Quantum Dots‐caused Retinal Degeneration in Zebrafish Regulated by Ferroptosis and Mitophagy in Retinal Pigment Epithelial Cells through Inhibiting Spliceosome

• Published in: Advanced science 2024-10, Vol.11 (46), p.e2406343-n/a
• Main Authors: Zheng, Naying, Liao, Tingting, Zhang, Chuchu, Zhang, Zheyang, Yan, Sen, Xi, Xiaohan, Ruan, Fengkai, Yang, Chunyan, Zhao, Qingliang, Deng, Wenbo, Huang, Jialiang, Huang, Zi‐Tao, Chen, Zhi‐Feng, Wang, Xiang, Qu, Qingming, Zuo, Zhenghong, He, Chengyong
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Embryos; Ferroptosis; Ferroptosis - genetics; Mitophagy - genetics; Morphology; Nanoparticles; Proteins; Quantum Dots; Retina; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Single‐cell RNA sequencing; Spliceosome; Spliceosomes - genetics; Spliceosomes - metabolism; Toxicity; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202406343

Quantum dots (QDs) are widely used, but their health impact on the visual system is little known. This study aims to elucidate the effects and mechanisms of typical metallic QDs on retinas using zebrafish. Comprehensive histology, imaging, and bulk RNA sequencing reveal that InP/ZnS QDs cause retinal degeneration. Furthermore, single‐cell RNA‐seq reveals a reduction in the number of retinal pigment epithelial cells (RPE) and short‐wave cone UV photoreceptor cells (PR(UV)), accompanied by an increase in middle‐ and long‐wave cone red, green, and blue photoreceptor cells [PR(RGB)]. Mechanistically, after endocytosis by RPE, InP/ZnS QDs inhibit the expression of splicing factor prpf8, resulting in gpx4b mRNA unsplicing, which finally decrease glutathione and induce ferroptosis and mitophagy. The decrease of RPE fails to engulf the damaged outer segments of PR, possibly promoting the differentiation of PR(UV) to PR(RGB). Knockout prpf8 or gpx4b with CRISPR/Cas9 system, the retinal damage is also observed. Whereas, overexpression of prpf8 or gpx4b, or supplement of glutathione can rescue the retinal degenerative damage caused by InP/ZnS QDs. In conclusion, this study illustrates the potential health risks of InP/ZnS QDs on eye development and provides valuable insights into the underlying mechanisms of InP/ZnS QDs‐caused retinal degeneration. This study delves into the impact of QDs on the visual system, emphasizing the profound retinal degeneration caused by InP/ZnS QDs in zebrafish. The results illustrate InP/ZnS QDs‐caused retinal degeneration regulated by ferroptosis and mitophagy in RPE cells via inhibiting PRPF8‐related spliceosome. Furthermore, potential therapeutic interventions are developed, including prpf8 or gpx4b overexpression, and glutathione supplement.