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• W3120485420 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. 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. In addition to iron being essential for oxygen transport by hemoglobin, iron is vital to the functioning of numerous other heme- and nonheme proteins (1Winter W.E. Bazydlo L.A. Harris N.S. The molecular biology of human iron metabolism.Lab. Med. 2014; 45: 92-102Crossref PubMed Scopus (91) Google Scholar, 2He X. Hahn P. Iacovelli J. Wong R. King C. Bhisitkul R. Massaro-Giordano M. Dunaief J.L. Iron homeostasis and toxicity in retinal degeneration.Prog. Retin. Eye Res. 2007; 26: 649-673Crossref PubMed Scopus (161) Google Scholar). In mitochondria iron-containing cytochrome proteins function in the synthesis of ATP by facilitating the transfer of electrons, the iron atom in the heme group being alternately oxidized and reduced (3Musallam K.M. Taher A.T. Iron deficiency beyond erythropoiesis: Should we be concerned?.Curr. Med. Res. Opin. 2018; 34: 81-93Crossref PubMed Scopus (42) Google Scholar). Other cytochromes primarily involved in the metabolism and detoxification of substrates belong to the large family of cytochrome P450 enzymes that utilize iron as a cofactor (3Musallam K.M. Taher A.T. Iron deficiency beyond erythropoiesis: Should we be concerned?.Curr. Med. Res. Opin. 2018; 34: 81-93Crossref PubMed Scopus (42) Google Scholar). Iron is also required for the activity of ribonucleoside reductase, the rate-limiting enzyme involved in the synthesis of DNA (4Puig S. Ramos-Alonso L. Romero A.M. Martinez-Pastor M.T. The elemental role of iron in DNA synthesis and repair.Metallomics. 2017; 9: 1483-1500Crossref PubMed Google Scholar) and aconitase, a nonheme iron–sulfur protein is involved in the first step of the tricarboxylic acid cycle (5Crooks D.R. Maio N. Lane A.N. Jarnik M. Higashi R.M. Haller R.G. Yang Y. Fan T.W. Linehan W.M. Rouault T.A. Acute loss of iron-sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells.J. Biol. Chem. 2018; 293: 8297-8311Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In retina, the visual cycle protein RPE65 is dependent on its iron-binding domain for activity (6Redmond T.M. Poliakov E. Yu S. Tsai J.Y. Lu Z. Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 13658-13663Crossref PubMed Scopus (298) Google Scholar). Iron is also a redox-active metal that exerts toxicity by generating highly reactive hydroxyl radicals (•OH) that attack proteins, lipids, and DNA. For this reason, several mechanisms operate to prevent iron overload or deficiency by regulating Fe import, storage, and export (7Halliwell B. Gutteridge J.M.C. Free Radicals in Biology and Medicine.3rd Ed. Oxford University Press, Oxford1999Google Scholar). For instance, the liver secretes hepcidin into the systemic circulation to reduce blood iron levels. Circulating hepcidin does this by causing the degradation of the cellular iron exporter ferroportin that is located on cell surfaces of intestinal epithelium and macrophages; loss of ferroportin attenuates iron export (8Nemeth E. Tuttle M.S. Powelson J. Vaughn M.B. Donovan A. Ward D.M. Ganz T. Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.Science. 2004; 306: 2090-2093Crossref PubMed Scopus (3276) Google Scholar). Null mutations of hepcidin in mice are associated with progressive accumulation of iron in the retina; elevation of ferritin, the iron storage protein; increased ferroportin and subsequent photoreceptor cell degeneration (9Hadziahmetovic M. Song Y. Ponnuru P. Iacovelli J. Hunter A. Haddad N. Beard J. Connor J.R. Vaulont S. Dunaief J.L. Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice.Invest. Ophthalmol. Vis. Sci. 2011; 52: 109-118Crossref PubMed Scopus (65) Google Scholar). We have previously shown that excessive iron in retinal pigment epithelial (RPE) cells of mice deficient in ceruloplasmin (Cp) and hephaestin (Heph) (Cp−/−; Heph−/− mice) (10Wolkow N. Song D. Song Y. Chu S. Hadziahmetovic M. Lee J.C. Iacovelli J. Grieco S. Dunaief J.L. Ferroxidase hephaestin's cell-autonomous role in the retinal pigment epithelium.Am. J. Pathol. 2012; 180: 1614-1624Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar) is associated with toxic bisretinoid photooxidation and degradation (11Ueda K. Kim H.J. Zhao J. Song Y. Dunaief J.L. Sparrow J.R. Iron promotes oxidative cell death caused by bisretinoids of retina.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 4963-4968Crossref PubMed Scopus (22) Google Scholar). Like hephaestin, ceruloplasmin is a ferroxidase that oxidizes iron from the ferrous (Fe2+, 4 unpaired electrons) to ferric (Fe3+, 5 unpaired electrons) state so that it can be accepted by transferrin in the circulation. RPE cells are subjected to photooxidative stress because of their content of bisretinoids. Bisretinoids are a family of photoreactive vitamin A aldehyde-derived adducts that form nonenzymatically as a by-product of the visual cycle; bisretinoids accumulate in RPE cells with age. These bisretinoid fluorophores present with two-side arms, a long and a short, consisting of conjugated systems of double bonds that are oxidized by both photo-mediated processes (12Wu Y. Yanase E. Feng X. Siegel M.M. Sparrow J.R. Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7275-7280Crossref PubMed Scopus (96) Google Scholar, 13Yoon K.D. Yamamoto K. Ueda K. Zhou J. Sparrow J.R. A novel source of methylglyoxal and glyoxal in retina: Implications for age-related macular degeneration.PLoS One. 2012; 7e41309Crossref PubMed Scopus (51) Google Scholar) and hydroxyl radical (•OH) production via the Fenton reaction (Fe2+ and H2O2) (11Ueda K. Kim H.J. Zhao J. Song Y. Dunaief J.L. Sparrow J.R. Iron promotes oxidative cell death caused by bisretinoids of retina.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 4963-4968Crossref PubMed Scopus (22) Google Scholar). Here in mechanistic studies, we embarked on an examination of RPE iron overload in liver-specific (LS) hepcidin knockout mice and tested for evidence of a photo-assisted Fenton reaction using visible light (14Xian T. Di L. Sun X. Li H. Zhou Y. Yang H. Photo-fenton degradation of AO7 and photocatalytic reduction of Cr(VI) over CQD-decorated BiFeO3 nanoparticles under visible and NIR light irradiation.Nanoscale Res. Lett. 2019; 14: 397Crossref PubMed Scopus (25) Google Scholar). As noted above, in RPE cells the enzyme Rpe65 is the iron-dependent isomerohydrolase essential for the conversion of all-trans-retinyl ester to 11-cis retinaldehyde (15Moiseyev G. Chen Y. Takahashi Y. Wu B.X. Ma J.X. RPE65 is the isomerohydrolase in the retinoid visual cycle.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12413-12418Crossref PubMed Scopus (382) Google Scholar); as such RPE65 catalyzes the rate-limiting step of the visual cycle. Thus we also tested for an effect of deferiprone (DFP) treatment on the activity of the visual cycle protein Rpe65. Importantly we discovered that iron levels are elevated in the retina of Abca4−/− mice and in a patient diagnosed with ABCA4-associated disease. Hepcidin that is secreted into the bloodstream by the liver serves to reduce blood iron levels by binding to and bringing about the degradation of the iron exporter ferroportin that is expressed on the surface of cells (8Nemeth E. Tuttle M.S. Powelson J. Vaughn M.B. Donovan A. Ward D.M. Ganz T. Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.Science. 2004; 306: 2090-2093Crossref PubMed Scopus (3276) Google Scholar). 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 (16Baumann B.H. Shu W. Song Y. Sterling J. Kozmik Z. Lakhal-Littleton S. Dunaief J.L. Liver-specific, but not retina-specific, hepcidin knockout causes retinal iron accumulation and degeneration.Am. J. Pathol. 2019; 189: 1814-1830Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). In histological sections through the ONH, LS-Hepc−/− mice presented with thickenings of displaced, stacked, and/or enlarged 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). Within these RPE cells, melanin density was markedly reduced. At the positions of these aberrations, the RPE monolayer was discontinued, outer segments were shortened, and photoreceptor cell nuclei spanning the ONL appeared to be reduced. Nevertheless, overall ONL area (calculated as sum of thickness measurements 0.2–1.0 mm from ONH × 0.2 mm) was not different in LS-Hepc−/− mice (7.59 × 104 ± 0.13 μm2) than in wild-type mice (7.26 × 104 ± 0.13 μm2 p > 0.05, t-test). An extension of the RPE monolayer at the edge of the ONH was often visible as a tuft of lightly pigmented cells (Fig. 1A). Atrophy of the optic nerve was not obvious, and the retinal ganglion cell layer was not changed relative to wild-type. In addition to the histological changes, we noted a pronounced peripapillary ring of hyperautofluorescence in 4 of 8 LS-Hepc−/− eyes that were imaged by SW-AF (Fig. 1D). This ring of AF was detectable at age 6 months and was more pronounced in images acquired at age 12 months. This peripapillary hyperautofluorescence could be indicative of increases in known fluorophores, modifications of known fluorophores, or autofluorescence from unknown fluorophores (12Wu Y. Yanase E. Feng X. Siegel M.M. Sparrow J.R. Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7275-7280Crossref PubMed Scopus (96) Google Scholar, 17Yamamoto K. Yoon K.D. Ueda K. Hashimoto M. Sparrow J.R. A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine.Invest. Ophthalmol. Vis. Sci. 2011; 52: 9084-9090Crossref PubMed Scopus (40) Google Scholar, 18Parish C.A. Hashimoto M. Nakanishi K. Dillon J. Sparrow J.R. Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium.Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 14609-14613Crossref PubMed Scopus (391) Google Scholar, 19Kim H.J. Sparrow J.R. Novel bisretinoids of human retina are lyso alkyl ether glycerophosphoethanolamine-bearing A2PE species.J. Lipid Res. 2018; 59: 1620-1629Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 20Kim S.R. Jang Y.P. Jockusch S. Fishkin N.E. Turro N.J. Sparrow J.R. The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 19273-19278Crossref PubMed Scopus (112) Google Scholar). Diminished autofluorescence screening by depigmented RPE at the edge of the ONH may also be a contributing factor. We also sought to determine whether the iron overload in RPE due to loss of liver-produced Hepc is associated with reduced bisretinoid levels. We measured bisretinoids in LS-Hepc−/− mice at 6 months of age using the noninvasive qAF approach. qAF intensity in LS-Hepc−/− mice (0.88 qAF units) versus wild-type mice (0.56 qAF units) did not reach a statistically significant difference at the age of 6 months (Fig. 1E). NIR-AF that originates primarily from RPE melanin was measured in a circular area centered on the ONH and having a diameter of 3 mm. There was no difference between wild-type and LS-Hepc−/− mice. At 12 months of age, however, while peaks attributable to the bisretinoids A2E, iso-A2E, A2-glycerophosphoethanolamine (A2-GPE), A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimer phosphatidylethanolamine (atRAL-di-PE) were observed in HPLC chromatograms generated with extracts of wild-type mice, these peaks were greatly diminished or undetectable in the chromatograms acquired from LS-Hepc−/− mice (Fig. 1F). HPLC quantitation of A2E in the LS-Hepc−/− mice revealed a 63% reduction in A2E relative to the wild-type mice (p < 0.01, unpaired two-tailed t-test). 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). The emission maximum recorded from both the mutant and wild-type eyes with 488 nm excitation was 590 nm. The spectra were also similar in shape as was the spectral width at half-maximal intensity (50 nm and 60 nm, LS-Hepc−/− and WT, respectively). At 561 nm excitation the peak emissions recorded from the LS-Hepc−/− and WT mice were red-shifted to 625 nm and the spectral width was narrower (40 nm in both mutant and WT mice) (Fig. 2B). The spectra recorded with 640 nm excitation had little structure within the emission range studied (Fig. 2D). The intensity difference between the mutant and wild-type mice was pronounced. The peak intensity was sevenfold and tenfold greater in the LS-Hepc−/− mice at 488 nm and 561 nm excitation, respectively (Fig. 2B). In mutant mice, auto-fluorescence emission was more intense when recorded at the RPE thickenings versus areas between the thickenings (Fig. 2, C and D). The Fenton reaction can efficiently generate highly reactive hydroxyl radicals (•OH) through the decomposition of H2O2 by Fe2+ (H2O2/Fe2+). We have shown that bisretinoids are oxidized both by photooxidative processes (12Wu Y. Yanase E. Feng X. Siegel M.M. Sparrow J.R. Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7275-7280Crossref PubMed Scopus (96) Google Scholar, 13Yoon K.D. Yamamoto K. Ueda K. Zhou J. Sparrow J.R. A novel source of methylglyoxal and glyoxal in retina: Implications for age-related macular degeneration.PLoS One. 2012; 7e41309Crossref PubMed Scopus (51) Google Scholar, 21Yoon K.D. Yamamoto K. Zhou J. Sparrow J.R. Photo-products of retinal pigment epithelial bisretinoids react with cellular thiols.Mol. Vis. 2011; 17: 1839-1849PubMed Google Scholar) and by iron-mediated formation of hydroxyl free radical via the Fenton reaction (11Ueda K. Kim H.J. Zhao J. Song Y. Dunaief J.L. Sparrow J.R. Iron promotes oxidative cell death caused by bisretinoids of retina.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 4963-4968Crossref PubMed Scopus (22) Google Scholar, 22Ueda K. Zhao J. Kim H.J. Sparrow J.R. Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 6904-6909Crossref PubMed Scopus (46) Google Scholar). We note, however, that the production of the hydroxyl radical via the Fenton reaction depends on continued availability of Fe2+ (ferrous iron). Thus we evaluated the ability of visible light to potentiate the oxidation of bisretinoid, presumably by the photoreduction of Fe3+ (ferric iron) to Fe2+ (ferrous iron) (photo-Fenton process) (14Xian T. Di L. Sun X. Li H. Zhou Y. Yang H. Photo-fenton degradation of AO7 and photocatalytic reduction of Cr(VI) over CQD-decorated BiFeO3 nanoparticles under visible and NIR light irradiation.Nanoscale Res. Lett. 2019; 14: 397Crossref PubMed Scopus (25) Google Scholar, 23Trawinski J. Skibinski R. Studies on photodegradation process of psychotropic drugs: A review.Environ. Sci. Pollut. Res. Int. 2017; 24: 1152-1199Crossref PubMed Scopus (53) Google Scholar). When A2E was incubated with FeSO4 and H2O2 at 37 °C for 30 min and then irradiated with 430 nm light (15 s) at an intensity of 290.6 lux (H2O2/Fe2+/light), UPLC quantitation of A2E revealed a 86% reduction in A2E as the substrate (p < 0.0001, one-way ANOVA, and Tukey's multiple comparisons test) (Fig. 3A). Incubation of A2E with FeSO4 and H2O2 in the absence of light was associated with a less pronounced decline (36%) in A2E (p < 0.0001, one-way ANOVA, and Tukey's multiple comparisons test), and A2E was decreased by 59% with irradiation at 430 nm alone (p < 0.0001, one-way ANOVA and Tukey's multiple comparisons test). Oxidation of A2E was also demonstrated by the detection of oxidized A2E (m/z 592 + 16). After irradiation at 430 nm the proportion of oxidized A2E in the sample increased 2.4 times compared with unirradiated A2E (p < 0.0001, one-way ANOVA, and Tukey's multiple comparisons test) while irradiation in the presence of FeSO4 and H2O2 was associated with a 1.9 times increase in oxidized A2E (p < 0.0001, one-way ANOVA, and Tukey's multiple comparisons test) (Fig. 3B). Within cells, the majority of iron is stored in ferritin, a cytosolic protein (24Picard E. Daruich A. Youale J. Courtois Y. Behar-Cohen F. From rust to quantum biology: The role of iron in retina physiopathology.Cells. 2020; 9: 705Crossref Scopus (7) Google Scholar). We measured iron levels in the RPE and neural retina of Abca4−/− and wild-type mice both pigmented and albino using a colorimetric assay based on ferrozine, a water-soluble chelator of Fe2+ (25Zhao X. Ting S.M. Liu C.H. Sun G. Kruzel M. Roy-O'Reilly M. Aronowski J. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage.Nat. Commun. 2017; 8: 602Crossref PubMed Scopus (52) Google Scholar, 26Hirayama T. Nagasawa H. Chemical tools for detecting Fe ions.J. Clin. Biochem. Nutr. 2017; 60: 39-48Crossref PubMed Scopus (67) Google Scholar) (Fig. 4A). Iron levels were higher in RPE than in neural retina, and this difference was significant in agouti Abca4−/− and albino Abca4−/− mice (p < 0.0001; for agouti Abca4−/−, p < 0.05 for albino Abca4−/− two-way ANOVA, Tukey’s multiple comparison test) (Fig. 4A). It is especially noteworthy that iron levels in RPE were higher in agouti and albino Abca4−/− mice than in RPE cells harvested from wild-type C57BL/6J and C57BL/6c2j mice (p < 0.0001, for agouti Abca4−/−, p < 0.001 for albino Abca4−/−two-way ANOVA, Tukey’s multiple comparison test) (Fig. 4A). While iron is considered to also be stored in association with melanin (24Picard E. Daruich A. Youale J. Courtois Y. Behar-Cohen F. From rust to quantum biology: The role of iron in retina physiopathology.Cells. 2020; 9: 705Crossref Scopus (7) Google Scholar), our measurements of iron levels were not significantly different in the RPE of albino C57BL/6c2j mice as compared with black-coated C57BL/6J mice (p > 0.05 two-way ANOVA, Tukey’s multiple comparison test) (Fig. 4A). Further indication of retinal iron overload was provided by measuring Tfrc mRNA levels in isolated neural retina and RPE by real-time qPCR. Relative Tfrc mRNA levels were significantly decreased in the neural retina of Abca4−/− mice (p < 0.001) and decreased but not significantly in the RPE of the Abca4−/− mice (Fig. 4B). This is additional evidence of increased intracellular iron levels in the RPE and NSR of the Abca4−/− mice. To further examine iron accumulation in the retina of Abca4−/− mice, we assessed retinal levels of the iron storage protein ferritin light chain (ferritin-L) using immunohistochemistry. The RPE and photoreceptor layers stained positively for ferritin-L in both the wildtype and Abca4−/− 8-month-old mice (Fig. 4C) but quantitation shows significantly increased ferritin-L positivity in the RPE and photoreceptor layers of the Abca4−/− mice (p < 0.001) (Fig. 4D). By immunocytochemical staining using mouse antihuman ferritin-light chain, we also observed increased ferritin, (indicative of increased iron) that was localized to RPE in cryostat sections of the eyes from patients diagnosed with STGD1 (Fig. 5). The FDA-approved iron chelator DFP is orally absorbed and cell-permeable and known to reduce serum iron and intracellular iron levels in the retina (11Ueda K. Kim H.J. Zhao J. Song Y. Dunaief J.L. Sparrow J.R. Iron promotes oxidative cell death caused by bisretinoids of retina.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 4963-4968Crossref PubMed Scopus (22) Google Scholar, 27Song D. Song Y. Hadziahmetovic M. Zhong Y. Dunaief J.L. Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina.Free Radic. Biol. Med. 2012; 53: 64-71Crossref PubMed Scopus (55) Google Scholar, 28Song D. Zhao L. Li Y. Hadziahmetovic M. Song Y. Connelly J. Spino M. Dunaief J.L. The oral iron chelator deferiprone protects against systemic iron overload-induced retinal degeneration in hepcidin knockout mice.Invest. Ophthalmol. Vis. Sci. 2014; 55: 4525-4532Crossref PubMed Scopus (31) Google Scholar). DFP not only binds iron, it also oxidizes Fe2+ to Fe3+, thus impeding the effects of Fe2+ the major catalyst of free radical damage to cells (29Timoshnikov V.A. Kobzeva T.V. Polyakov N.E. Kontoghiorghes G.J. Inhibition of Fe(2+)- and Fe(3+)- induced hydroxyl radical production by the iron-chelating drug deferiprone.Free Radic. Biol. Med. 2015; 78: 118-122Crossref PubMed Scopus (26) Google Scholar). We treated BALB/cJ mice with oral DFP from age 2 months to 4 months and observed a 25% increase in the bisretinoid A2E and a 28% increase in A2-GPE (Fig. 6A). We also measured bisretinoid noninvasively (30Sparrow J.R. Blonska A. Flynn E. Duncker T. Greenberg J.P. Secondi R. Ueda K. Delori F.C. Quantitative fundus autofluorescence in mice: Correlation with HPLC quantitation of RPE lipofuscin and measurement of retina outer nuclear layer thickness.Invest. Ophthalmol. Vis. Sci. 2013; 54: 2812-2820Crossref PubMed Scopus (44) Google Scholar) by employing in vivo fundus autofluorescence after only 1 month of DFP treatment. With this shorter duration of treatment, the difference in fluorophore accumulation between DFP-treated and untreated mice was less pronounced (p > 0.05, two-tailed t-test). We surmised that the changes in levels of bisretinoid were indicative of DFP-mediated reduction in endogenous iron-associated degradation of A2E and A2-GPE. The rate limiting enzyme of the visual cycle is Rpe65, the isomerohydrolase essential for the conversion of all-trans-retinyl ester to 11-cis retinaldehyde (15Moiseyev G. Chen Y. Takahashi Y. Wu B.X. Ma J.X. RPE65 is the isomerohydrolase in the retinoid visual cycle.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 12413-12418Crossref PubMed Scopus (382) Google Scholar). Rpe65 has an iron binding domain and the catalytic activity of Rpe65 is dependent on the availability of iron (6Redmond T.M. Poliakov E. Yu S. Tsai J.Y. Lu Z. Gentleman S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 13658-13663Crossref PubMed Scopus (298) Google Scholar). Thus we examined for an effect of iron chelation on steady-state levels of retinoids in dark-adapted BALB/cJ mice (age 2 months) that were treated with DFP in drinking water for 1 month. BALB/cJ mice were used for these experiments because the latter mice carry wild-type Rpe65 (Rpe65-Leucine 450) while C57BL/6J mice carry the methionine variant. No differences in DFP-treated versus untreated mice were observed for 11-cis-retinal, all-trans-retinol and all-trans-retinyl ester, 11-cis-retinol, and 11-cis-retinyl ester. However, inexplicably all-trans-retinal was more abundant in the DFP-treated mice (Fig. 6B). We also measured the recovery of 11-cis-retinal levels 1 h after exposure to bleaching light in dark-adapted mice (BALB/cJ, age 3 months). UPLC measurement of retinoids in mice maintained in darkness for 1 h after the bleach revealed that in mice treated with DFP for 1 month, 11-cis-retinal, 11-cis-retinol, and all-trans-retinol were not different than in the untreated BALB/cJ mice (p > 0.05, two-way ANOVA, and Sidak’s multiple comparison test). In the DFP-treated mice, there was, however, a small increase in all-trans-retinyl ester (8% increase) and a 27% decrease in 11-cis-retinyl ester, both of which reached statistical significance (p < 0.05) (Fig. 6D). For an additional test of iron chelation on the visual cycle, we also compared DFP-treated and untreated mice in terms of the time to recovery of dark-adapted ERG b-wave amplitudes after photobleaching (90% bleach). The DFP-treated and nontreated dark adapted mice exhibited similar postbleach recovery of the b-wave amplitude (Fig. 6C). STGD1 is an early onset monogenic disease caused by mutations in the ABCA4 gene. 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 (31Sun H. Molday R.S. Nathans J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease.J. Biol. Chem. 1999; 274: 8269-8281Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 32Molday R.S. ATP-binding cassette transporter ABCA4: Molecular properties and role in vision and macular degeneration.J. Bioenerg. Biomembr. 2007; 39: 507-517Crossref PubMed Scopus (66) Google Scholar). ABCA4 insufficiency in STGD1 allows for reaction of NRPE with a second molecule of retinaldehyde thereby leading to the formation of bisretinoid. The latter fluorophores are subsequently transferred to RPE within phagocytosed outer segment discs. Evidence available from mouse models and clinical studies of ABCA4-related disease indicates that accelerated bisretinoid formation is the cause of retinal degeneration in STGD1 (22Ueda K. Zhao J. Kim H.J. Sparrow J.R. 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