Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

Abstract

Age-related macular degeneration (AMD) is a leading cause of severe visual loss and irreversible blindness in the elderly population worldwide. Retinal pigment epithelial (RPE) cells are the major site of pathological alterations in AMD. They are responsible for the phagocytosis of shed photoreceptor outer segments (POSs) and clearance of cellular waste under physiological conditions. Age-related, cumulative oxidative stimuli contribute to the pathogenesis of AMD. Excessive oxidative stress induces RPE cell degeneration and incomplete digestion of POSs, leading to the continuous accumulation of cellular waste (such as lipofuscin). Autophagy is a major system of degradation of damaged or unnecessary proteins. However, degenerative RPE cells in AMD patients cannot perform autophagy sufficiently to resist oxidative damage. Increasing evidence supports the idea that enhancing the autophagic process can properly alleviate oxidative injury in AMD and protect RPE and photoreceptor cells from degeneration and death, although overactivated autophagy may lead to cell death at early stages of retinal degenerative diseases. The crosstalk among the NFE2L2, PGC-1, p62, AMPK, and PI3K/Akt/mTOR pathways may play a crucial role in improving disturbed autophagy and mitigating the progression of AMD. In this review, we discuss how autophagy prevents oxidative damage in AMD, summarize potential neuroprotective strategies for therapeutic interventions, and provide an overview of these neuroprotective mechanisms.

MicroRNA-100 Mediates Hydrogen Peroxide-Induced Apoptosis of Human Retinal Pigment Epithelium ARPE-19 Cells

“…Therefore, the dual cytoprotective mechanisms of p62 restoration through the activation of Nrf2 signaling and autophagy clearance of misfolded proteins have been claimed to be a potential target for preventing oxidative cell death of RPE and treating AMD [ 43 ]. While the role of p62 expression has been linked with autophagy function, scavenger receptor expression, and phagocytosis [ 50 , 51 ], the effect of miR-100 antagomir treatment on autophagic and phagocytic functions of RPE deserves further elucidation. Moreover, a negative correlation between miR-100 and p62 expression is significantly noted in hepatocellular carcinoma cells [ 30 ], supporting their reciprocal regulation in the cells.…”

The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

“…The endogenous anti-oxidant defences are particularly important in the protection of RPE cells, which are exposed to high levels of oxidative stress due to their phagocytosis activity, which is associated with H 2 O 2 production [ 55 ]. Recently, multiple evidences have demonstrated that the autophagy pathway is activated by oxidative stress and acts by removing defective cellular components, such as mitochondria damaged by ROS [ 56 ]. Impairment of autophagy is an important event in AMD [ 57 ], and initiates a vicious cycle, which culminates in caspase-mediated apoptosis [ 58 , 59 , 60 ].…”

“…Lipofuscin induces photosensitization of RPE cells which culminates in oxidative stress burden and further cellular damage. On the other hand, a strong relationship has been identified between lipofuscin and cellular senescence [ 122 ], autophagy [ 56 , 123 ], and pro-angiogenic signalling [ 124 ]. Autophagy is physiologically relevant for RPE cells mediating the removal of damaged organelles and is involved in the process of POS phagocytosis, through a non-canonical autophagy mechanism called LAP (LC3-associated phagocytosis) [ 125 ].…”

“…Under stress conditions, the autophagy flux is altered. Specifically, it has been demonstrated that autophagy activation acts as a protective mechanism in AMD through inducing the removal of waste material [ 56 ]. On the other hand, other studies indicate that sustained activation of autophagy is linked with cell death [ 126 ].…”

Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

“…The physiological functions of RPE cells are responsible for the phagocytosis of shed photoreceptor outer segments (POSs), which contain large quantities of unsaturated fatty acids [ 73 ]. The process of POS phagocytosis requires high oxygen consumption, and large amounts of ROS are generated by NOX or peroxidase in the phagocytic bodies via oxidizing these fatty acids in POSs [ 74 ]. A study by Mitter et al revealed that autophagy plays a pivotal role in protection of the RPE from oxidative stress [ 75 ].…”