Age-related Macular Degeneration (AMD), the leading cause of blindness worldwide, is a multifactorial disease with mitochondrial dysfunction recognized as an early pathogenic event. In our preclinical studies, we demonstrated that a single Cerium-Oxide Nanoparticles (CeO2-NPs) intravitreal injection in a light-induced degeneration model, was able to counteract the retinal degeneration. Our aim was to investigate whether neuroprotection activity could be correlated with mitochondrial morpho-functional preservation. Bulk transcriptomic profiling of whole retinal tissue revealed that light-induced retinal injury was associated with suppression of mitochondrial-related gene networks, including components of the electron transport chain and regulators of mitochondrial dynamics, whereas CeO2-NPs treatment restored the expression of antioxidant and mitochondrial biogenesis-related genes. Ultrastructural analysis by electron microscopy showed preservation of Retinal Pigmented Epithelial mitochondria's morphology and by high-resolution crystallographic analysis confirmed the intracellular localization of CeO2-NPs in proximity to mitochondria. Furthermore, Western blot analysis demonstrated that CeO2-NPs maintained mitophagy markers at basal levels, preventing excessive activation of mitochondrial quality-control pathways. Together, these findings support mitochondrial preservation as a key mechanism underlying nanoceria-mediated retinal neuroprotection and highlight CeO2-NPs as promising candidates for maintaining retinal homeostasis in AMD.
