Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China.
Bourns Engineering, The University of California, Riverside, Riverside, CA, 92521, United States.
Exp Eye Res. 2024 May;242:109860. doi: 10.1016/j.exer.2024.109860. Epub 2024 Mar 11.
Recent studies have highlighted that retinal neurodegeneration precedes microvascular changes in diabetic retinopathy (DR), but the specific mechanisms remain unclear. Given the pivotal role of dysfunctional mitochondria and oxidative stress in early DR, our objective was to observe mitochondria-related alterations in the neural retina of type one diabetic mellitus mice with no evidence of DR (T1DM-NDR). We aimed to identify the key mitochondrial-related proteins contributing to mitochondrial injury. Our study revealed that T1DM-NDR mice exhibited outer retina thinning, including the ellipsoid zone, inner segment, and outer segment. Additionally, there was an impaired amplitude of the b-wave in electroretinogram (ERG) and a disorganized arrangement of the photoreceptor layer. In both the retina of DM mice and high glucose (HG)-treated 661w cells, mitochondria appeared swollen and fragmented, with disrupted cristae, disorganized or shortened branches in the mitochondrial network, and decreased mitochondrial membrane potential. Among the mitochondrial-related proteins, dynamin-related protein 1 (Drp1) was upregulated, and the ratio of phosphorylated Drp1 protein at serine 616 (S616) and serine 637 (S637) sites significantly increased in the retina of DM mice. The administration of Mdivi-1 ameliorated high-glucose-induced dysfunctional mitochondria, thereby protecting T1DM-NDR mice retina from morphological and functional injuries. Our findings suggest that hyperglycemia promotes Drp1-mediated mitochondrial dysfunction, which may be a significant factor in the development of DR. The inhibition of high-glucose-induced mitochondrial fission emerges as a potential and innovative intervention strategy for preventing DR.
最近的研究强调，糖尿病视网膜病变（DR）中视网膜神经退行性变先于微血管变化，但具体机制仍不清楚。鉴于功能失调的线粒体和氧化应激在早期 DR 中的关键作用，我们的目的是观察无 DR 证据的 1 型糖尿病（T1DM-NDR）小鼠神经视网膜中的与线粒体相关的改变。我们旨在确定导致线粒体损伤的关键线粒体相关蛋白。我们的研究表明，T1DM-NDR 小鼠表现出外视网膜变薄，包括椭圆体带、内节和外节。此外，视网膜电图（ERG）中的 b 波振幅受损，光感受器层排列紊乱。在 DM 小鼠的视网膜和高糖（HG）处理的 661w 细胞中，线粒体出现肿胀和碎片化，嵴断裂，线粒体网络中的分支排列紊乱或缩短，线粒体膜电位降低。在与线粒体相关的蛋白中，动力相关蛋白 1（Drp1）上调，DM 小鼠视网膜中磷酸化 Drp1 蛋白在丝氨酸 616（S616）和丝氨酸 637（S637）位点的比例显著增加。Mdivi-1 的给药改善了高葡萄糖诱导的功能失调的线粒体，从而保护 T1DM-NDR 小鼠的视网膜免受形态和功能损伤。我们的研究结果表明，高血糖促进 Drp1 介导的线粒体功能障碍，这可能是 DR 发展的重要因素。抑制高葡萄糖诱导的线粒体分裂可能成为预防 DR 的一种有潜力和创新的干预策略。
