PEDF-Mediated Mitophagy Triggers the Visual Cycle by Enhancing Mitochondrial Functions in a H(2)O(2)-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 (H(2)O(2))-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 H(2)O(2)-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 H(2)O(2)-injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.