MiRNA-122-5p promotes retinal ganglion cell oxidative damage by targeting DJ-1 in hyperglycemic retina

Mitochondrial dysfunction, induced by prolonged hyperglycemia, is widely regarded as a central factor in oxidative stress and retinal ganglion cell (RGC) degeneration in diabetic retinopathy (DR). DJ-1 (PARK7) acts as a crucial antioxidant defense mechanism, stabilizing mitochondrial structure and redox balance. However, its expression is dramatically suppressed under diabetic conditions, and the upstream regulatory mechanisms remain incompletely characterized. Growing evidence from epigenetic research implicates MicroRNAs (miRNAs) as important players in the molecular pathways underlying DR progression. Among these, miRNA-122-5p has drawn increasing attention due to its aberrant activity under diabetic stress and its putative interaction with PARK7. In this study, we employed a streptozotocin-induced type 1 diabetes mouse model and glucose-stimulated R28 cells to explore the contribution of miRNA-122-5p to mitochondrial damage, oxidative stress, and RGC injury. In diabetic mice, we observed significant oxidative imbalance, increased apoptotic activity, RGC loss, and diminished retinal function. MiRNA profiling identified miRNA-122-5p as the most upregulated among candidate miRNAs. Inhibition of miRNA-122-5p attenuated these pathological changes and preserved both cellular integrity and visual function. In vitro, high glucose triggered mitochondrial fragmentation, membrane potential collapse, and excessive Reactive Oxygen Species generation in R28 cells. Suppressing miRNA-122-5p alleviated these injuries. Dual-luciferase assays confirmed that miRNA-122-5p directly targets PARK7, thereby post-transcriptionally repressing DJ-1 expression and compromising mitochondrial resilience. These findings establish miRNA-122-5p as a critical upstream regulator of DJ-1-mediated antioxidant defense. By aggravating mitochondrial oxidative stress, it contributes to RGC vulnerability in DR. Targeted modulation of miRNA-122-5p may offer a novel therapeutic approach to preserve retinal neurons and counteract neurodegeneration in DR.

DJ-1; Diabetic retinopathy; MicroRNA-122-5p; Mitochondria; Oxidative stress; Retinal ganglion cells.