1. Academic Validation
  2. m6A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis

m6A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis

  • Cell Rep. 2022 Nov 15;41(7):111671. doi: 10.1016/j.celrep.2022.111671.
Xue Chen 1 Ying Wang 2 Jia-Nan Wang 2 Qiu-Chen Cao 2 Ru-Xu Sun 2 Hong-Jing Zhu 2 Ye-Ran Zhang 2 Jiang-Dong Ji 2 Qing-Huai Liu 3
Affiliations

Affiliations

  • 1 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China. Electronic address: drcx1990@vip.163.com.
  • 2 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China.
  • 3 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China. Electronic address: liuqh@njmu.edu.cn.
Abstract

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 N6-methyladenosine (m6A) 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 m6A 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.

Keywords

CP: Neuroscience; age-related macular degeneration; circular RNA; m(6)A; oxidative stress; retinal pigment epithelium.

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