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Review
. 2021 Apr 1;12(2):529-551.
doi: 10.14336/AD.2020.0912. eCollection 2021 Apr.

Iron Accumulation and Lipid Peroxidation in the Aging Retina: Implication of Ferroptosis in Age-Related Macular Degeneration

Tantai Zhao  1   2 , Xiaojian Guo  1   2 , Yun Sun  1   2
Affiliations
Review

Iron Accumulation and Lipid Peroxidation in the Aging Retina: Implication of Ferroptosis in Age-Related Macular Degeneration

Tantai Zhao et al. Aging Dis. .

Abstract

Iron is an essential component in many biological processes in the human body. It is critical for the visual phototransduction cascade in the retina. However, excess iron can be toxic. Iron accumulation and reduced efficiency of intracellular antioxidative defense systems predispose the aging retina to oxidative stress-induced cell death. Age-related macular degeneration (AMD) is characterized by retinal iron accumulation and lipid peroxidation. The mechanisms underlying AMD include oxidative stress-mediated death of retinal pigment epithelium (RPE) cells and subsequent death of retinal photoreceptors. Understanding the mechanism of the disruption of iron and redox homeostasis in the aging retina and AMD is crucial to decipher these mechanisms of cell death and AMD pathogenesis. The mechanisms of retinal cell death in AMD are an area of active investigation; previous studies have proposed several types of cell death as major mechanisms. Ferroptosis, a newly discovered programmed cell death pathway, has been associated with the pathogenesis of several neurodegenerative diseases. Ferroptosis is initiated by lipid peroxidation and is characterized by iron-dependent accumulation. In this review, we provide an overview of the mechanisms of iron accumulation and lipid peroxidation in the aging retina and AMD, with an emphasis on ferroptosis.

Keywords: age-related macular degeneration; ferroptosis; iron; lipid peroxidation; retina.

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Conflict of interest statement

Conflicts of Interest We declare that we have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Illustration of the bulbus oculi with an enlarged view of the retinal layers and distribution of the proteins involved in iron metabolism in the retina.
Figure 2.
Figure 2.
Illustration of the processes of iron uptake, storage, and efflux in the retinal pigment epithelium (RPE) cells. Two Fe3+atoms oxidized from Fe2+ by ferroxidase hephaestin (Heph) or ceruloplasmin (Cp) bind to the iron transport protein transferrin (Tf). Tf then binds to Tf receptor 1/2 (TfR1/2) in the basolateral membrane of RPE, modulated by HFE. In some conditions, retinal non-Tf bound iron import may be absorbed by Zip8 and/or Zip14 independent of the canonical Tf-TfR pathway without being oxidized. A ferrireductase, α-synuclein (α-syn) expressed in RPE cells can facilitate the uptake of Tf-bound iron but not non-Tf bound iron. Once inside cells, Fe3+ dissociates from the Tf-TfR complex in acidified endosomes followed by reduction of Fe3+ to Fe2+ catalyzed by ferrireductases, such as Steap3 and Dcytb, then transported across the endosomal membrane into the cytoplasm by the ferrous iron transporter DMT1. Fe2+ may then be stored into Ft in the cytoplasm or FtMt in the mitochondria, both of which are regulated by iron regulatory proteins (IRPs). Fe2+ is released from Ft through Ft degradation and is selectively recognized by the cytosolic and mitochondrial Fe2+ chaperones PCBPs1/2 and frataxin, respectively, then eventually utilized by diverse Fe2+-dependent proteins. The remaining Fe2+ enters the labile iron pool as the source of active-redox iron. Fe2+ that is not utilized or stored by the cell is exported by the transmembrane protein Fpn through post-translational regulation by hepcidin (Hepc). Fpn is also regulated by HFE, which is located at the basolateral membrane and by hemojuvelin (Hjv) and matriptase2, which are located at the apical membrane of the RPE through their regulatory effect towards Hepc. Fe2+ efflux is subsequently oxidized by ferroxidase Heph or Cp to facilitate the next cycle of iron uptake.
Figure 3.
Figure 3.
Iron accumulation and lipid peroxidation in the aging retina and AMD. (A) Life-long irradiation exposure causes constant phagocytosis of iron-laden and polyunsaturated fatty acid (PUFA)-enriched photoreceptor outer segments in the RPE. Reactive oxygen species (ROS) generated from accumulated iron in the RPE via Fenton reactions further reacts with PUFAs to generate lipid-ROS and promote lipid peroxidation. Products of lipid peroxidation, including carboxyethylpyrrole (CEP), 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA), cause a series of inflammatory responses and AMD features. (B) Patterns of AMD. Left: Normal structure of the macula. Middle: Dry AMD, also known as non-exudative AMD. is characterised by heterogeneous debris (drusen) accumulation between the RPE and Bruch’s membrane. Right: Wet AMD (also known as exudative AMD) is characterised by choroidal neovascularization underneath the RPE and macula. Abnormal blood vessels may then break the continuity of RPE and Bruch’s membrane and cause sub-retinal hemorrhage.
Figure 4.
Figure 4.
Schematic of the proposed involvement of ferroptosis in the aging retina and AMD. Cargo receptor NCOA4 delivers iron-storage macromolecule Ft to the lysosomes, where Ft is then degraded. Fe2+released into the cytoplasm from degraded Ft constitutes the labile iron pool. With aging, accumulated iron exceeds the storage capacity of retinal cells, enters the labile iron pool and expands the redox-active iron pool. Fe2+ from the labile iron pool subsequently generates ROS via Fenton reactions. ROS further react with PUFAs to generate lipid-ROS and promote lipid peroxidation. Conversely, a decline in lipid antioxidants with aging, particularly GSH, alters the antioxidative capacity of retinal cells. Synthesis of GSH from glutamate, cysteine (Cys), and glycine occurs via two steps catalyzed by two ATP-dependent cytoplasmic enzymes namely glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS). Intracellular GSH biosynthesis is dependent on the availability of Cys, the reduced form of cystine (Cys2) catalyzed by thioredoxin reductase (TrxR). Cys2 uptake is mainly mediated by the system xc-, the upstream determinant of ferroptosis. Decline in GSH with aging ultimately inactivates GPX4, the sole enzyme that reduces lipid hydroperoxides within biological membranes. Iron-mediated melanosome degradation reduces its ability to inhibit iron-induced lipid peroxidation. Iron accumulation and decline in lipid antioxidants, coordinatively aggravate age-related iron-induced lipid peroxidation, initiating ferroptosis.
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