Antioxidative Role of Heterophagy, Autophagy, and Mitophagy in the Retina and Their Association with the Age-Related Macular Degeneration (AMD) Etiopathogenesis

Abstract

Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize the role of heterophagy, autophagy, and mitophagy in maintaining homeostasis in the retina. Relevantly modifying the activity of both macroautophagy and mitophagy pathways represents one of the new therapeutic strategies in AMD. Our review provides an overview of the antioxidative roles of heterophagy, autophagy, and mitophagy and presents associations between dysregulations of these molecular mechanisms and AMD etiopathogenesis. The authors performed an extensive analysis of the literature, employing PubMed and Google Scholar, complying with the 2013-2023 period, and using the following keywords: age-related macular degeneration, RPE cells, reactive oxygen species, oxidative stress, heterophagy, autophagy, and mitophagy. Heterophagy, autophagy, and mitophagy play antioxidative roles in the retina; however, they become sluggish and dysregulated with age and contribute to AMD development and progression. In the retina, antioxidative roles also play in RPE cells, NFE2L2 and PGC-1α proteins, NFE2L2/PGC-1α/ARE signaling cascade, Nrf2 factor, p62/SQSTM1/Keap1-Nrf2/ARE pathway, circulating miRNAs, and Yttrium oxide nanoparticles performed experimentally in animal studies.

Keywords: RPE cells; age-related macular degeneration; autophagy; heterophagy; mitophagy; oxidative stress; reactive oxygen species.

Figure 1

Schematic presentation of binding, ingestion, and digestion stages of heterophagy process. POS; photoreceptors’ outer segments, MerTK; tyrosine-protein kinase c-Mer; RPE; retinal pigment epithelium.

Figure 2

Schematic presentation of macroautophagy, chaperone-mediated autophagy, and microautophagy processes, which differ in how the targeted cytosolic content reaches the lysosomes for degradation. With regard to macroautophagy: (1) membrane isolation, vesicle nucleation, elongation, and phagophore (pre-autophagosomal structure) formation in cytosol, adjacent to the ER; (2) double-membrane autophagosome completed and matured; (3) lysosomes filled with hydrolytic enzymes; (4) vesicle breakdown, fusion of autophagosome with lysosome and autophagolysosome formation; (5) cargo degradation; (6) recycling of metabolites and nutrients to restore the nutrient balance. With regard to chaperone-mediated autophagy: (1) CMA substrates containing KFERQ-like motif are recognized by the HSC70 protein (chaperone) in the cytosol; (2) CMA substrates bind to LAMP2A; lysosome-associated membrane protein 2A. LAMP2A forms a translocation cluster through which the CMA substrates are translocated into the lysosomal lumen; (3) cargo degradation; (4) recycling of metabolites and nutrients. With regard to microautophagy: (1) direct engulfing of the cargo by invaginated lysosomal membrane without forming autophagosome; (2) cargo degradation; (3) recycling of metabolites and nutrients.

Figure 3

Reactive oxygen species (ROS) depolarize the inner mitochondrial membrane (IMM) and activate PINK1 Parkin-derived pathway of mitophagy. In dysfunctional mitochondria, with a loss of IMM potential, PINK1 degradation is inhibited. Accumulation of PINK1 triggers recruitment of cytoplasmic Parkin. Parkin recruited to the mitochondrial surface is ubiquitinated (U) and phosphorylated (P) by PINK1. Then, active Parkin initiates the ubiquitination of mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), Miro 1, and dynamin-related protein 1 (Drp1). Inhibited activity of Mfn1, Mfn2, and Miro1 proteins facilitates disconnection of mitochondria from the microtubule. Active Drp1 results in fission (segregation) of damaged mitochondrion, which is finally escorted to the autophagic machinery for degradation. Mitophagy receptors p62/SQSTM1 (sequestosome-1), NBR1 (neighbor of BRCA1 gene 1 protein), NDP52 (nuclear domain 10 protein 52), TAX1BP1 (Tax1-binding protein 1) and OPTN (optineurin) contain a ubiquitin-binding domain, which allows their attachment to LC3 (microtubule-associated proteins 1A/1B light chain 3). The LC3 adapter is present on the surface of a maturing autophagosome. When a damaged mitochondrion is attached to an autophagosome, the autophagosome membrane elongates and closes the mitochondrion inside for lysis.

Figure 4

AMBRA1 acts as activator of Parkin/p62-dependent (canonical) pathway in basal conditions. However, AMBRA1 accumulation on OMM (outer mitochondrial membrane) changes mitophagy process in Parkin/p62-independent manner since AMBRA1 has the possibility to bind to the LC3 and GABARP adapter through an LIR motif, regardless of Parkin/p62 recruitment. AMBRA1 interacts with HUWE1 ligase, and such collaboration regulates mitochondrial clearance in two steps. AMBRA1 favors HUWE1 translocation from the cytosol to OMM and HUWE1 binding to Mnf2. HUWE1–Mnf2 interaction leads to Mfn2 ubiquitylation (U) and its targeting to the proteasome for enzymatic degradation. In the second step, HUWE1 induces phosphorylation (P) of LIR motif of AMBRA1 receptor, mediated by IKKα kinase, and triggers Parkin/p62-independent mitophagy.