Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Department of Ophthalmology, Kosin University College of Medicine, #262 Gamcheon-ro, Seo-gu, Busan 49267, Korea.
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
Cell Rep. 2023 Sep 26;42(9):113054. doi: 10.1016/j.celrep.2023.113054. Epub 2023 Aug 31.
Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.
大多数视网膜色素变性（RP）的突变发生在视杆细胞中，但负责高分辨率日光和色觉的视锥细胞随后会受到影响，导致疾病的最严重特征。我们使用质谱法来跟踪递送至外视网膜的 C 代谢物，并使用单细胞 RNA 测序来评估感光细胞转录组。S 锥细胞代谢转录组提示三羧酸循环的参与和对 ROS 的持续反应，这是氧化磷酸化的特征，我们将其与它们的组蛋白修饰转录组联系起来。肿瘤坏死因子（TNF）及其下游效应物 RIP3 通过线粒体功能障碍驱动 ROS 的产生，在 RP 中 S 锥细胞早期凋亡时被诱导和激活。长/中波（L/M）锥细胞转录组显示出增强的糖酵解能力，这使其在 RP 进展过程中保持功能。然后，随着细胞外葡萄糖最终减少，L/M 锥细胞通过乳酸代谢维持长期休眠。
