ-glutamylphenylalanine, serine- and glycine-related metabolites, PHGDH, and SHMT2 were increased, consistent with remodeling of sulfur amino acid and one-carbon pathways in a redox-stressed metabolic environment. Lipidomics further showed increased triglycerides and membrane phospholipids, accompanied by increased CD36, FATP2, ACC1, and SCD1 and reduced PPARα, FADS1, FADS2, and ELOVL5, indicating a shift toward fatty acid uptake and synthesis at the expense of oxidation and polyunsaturated fatty acid processing. Together, these findings defined an early redox-vulnerable metabolic state in the myopic retina, in which enhanced glycolytic carbon use, compensatory amino acid remodeling, mitochondrial structural stress, and lipid redistribution occur in parallel. The identified network was hypothesis-generating and provided a framework for future cell-specific and intervention-based studies.