Nishikawa Keiichi, Murakami Tomoaki, Yoshida Miyo, Terada Noriko, Ishihara Kenji, Mori Yuki, Ito Shinji, Tsujikawa Akitaka
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Diabetes. 2025 Mar 1;74(3):409-415. doi: 10.2337/db24-0040.
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.
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.
眼底成像技术的进步揭示了糖尿病视网膜病变（DR）中神经血管单元的破坏。在抗血管内皮生长因子治疗的时代，在DR患者得到充分治疗之前，对神经退行性变进行全面表征至关重要。在此，我们证明细胞外线粒体加剧了DR中的视网膜色素上皮（RPE）变性和炎症。DR患者玻璃体中的细胞外线粒体增加，且与视力损害相关，但与增殖性糖尿病视网膜病变或糖尿病性黄斑水肿无关。动物实验证明细胞外线粒体对RPE和光感受器有有害影响。RPE细胞中由细胞外线粒体诱导的溶酶体细胞死亡需要线粒体DNA，但不需要其模式识别受体。此外，生化筛选确定了DNA受体的候选物。其中，DNA依赖性蛋白激酶在体外和体内实验中都是细胞外线粒体诱导细胞死亡所必需的。细胞外线粒体还以Toll样受体9依赖性方式进一步诱导RPE细胞中白细胞介素-1β和肿瘤坏死因子-α的表达。RNA测序表明，细胞外线粒体至少部分通过促进巨噬细胞的增殖和迁移来加剧炎症。总之，细胞外线粒体被确定为DR中RPE变性的一种新的加剧因素。
应在糖尿病视网膜病变中制定针对视网膜色素上皮变性的治疗策略。我们研究了糖尿病视网膜病变中细胞外线粒体导致视网膜色素上皮变性的分子机制。在糖尿病视网膜病变患者的玻璃体液中发现了细胞外线粒体，其通过DNA依赖性蛋白激酶、经由Toll样受体9的细胞因子表达和巨噬细胞激活加剧了视网膜色素上皮变性。细胞外线粒体被确定为糖尿病视网膜病变中神经退行性变和炎症的加重因素。
