From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology

Abstract

Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe2+ to Fe3+ involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review is to illustrate the primordial role of iron and local iron homeostasis in retinal physiology and vision, as well as the pathological consequences of iron excess in animal models of retinal degeneration and in human retinal diseases. We summarize evidence of the potential therapeutic effect of iron chelation in retinal diseases and especially the interest of transferrin, a ubiquitous endogenous iron-binding protein, having the ability to treat or delay degenerative retinal diseases.

La dégénérescence maculaire liée à l’âge: La piste du fer

“…BMP6, sécrétée par la rétine et l'EPR, se lie, au niveau apical de l'EPR, à ses récepteurs couplés à l'hémojuveline (HJV) afin d'activer la synthèse d'hepcidine. Les hypoxia inducible factors (HIF) 3 interviennent également comme facteurs de transcription de certains gènes impliqués dans l'homéostasie du fer, comme Tf, Tfr1, Dmt1 (divalent metal transporter 1), ainsi que ceux codant la ferroportine et la céruloplasmine. Ces facteurs se fixent sur un site spécifique de leurs ARNm, le site hypoxia-responsive element (HRE).…”

“…La rétine est soumise à de nombreux stress, tels que la lumière et l'oxygénation due au métabolisme oculaire particulièrement élevé. Bien que la présence du fer dans la rétine soit soupçonnée depuis deux siècles [2], ce n'est que récemment que l'étude de son métabolisme dans la rétine et de son lien avec de nombreuses maladies, y compris la dégénérescence maculaire liée à l'âge (DMLA), a réellement été initiée, ouvrant de nouvelles perspectives thérapeutiques (pour revue voir [3]). > En raison de l'intense activité physiologique de la fonction visuelle, l'homéostasie du fer dans la rétine y est contrôlée localement.…”

Transferrin Non-Viral Gene Therapy for Treatment of Retinal Degeneration

“…Intracellular iron is supplied to cytosolic proteins for storage (ferritins), taken up by the mitochondria or released from the cell by ferroportin, a membrane transporter requiring ferroxidases, such as ceruloplasmin or hephaestin, to convert the ferrous Fe 2+ to ferric Fe 3+ form. In addition, iron-sensitive intracellular proteins, such as iron-regulatory proteins (IRP1 and IRP2), hepcidin or hypoxia-inducing factor (HIF), serve as check points to control the intracellular iron concentration (recently reviewed in [2]).…”

“…Whether loss of iron homeostasis is a cause or a consequence of various retinal diseases remains unknown, but it is undeniable that an excess of free iron is pathogenic, and that its neutralization with chemical chelators protects the retina not only in rodent models with impaired mechanisms of iron homeostasis [22,23] but also in models of inherited retinal dystrophies [24][25][26]. Chemical iron chelators failed so far to reach clinical stage because of limited ocular bioavailability and/or ocular side-effects (cataract, retinopathy optic neuritis) probably due to chelation of intracellular iron store necessary for retina cells' function [2,27]. Conversely, the natural iron transporter TF was proven to be safe in the eye when overexpressed in transgenic mouse or when delivered intraperitoneally or intravitreally in the rat even after repeated administration of high doses (up to 240 µg per eye) [19,[28][29][30].…”

“…Iron is essential for retinal metabolism and visual cycle, but excessive ferrous iron (Fe 2+ ) can generate reactive oxygen species (ROS) and consecutive oxidative damage to the cellular environment (reviewed in [ 1 , 2 ]). Iron particles cause oxidative damage to rat photoreceptors, with greater damage to cones than rods [ 3 ] and iron-induced photoreceptor cell death was associated with lipid peroxidation [ 4 ], activation of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, and induction of necrotic and apoptotic markers [ 3 , 5 , 6 ].…”