Oxidative Stress-Involved Mitophagy of Retinal Pigment Epithelium and Retinal Degenerative Diseases

Abstract

The retinal pigment epithelium (RPE) is a highly specialized and polarized epithelial cell layer that plays an important role in sustaining the structural and functional integrity of photoreceptors. However, the death of RPE is a common pathological feature in various retinal diseases, especially in age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitophagy, as a programmed self-degradation of dysfunctional mitochondria, is crucial for maintaining cellular homeostasis and cell survival under stress. RPE contains a high density of mitochondria necessary for it to meet energy demands, so severe stimuli can cause mitochondrial dysfunction and the excess generation of intracellular reactive oxygen species (ROS), which can further trigger oxidative stress-involved mitophagy. In this review, we summarize the classical pathways of oxidative stress-involved mitophagy in RPE and investigate its role in the progression of retinal diseases, aiming to provide a new therapeutic strategy for treating retinal degenerative diseases. The role of mitophagy in AMD and DR. In AMD, excessive ROS production promotes mitophagy in the RPE by activating the Nrf2/p62 pathway, while in DR, ROS may suppress mitophagy by the FOXO3-PINK1/parkin signaling pathway or the TXNIP-mitochondria-lysosome-mediated mitophagy.

Keywords: Age-related macular degeneration; Diabetic retinopathy; Mitophagy; Oxidative stress; Retinal pigment epithelium.

Fig. 1

The signaling pathways of mitophagy. (1) Non-Receptor-Mediated Mitophagy: Activation of PINK1 leads to recruitment of ubiquitin and Parkin. Parkin ubiquitinates and phosphorylates mitochondrial proteins (such as VDAC1, MFN1, and MFN2), and this initiates receptor adaptor protein recruitment (p62, NDP52, OPTN, TAX1BP1, and NBR1). These adaptor proteins interact with LC3 to form the autophagosome. (2) Receptor-Mediated Mitophagy: Mitochondrial receptor proteins (BNIP3, NIX, FUNC1) are ubiquitinated and phosphorylated. This facilitates their interaction with LC3 and GABARAP for autophagosome formation

Fig. 2

The role of oxidative stress in RPE. Aging, light injury, cigarette, and HFD are the risk factors. Overactive energy metabolism and excessive signal transduction in RPE and photoreceptor cells produce many ROS. Daily phagocytosis of POSs in RPE cells is also an important source of ROS. In addition, RPE is continuously exposed to high oxygen pressure