Paper

High-glucose Induces Retinal Pigment Epithelium Mitochondrial Pathways of Apoptosis and Inhibits Mitophagy by Regulating ROS/PINK1/Parkin Signal Pathway

Zha, Xu, Yan, Mei, Zhou, Liqiong, Zhao, Xueying, Zhang, Yuanping, Ma, Minjun, Yang, Yanni, Xi, Xiaoting, Liu, Sili

2018

Overview

Diabetic retinopathy (DR) caused visual performance degradation seriously endangers human beings, uncovering the underlying mechanism might shed light on the discovery of DR therapeutic treatments. In this study, we found that the effects of glucose on retinal pigment epithelium (RPE) varies in a dose dependent manner, high-glucose promotes ROS generation and cell apoptosis, inhibits mitophagy as well as proliferative abilities, while low-glucose induces ROS production and cell mitophagy, but has little impacts on cell apoptosis and proliferation. Of note, the toxic effects of high-glucose on RPE are alleviated by ROS scavengers and aggravated by autophagy inhibitor 3-methyladenine (3-MA) or mitophagy inhibitor cyclosporin A (CsA). High-glucose induced ROS generation is merely eliminated by ROS scavengers instead of mitophagy or autophagy inhibitor. We also proved that high-glucose inhibits cell proliferation and promotes cell apoptosis by regulating ROS mediated inhibition of mitophagy. In addition, mitophagy associated proteins PINK1 and Parkin are downregulated by high-glucose or hydrogen peroxide treatments, which are reversed by ROS scavengers. Of note, Knock-down of PINK1 decreases phospharylated Parkin instead of total Parkin levels in RPE. Intriguingly, the inhibiting effects of high-glucose on cell mitophagy as well as proliferation and its promoting effects on cell apoptosis are reversed by either PINK1 or Parkin overexpression. Therefore, we concluded that high-glucose promotes RPE apoptosis and inhibits cell proliferation as well as mitophagy by regulating oxidative stress mediated inactivation of ROS/PINK1/Parkin signal pathway.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Apoptosis / Autophagy / Cell Biology / Cell growth / Cell proliferation / Cyclosporin A / Diabetes mellitus / Diabetic retinopathy / Epithelium / Glucose / Hydrogen peroxide / Mitochondria / Mitophagy / Oxidative stress / Parkin protein / Phagocytosis / PTEN-induced putative kinase / Retina / Retinal pigment epithelium / Retinopathy