Iron promotes oxidative cell death caused by bisretinoids of retina

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 19; pp. 4963 - 4968
• Main Authors: Ueda, Keiko, Kim, Hye Jin, Zhao, Jin, Song, Ying, Dunaief, Joshua L., Sparrow, Janet R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.05.2018
• Subjects: Adducts; Animals; ATP-Binding Cassette Transporters - deficiency; Biological Sciences; Cell death; Cell Death - drug effects; Cell Death - genetics; Cells; Ceruloplasmin; Chromatography; Deferiprone; Electron transfer; Gene expression; High performance liquid chromatography; Intracellular; Iron; Iron Chelating Agents - pharmacology; Lipofuscin - genetics; Lipofuscin - metabolism; Liquid chromatography; Mice; Mice, Knockout; Organic chemistry; Oxidation; Photodegradation; Proteins; Pyridones - pharmacology; Reactive oxygen species; Retina; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinaldehyde; Retinaldehyde - genetics; Retinaldehyde - metabolism; Retinoids - metabolism; Transferrin; Transferrins; Vitamin A; iron; lipofuscin; bisretinoid; retinal pigment epithelium; macular degeneration
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1722601115

Intracellular Fe plays a key role in redox active energy and electron transfer. We sought to understand how Fe levels impact the retina, given that retinal pigment epithelial (RPE) cells are also challenged by accumulations of vitamin A aldehyde adducts (bisretinoid lipofuscin) that photogenerate reactive oxygen species and photodecompose into damaging aldehyde- and dicarbonyl-bearing species. In mice treated with the Fe chelator deferiprone (DFP), intracellular Fe levels, as reflected in transferrin receptor mRNA expression, were reduced. DFP-treated albino Abca4 −/− and agouti wild-type mice exhibited elevated bisretinoid levels as measured by high-performance liquid chromatography or noninvasively by quantitative fundus autofluorescence. Thinning of the outer nuclear layer, a parameter indicative of the loss of photoreceptor cell viability, was also reduced in DFP-treated albino Abca4 −/−. In contrast to the effects of the Fe chelator, mice burdened with increased intracellular Fe in RPE due to deficiency in the Fe export proteins hephaestin and ceruloplasmin, presented with reduced bisretinoid levels. These findings indicate that intracellular Fe promotes bisretinoid oxidation and degradation. This interpretation was supported by experiments showing that DFP decreased the oxidative/degradation of the bisretinoid A2E in the presence of light and reduced cell death in cell-based experiments. Moreover, light-independent oxidation and degradation of A2E by Fenton chemistry products were evidenced by the consumption of A2E, release of dicarbonyls, and generation of oxidized A2E species in cell-free assays.