A vicious cycle of bisretinoid formation and oxidation relevant to recessive Stargardt disease

Jin Zhao,Hye Jin Kim,Keiko Ueda,Kevin Zhang,Diego Montenegro,Joshua L Dunaief,Janet R Sparrow

doi:10.1016/j.jbc.2021.100259

Abstract

The ability of iron to transfer electrons enables the contribution of this metal to a variety of cellular activities even as the redox properties of iron are also responsible for the generation of hydroxyl radicals (•OH), the most destructive of the reactive oxygen species. We previously showed that iron can promote the oxidation of bisretinoid by generating highly reactive hydroxyl radical (•OH). Now we report that preservation of iron regulation in the retina is not sufficient to prevent iron-induced bisretinoid oxidative degradation when blood iron levels are elevated in liver-specific hepcidin knockout mice. We obtained evidence for the perpetuation of Fenton reactions in the presence of the bisretinoid A2E and visible light. On the other hand, iron chelation by deferiprone was not associated with changes in postbleaching recovery of 11-cis-retinal or dark-adapted ERG b-wave amplitudes indicating that the activity of Rpe65, a rate-determining visual cycle protein that carries an iron-binding domain, is not affected. Notably, iron levels were elevated in the neural retina and retinal pigment epithelial (RPE) cells of Abca4−/− mice. Consistent with higher iron content, ferritin-L immunostaining was elevated in RPE of a patient diagnosed with ABCA4-associated disease and in RPE and photoreceptor cells of Abca4−/− mice. In neural retina of the mutant mice, reduced Tfrc mRNA was also an indicator of retinal iron overload. Thus iron chelation may defend retina when bisretinoid toxicity is implicated in disease processes.

Highlights

Step of the tricarboxylic acid cycle [5]
In histological sections through the optic nerve head (ONH), LS-Hepc−/− mice presented with thickenings of displaced, stacked, and/or enlarged retinal pigment epithelial (RPE) cells that projected into the subretinal space at multiple locations in posterior retina; all LS-Hepc−/− mice presented with these changes (Fig. 1, B and C)
The ABCA4 protein is located in the outer segments of rod and cone photoreceptor cells and assists in the removal of retinaldehyde by flipping N-retinylidene-phosphatidylethanolamine (NRPE), the Schiff base that forms by reaction of retinaldehyde with phosphatidylethanolamine in the disc membrane [31, 32]

Summary

Introduction

Step of the tricarboxylic acid cycle [5]. In retina, the visual cycle protein RPE65 is dependent on its iron-binding domain for activity [6]. It has been shown that liver-specific Hepc knockout (LS-Hepc−/−) mice exhibit elevated iron in blood and increased free (labile) iron levels in the retina and RPE cells [16]. The fluorescence emission generated from bisretinoid lipofuscin in the RPE of LS-Hepc knockout mice (age 11, 13, 14.5 months) and in wild-type controls (age 13 months) was recorded at 488, 561, and 640 nm (Fig. 2).

Results

Conclusion