Iron, the retina and the lens: a focused review

Abstract

This review is focused on iron metabolism in the retina and in the lens and its relation to their respective age-related pathologies, macular degeneration (AMD) and cataract (ARC). Several aspects of iron homeostasis are considered first in the retina and second in the lens, paying particular attention to the transport of iron through the blood-retinal barrier and through the lens epithelial cell barrier, to the immunochemistry of iron-related proteins and their expression in both the retina and the lens, and to the nature of the photochemical damage caused by UV light on both tissues. A comparative overview of some iron related parameters (total iron, transferrin (Tf), transferrin saturation and total iron binding capacity), in plasma and ocular tissues and fluids of three animal species is also presented. Based on results selected from the literature reviewed, and our own results, a scheme for the overall circulation of iron within and out of the eye is proposed, in which, (i) iron is pumped from the retina to the vitreous body by a ferroportin/ferroxidase-mediated process at the endfeet of Müller cells, (ii) vitreal Tf binds this iron and the complex diffuses towards the lens, (iii) the iron/Tf complex is incorporated into the lens extracellular space probably at the lens equator and moves to the epithelial-fiber interface, (iv) upon interaction with Tf receptors of the apical pole of lens epithelial cells, the iron/Tf complex is endocytosed and iron is exported as Fe(3+) by a ferroportin/ferroxidase-mediated process taking place at the basal pole of the epithelial cells, and (v) Fe(3+) is bound to aqueous humor Tf and drained with the aqueous humor into systemic blood circulation for recycling. The proposed scheme represents an example of close cooperation between the retina and the lens to maintain a constant flow of iron within the eye that provides an adequate supply of iron to ocular tissues and secures the systemic recycling of this element. It does not discount the existence of additional ways for iron to leave the eye through the blood-retinal barrier. In this review both AMD and ARC are recognized as multifactorial diseases with an important photoxidative component, and exhibiting a remarkable similitude of altered local iron metabolism. The epidemiological relationship between ARC and ferropenic anemia is explained on the basis that hepcidin, the hormone responsible for the anemia of chronic inflammation, could paradoxically cause intracellular iron overload in the lens by interfering with the proposed ferroportin/ferroxidase-mediated export of iron at the basal side of the anterior lens epithelium. Other authors have suggested that a similar situation is created in the retina in the case of AMD.

Figure 1

Reactive oxygen species and redox cycling of iron. Fenton reaction is represented by equation (1), Haber-Weiss reaction by equation (2), and iron-catalyzed Haber –Weiss reaction by equation (3), also known as superoxide-driven Haber-Weiss reaction (Halliwell and Gutteridge, 1990). Fenton reaction describes the decomposition of hydrogen peroxide to the highly reactive hydroxyl radical, in the presence of ferrous iron.

Figure 2

Iron and iron-related parameters in three animal species, cow, pig, and rat (Vázquez-Quiñones and García-Castiñeiras, 2007). A: Total iron (TI) and Total iron binding capacity (TIBC). B: Transferrin (Tf) and % saturation of TIBC(Tf). C: anatomical identification key. A and B are reproduced with permission from the Puerto Rico Health Sciences Journal.

Figure 2

Iron and iron-related parameters in three animal species, cow, pig, and rat (Vázquez-Quiñones and García-Castiñeiras, 2007). A: Total iron (TI) and Total iron binding capacity (TIBC). B: Transferrin (Tf) and % saturation of TIBC(Tf). C: anatomical identification key. A and B are reproduced with permission from the Puerto Rico Health Sciences Journal.

Figure 2

Iron and iron-related parameters in three animal species, cow, pig, and rat (Vázquez-Quiñones and García-Castiñeiras, 2007). A: Total iron (TI) and Total iron binding capacity (TIBC). B: Transferrin (Tf) and % saturation of TIBC(Tf). C: anatomical identification key. A and B are reproduced with permission from the Puerto Rico Health Sciences Journal.

Figure 3

A model of the iron outflow pathway in the eye. The scheme represents the proposed movement of iron within the eye, starting at the endfeet of Müller cells in the retina (insert A) where a strong immunoreactivity for ferroportin and the ferroxidases ceruloplasmin/hephestin has been described (He et al., 2007) that permits the export of Fe²⁺ as Fe³⁺ towards the vitreous cavity. In the vitreous body, Fe³⁺ binds to Tf, and diffuses forward towards the lens. At the equatorial region of the lens (insert B) diferric transferrin could preferentially reach the apical interface (EFI) of the lens given the lack of tight junctions between fibers cells in that region (Kuszak and Brown, 1994), to be endocytosed by Tf receptors in the apical membranes of the lens epithelium. Intracellular events could be as described for many cells (Aisen, 1992): after acidification of the endosomes with a proton-ATPase, Fe³⁺ dissociates from Tf, is reduced to Fe²⁺ by some ferrireductase activity, and is transferred to a labile cytoplasmic pool through the H⁺/Fe²⁺ symporter DMT1. This leaves apoTf ready to move back to the apical pole of the cells and restart the cycle. Cytoplasmic iron moves towards the basal pole of the cells by not yet characterized mechanisms. A second ferroportin/ferroxidase system in the basal membranes is being proposed that pumps Fe³⁺ into the aqueous humor, where it is bound again to Tf and then recycled into systemic circulation through the trabecular meshwork and Schlemm’s canal with the aqueous humor bulk flow at the iridocorneal angle. Other destinations of the cytoplasmic pool of iron to, for example, meet the epithelial cells own need for iron or to store iron as ferritin, are not represented in this diagram. Also undepicted is a potential backflow of iron through the blood-retinal barrier.