m 6 A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis

• Published in: Cell reports (Cambridge) Vol. 41; no. 7; p. 111671
• Main Authors: Chen, Xue, Wang, Ying, Wang, Jia-Nan, Cao, Qiu-Chen, Sun, Ru-Xu, Zhu, Hong-Jing, Zhang, Ye-Ran, Ji, Jiang-Dong, Liu, Qing-Huai
• Format: Journal Article
• Language: English
• Published: United States 15.11.2022
• Subjects: Aged; Animals; Homeostasis; Humans; Macular Degeneration - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Oxidative Stress - genetics; Retina - metabolism; Retinal Pigment Epithelium - pathology; RNA, Circular - genetics; mA; CP: Neuroscience; circular RNA; retinal pigment epithelium; age-related macular degeneration; oxidative stress
• ISSN: 2211-1247

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population with unclear pathogenic mechanism. Herein, we detect downregulated circSPECC1 expression in retinal pigment epithelium (RPE) of AMD patients. In RPE cells, circSPECC1 insufficiency leads to oxidative stress-induced ferroptosis, depolarization, and irregular lipid metabolism. Consistently, in mice, circSPECC1 deficiency induces visual impairments and RPE anomalies and interrupts retinal homeostasis. Mechanically, nuclear export of circSPECC1 transcript depends on its N -methyladenosine (m A) level with YTHDC1 as the reader. CircSPECC1 directly sponges miR-145-5p to block its interaction with CDKN1A. Overexpressing miR-145-5p aggravates RPE dysfunctions, mimicking circSPECC1 silencing effects. Retinal phenotypes induced by circSPECC1 insufficiency are alleviated by miR-145-5p inhibition and are aggravated by miR-145-5p overexpression. Collectively, circSPECC1, mediated by m A modification and sponging miR-145-5p, resists oxidative stress injuries and maintains lipid metabolism in RPE. Pharmacological supplementation of circSPECC1 is a promising therapeutic option for atrophic retinopathies like AMD.