1. Academic Validation
  2. ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway

ALKBH5 causes retinal pigment epithelium anomalies and choroidal neovascularization in age-related macular degeneration via the AKT/mTOR pathway

  • Cell Rep. 2023 Jul 11;42(7):112779. doi: 10.1016/j.celrep.2023.112779.
Ru-Xu Sun 1 Hong-Jing Zhu 1 Ye-Ran Zhang 1 Jia-Nan Wang 1 Ying Wang 1 Qiu-Chen Cao 1 Jiang-Dong Ji 1 Chao Jiang 1 Song-Tao Yuan 2 Xue Chen 3 Qing-Huai Liu 4
Affiliations

Affiliations

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

Retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) are predominant features of age-related macular degeneration (AMD), with an unclear mechanism. Herein, we show that RNA demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) is up-regulated in AMD. In RPE cells, ALKBH5 overexpression associates with depolarization, oxidative stress, disturbed Autophagy, irregular lipid homeostasis, and elevated VEGF-A secretion, which subsequently promotes proliferation, migration, and tube formation of vascular endothelial cells. Consistently, ALKBH5 overexpression in mice RPE correlates with various pathological phenotypes, including visual impairments, RPE anomalies, choroidal neovascularization (CNV), and interrupted retinal homeostasis. Mechanistically, ALKBH5 regulates retinal features through its demethylation activity. It targets PIK3C2B and regulates the Akt/mTOR signaling pathway with YTHDF2 as the N6-methyladenosine reader. IOX1, an ALKBH5 inhibitor, suppresses hypoxia-induced RPE dysfunction and CNV progression. Collectively, we demonstrate that ALKBH5 induces RPE dysfunction and CNV progression in AMD via PIK3C2B-mediated activation of the Akt/mTOR pathway. Pharmacological inhibitors of ALKBH5, like IOX1, are promising therapeutic options for AMD.

Keywords

ALKBH5; CP: Cell biology; IOX1; N(6)-methyladenosine; age-related macular degeneration; choroidal neovascularization; retinal pigment epithelium.

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