Zinc and Autophagy in Age-Related Macular Degeneration

Abstract

Zinc supplementation is reported to slow down the progression of age-related macular degeneration (AMD), but there is no general consensus on the beneficiary effect on zinc in AMD. As zinc can stimulate autophagy that is declined in AMD, it is rational to assume that it can slow down its progression. As melanosomes are the main reservoir of zinc in the retina, zinc may decrease the number of lipofuscin granules that are substrates for autophagy. The triad zinc-autophagy-AMD could explain some controversies associated with population studies on zinc supplementation in AMD as the effect of zinc on AMD may be modulated by genetic background. This aspect was not determined in many studies regarding zinc in AMD. Zinc deficiency induces several events associated with AMD pathogenesis, including increased oxidative stress, lipid peroxidation and the resulting lipofuscinogenesis. The latter requires autophagy, which is impaired. This is a vicious cycle-like reaction that may contribute to AMD progression. Promising results with zinc deficiency and supplementation in AMD patients and animal models, as well as emerging evidence of the importance of autophagy in AMD, are the rationale for future research on the role of autophagy in the role of zinc supplementation in AMD.

Keywords: AMD; age-related macular degeneration; autophagy; lipofuscin; melanosomes; zinc.

Figure 1

Age-related macular degeneration (AMD). The normal retina contains photoreceptors, not shown here, that interact with the retinal pigment epithelium (RPE)/Bruch’s membrane/choriocapillaris (CC) complex, which is supported by the large choroidal blood vessels (not presented). In dry AMD, some RPE cells are damaged, and some are lost when the disease progresses. Some CCs are also lost (broken lines) in dry AMD, but in the wet form of the disease, they are lost almost completely. In wet AMD, RPE cells release several factors (multicolor small objects) that support angiogenesis, including vascular endothelial growth factor, which leads to choroidal neovascularization. Fundus color images of dry and wet AMD. Light orange spots in the retina termed drusen can be observed in both dry and wet AMD, whereas wet AMD is featured by hemorrhages and edema. AMD can ruin the central vision of affected individuals.

Figure 2

A simplified scheme of macro autophagy (further: autophagy). Mechanistic targets of rapamycin (mTOR) and AMP-activated kinase (AMPK) are the primary autophagy inhibitor and inducer, respectively. On autophagy initiation, the cytoplasmic material to be degraded (cargo) is gradually encapsulated by double membranes: phagophores to encapsulated vesicles (autophagosomes), which then fuse with lysosomes to form autolysosomes, where cargo is degraded and then released into cytoplasm to be used again (recycling). Autophagy is regulated by many proteins, the autophagy-related proteins (ATGs), and their complexes. The initiation process is led by the Unc − 51-like kinase 1 (ULK1) complex, the formation of the double membrane, provided by ATG − 9-containing vesicles, and autophagosome—by the class III PI3K (phosphatidylinositol 3-kinase) nucleation complex and the phosphatidylinositol 3-phosphate (PI3P)-binding complex, which includes ATG12, Beclin 1, and the microtubule-associated protein light chain 3/γ-aminobutyric acid receptor-associated proteins (LC3/GABARAPs), represented here only by LC3. ATG12 attaches to ATG5, which is then associated with ATG16L1. This complex stimulates the cleavage of LC3 by ATG4 to form LC3-I, which is then conjugated with phosphatidylethanolamine (PE) to form LC3-II. On the incorporation into autophagosomal membranes, LC3 interacts with cargo receptors, which have LC3-interacting motifs (LIRs).

Figure 3

Cellular homeostasis of zinc in humans. There are at least 14 ZIP (Zn²⁺-regulated metal transporter, Iron-regulated metal transporter-like protein) proteins responsible for the transport of zinc ions into the cytosol and 10 zinc transporters, ZnTs (Zn²⁺ Transporter), acting in a reverse direction. Zinc is present in many human proteins, and metallothioneins (MTs) release zinc into the cytosol in oxidative conditions. The transport of zinc in/out of mitochondria (Mt) is not completely understood, and ZnT2 and ZnT9 presented here are likely not the only ones involved. Not all zinc transporters are presented in this figure, as many of them are expressed only in specific cells, such as ZnT8, which is specific to pancreatic cell islets. ER — endoplasmic reticulum.