Extracellular Mitochondria Exacerbate Retinal Pigment Epithelium Degeneration in Diabetic Retinopathy

Advancements in fundus imaging are revealing disruptions in the neurovascular unit in diabetic retinopathy (DR). In the era of anti–vascular endothelial growth factor treatment, a thorough characterization of neurodegeneration is imperative until patients with DR are sufficiently treated. Here, we demonstrate that extracellular mitochondria exacerbate retinal pigment epithelium (RPE) degeneration and inflammation in DR. Extracellular mitochondria increased in the vitreous of patients with DR and were associated with visual impairment but not with proliferative diabetic retinopathy or diabetic macular edema. Animal experiments demonstrated detrimental effects of extracellular mitochondria on RPE and photoreceptors. Lysosomal cell death induced by extracellular mitochondria in RPE cells required mitochondrial DNA but not its pattern recognition receptors. Furthermore, biochemical screening identified candidates for DNA receptors. Among them, DNA-dependent protein kinase was necessary for extracellular mitochondria-induced cell death in both in vitro and in vivo experiments. Extracellular mitochondria further induced interleukin-1β and tumor necrosis factor-α expression in RPE cells in a Toll-like receptor 9–dependent manner. RNA sequencing suggested that extracellular mitochondria exacerbate inflammation by promoting the proliferation and migration of macrophages, at least in part. In summary, extracellular mitochondria are designated as a novel exacerbating factor of RPE degeneration in DR. Article Highlights A therapeutic strategy for retinal pigment epithelium degeneration should be developed in diabetic retinopathy. We investigated the molecular mechanisms underpinning retinal pigment epithelium degeneration by extracellular mitochondria in diabetic retinopathy. Extracellular mitochondria were found in the vitreous humor of patients with diabetic retinopathy and exacerbated retinal pigment epithelium degeneration through DNA-dependent protein kinase, cytokine expression via Toll-like receptor 9, and macrophage activation. Extracellular mitochondria are designated as an aggravating factor of neurodegeneration and inflammation in diabetic retinopathy.