PEDF-Mediated Mitophagy Triggers the Visual Cycle by Enhancing Mitochondrial Functions in a H₂O₂-Injured Rat Model

Retinal degenerative diseases result from oxidative stress and mitochondrial dysfunction, leading to the loss of visual acuity. Damaged retinal pigment epithelial (RPE) and photoreceptor cells undergo mitophagy. Pigment epithelium-derived factor (PEDF) protects from oxidative stress in RPE and improves mitochondrial functions. Overexpression of PEDF in placenta-derived mesenchymal stem cells (PD-MSCs; PD-MSCs^PEDF) provides therapeutic effects in retinal degenerative diseases. Here, we investigated whether PD-MSCs^PEDF restored the visual cycle through a mitophagic mechanism in RPE cells in hydrogen peroxide (H₂O₂)-injured rat retinas. Compared with naïve PD-MSCs, PD-MSCs^PEDF augmented mitochondrial biogenesis and translation markers as well as mitochondrial respiratory states. In the H₂O₂-injured rat model, intravitreal administration of PD-MSCs^PEDF restored total retinal layer thickness compared to that of naïve PD-MSCs. In particular, PTEN-induced kinase 1 (PINK1), which is the major mitophagy marker, exhibited increased expression in retinal layers and RPE cells after PD-MSC^PEDF transplantation. Similarly, expression of the visual cycle enzyme retinol dehydrogenase 11 (RDH11) showed the same patterns as PINK1 levels, resulting in improved visual activity. Taken together, these findings suggest that PD-MSCs^PEDF facilitate mitophagy and restore the loss of visual cycles in H₂O₂-injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.