METTL14-mediated m6A methylation regulates pathological retinal neovascularization by targeting autophagy

• Published in: Experimental cell research 2024-11, Vol.443 (1), p.114291, Article 114291
• Main Authors: Yu, Yang, Nie, Huiling, Qin, Xun, Chen, Xi, Li, Xiumiao, Yao, Jin
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Angiogenesis; Animals; Autophagy; Autophagy - genetics; Autophagy-Related Protein 7 - genetics; Autophagy-Related Protein 7 - metabolism; Endothelial Cells - metabolism; Endothelial Cells - pathology; Humans; Methylation; Methyltransferases - genetics; Methyltransferases - metabolism; METTL14; Mice; Mice, Inbred C57BL; N6-methyladenosine modification; Ocular neovascular diseases; Retina - metabolism; Retina - pathology; Retinal neovascularization; Retinal Neovascularization - genetics; Retinal Neovascularization - metabolism; Retinal Neovascularization - pathology; Retinal Vessels - metabolism; Retinal Vessels - pathology
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114291

Pathological retinal neovascularization (RNV) is a prevalent characteristic of various ocular diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and retinal vein occlusion (RVO). While the importance of N6-methyladenosine (m6A) modification in diverse disease contexts is well-established, its functional role in pathological RNV remains unclear. Herein, we investigated the involvement of m6A modification and its core methyltransferase, METTL14, in a model of oxygen-induced retinopathy (OIR) to elucidate their contribution to retinal angiogenesis. In this study, we observed heightened levels of m6A modification and elevated expression of METTL14 in the OIR model, suggesting their potential implication in pathological RNV. Employing targeted knockdown of METTL14, we revealed that its depletion activated autophagy flux in human retinal vascular endothelial cells (HRVECs), consequently inhibiting the angiogenic capacity of endothelial cells. Mechanistically, we demonstrated that METTL14 exerts its regulatory influence on autophagy flux by modulating the stability of ATG7, a pivotal protein involved in autophagy. Specifically, METTL14 knockdown led to increased ATG7 expression at both mRNA and protein levels, accompanied by reduced m6A methylation of ATG7 mRNA and enhanced mRNA stability. Moreover, silencing of ATG7 counteracted the effects of METTL14 knockdown on endothelial cell functions, emphasizing ATG7 as a downstream target of METTL14-mediated autophagy in HRVECs. After all, our findings provide valuable insights into the pathogenesis of retinal pathological angiogenesis and potential therapeutic targets for the treatment of ocular neovascular diseases. •METTL14 was found to be highly expressed in OIR model mice.•METTL14 knockdown suppresses ocular neovascularization in vivo and angiogenic functions of human retinal endothelial cells in vitro.•Knockdown of METTL14 up-regulation of autophagy in human retinal endothelial cells. The role of METTL14 in endothelial cells angiogenic function is associated with autophagy.•METTL14 affects autophagy flux via regulating the expression of ATG7 in a m6A dependent manner.