Stage- and compartment-specific remodeling of autophagy and selective mitophagy in glaucoma: from aqueous outflow dysfunction to retinal ganglion cell neurodegeneration.

Background: Glaucoma is a leading cause of irreversible blindness and is increasingly understood as a chronic neurodegenerative disorder rather than a disease explained solely by elevated intraocular pressure (IOP). Although IOP lowering remains the cornerstone of treatment, many patients continue to progress despite apparently adequate pressure control, indicating that additional mechanisms shape retinal ganglion cell (RGC) vulnerability and disease course. Among these, autophagy and mitophagy have emerged as central regulators of cellular stress adaptation in both anterior and posterior ocular tissues. Main Body: This review argues that glaucoma can be more coherently interpreted through a stage- and compartment-specific framework of autophagy and selective mitophagy. In the conventional outflow pathway, autophagy contributes to mechanoadaptation, proteostasis, and extracellular matrix homeostasis, whereas chronic oxidative and biomechanical stress may impair lysosomal function and autophagic flux, thereby promoting outflow dysfunction and ocular hypertension. In the posterior segment, RGCs and their axons are highly dependent on autophagy for proteostasis and mitochondrial quality control because of their polarized morphology and substantial metabolic demand. Experimental work suggests that autophagy may be protective during early or acute stress but become insufficient, stalled, or maladaptive during chronic injury. Recent human stem cell and animal studies further implicate optineurin-linked autophagic-lysosomal dysfunction, AMPK-mTORC1 imbalance, and reduced PINK1/Parkin-associated mitophagy as mechanistic nodes linking mitochondrial stress to RGC degeneration. These observations support a model in which glaucoma progression reflects not simply more or less autophagy, but failure to maintain effective quality control across distinct ocular compartments and disease stages. Conclusion: A compartment-aware and time-resolved view of autophagy and mitophagy offers a more nuanced framework for glaucoma pathogenesis and therapy. Future progress will likely depend less on indiscriminate pathway modulation than on restoring selective, flux-competent quality control, particularly mitochondrial turnover, in the appropriate tissue and at the appropriate stage of disease.