Hypoxia-induced retinal cell death: roles of metabolic remodeling and mitochondrial dysfunction

The retina is one of the most metabolically demanding tissues in the human body, characterized by exceptionally high oxygen consumption, robust aerobic glycolysis, and a tightly orchestrated metabolic ecosystem between photoreceptors, Müller glia, and the retinal pigment epithelium (RPE). This metabolic specialization renders the retina uniquely vulnerable to hypoxic insults, which arise in both acute settings such as central retinal artery occlusion (CRAO), retinal vein occlusion (RVO), and ischemia–reperfusion (I/R) injury, and in chronic disease contexts including diabetic retinopathy (DR), age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and glaucoma. Hypoxia activates hypoxia-inducible factor (HIF)-driven transcriptional programs that drive metabolic remodeling, with shifts toward glycolysis, alterations in mitochondrial substrate utilization, and lipid droplet accumulation. These changes can contribute to mitochondrial dysfunction, including electron transport chain (ETC) impairment, excessive reactive oxygen species (ROS) generation, mitochondrial membrane permeabilization, and disrupted mitochondrial dynamics. Mitochondrial injury can intersect with regulated cell death (RCD) pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, and parthanatos, although the contribution of each pathway and its dependence on hypoxia vary across retinal cell types and disease models. Cell-type-specific metabolic dependencies dictate differential vulnerability: photoreceptors rely on glycolytic flux supported by RPE substrate exchange, while retinal ganglion cells (RGCs) depend heavily on oxidative phosphorylation (OXPHOS) and exhibit particular susceptibility to hypoxic mitochondrial collapse. Experimental retinal I/R studies support a contribution of the HIF-1α/BNIP3 axis to mitochondrial injury and RGC loss, whereas its involvement in other retinal disease settings requires further validation. Complementary studies using conditional HIF/VHL knockout models, oxygen-induced retinopathy (OIR), and unilateral common carotid artery occlusion (UCCAO) have identified context-dependent roles for HIF signaling and metabolic remodeling. Pharmacological HIF inhibitors (halofuginone, topotecan, lactoferrin) and metabolic modulators (pemafibrate, NMN) have shown protective effects in selected preclinical models. This review synthesizes current understanding of how hypoxia drives metabolic remodeling and mitochondrial dysfunction to trigger retinal cell death, integrates clinical relevance for chronic retinal diseases, and outlines therapeutic strategies and future directions.