Melatonin prevents blood-retinal barrier breakdown and mitochondrial dysfunction in high glucose and hypoxia-induced in vitro diabetic macular edema model

Diabetic macular edema (DME) is a leading cause of blindness in diabetic retinopathy. Prolonged hyperglycemia plus hypoxia contributes to DME pathogenesis. Retinal pigmented epithelial cells comprise the outer blood-retinal barrier and are essential for maintaining physiological functioning of the retina. Melatonin acts as an antioxidant and regulator of mitochondrial bioenergetics and has a protective effect against ocular diseases. However, the role of mitochondrial dysfunction and the therapeutic potential of melatonin in DME remain largely unexplored. Here, we used an in vitro model of DME to investigate blood-retinal barrier integrity and permeability, angiogenesis, mitochondrial dynamics, and apoptosis signaling to evaluate the potential protective efficacy of melatonin in DME. We found that melatonin prevents cell hyper-permeability and outer barrier breakdown by reducing HIF-1α, HIF-1β and VEGF and VEGF receptor gene expression. In addition, melatonin reduced the expression of genes involved in mitochondrial fission (DRP1, hFis1, MIEF2, MFF), mitophagy (PINK, BNip3, NIX), and increased the expression of genes involved in mitochondrial biogenesis (PGC-1α, NRF2, PPAR-γ) to maintain mitochondrial homeostasis. Moreover, melatonin prevented apoptosis of retinal pigmented epithelial cells. Our results suggest that mitochondrial dysfunction may be involved in DME pathology, and melatonin may have therapeutic value in DME, by targeting signaling in mitochondria.