Iron promotes oxidative cell death caused by bisretinoids of retina
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 re...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 19; pp. 4963 - 4968 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
08.05.2018
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1722601115 |
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| Abstract | 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. |
|---|---|
| AbstractList | Cells are subject to metabolic sources of oxidizing species and to the need to regulate Fe, a redox-active metal. Retinal pigment epithelial (RPE) cells have to contend with an additional, unique source of oxidative stress: photooxidative insult from bisretinoids that accumulate as lipofuscin. Here we report that Fe can interact with bisretinoids in RPE to promote cell damage. These findings inform disease processes in both Fe-related and bisretinoid-associated retinal degeneration. The link between Fe and bisretinoid oxidation also highlights opportunities for repurposed and combination therapies. This could include visual cycle inhibitors as a treatment for maculopathy associated with elevated retinal Fe, and Fe chelation to aid in suppressing the damaging effects of bisretinoids in juvenile and age-related macular degeneration.
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. 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 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 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. 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. 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.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. 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. |
| Author | Kim, Hye Jin Ueda, Keiko Sparrow, Janet R. Song, Ying Zhao, Jin Dunaief, Joshua L. |
| Author_xml | – sequence: 1 givenname: Keiko surname: Ueda fullname: Ueda, Keiko organization: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032 – sequence: 2 givenname: Hye Jin surname: Kim fullname: Kim, Hye Jin organization: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032 – sequence: 3 givenname: Jin surname: Zhao fullname: Zhao, Jin organization: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032 – sequence: 4 givenname: Ying surname: Song fullname: Song, Ying organization: F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 5 givenname: Joshua L. surname: Dunaief fullname: Dunaief, Joshua L. organization: F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104 – sequence: 6 givenname: Janet R. surname: Sparrow fullname: Sparrow, Janet R. organization: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29686088$$D View this record in MEDLINE/PubMed |
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| Keywords | iron lipofuscin bisretinoid retinal pigment epithelium macular degeneration |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author contributions: J.L.D. and J.R.S. designed research; K.U., H.J.K., J.Z., and Y.S. performed research; J.L.D. contributed new reagents/analytic tools; K.U., H.J.K., J.Z., and J.R.S. analyzed data; and J.L.D. and J.R.S. wrote the paper. Edited by Paul S. Bernstein, University of Utah School of Medicine, Salt Lake City, UT, and accepted by Editorial Board Member Jeremy Nathans April 5, 2018 (received for review January 2, 2018) |
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| Snippet | 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... Cells are subject to metabolic sources of oxidizing species and to the need to regulate Fe, a redox-active metal. Retinal pigment epithelial (RPE) cells have... |
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| SubjectTerms | 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 |
| Title | Iron promotes oxidative cell death caused by bisretinoids of retina |
| URI | https://www.jstor.org/stable/26509584 https://www.ncbi.nlm.nih.gov/pubmed/29686088 https://www.proquest.com/docview/2101971172 https://www.proquest.com/docview/2031034021 https://pubmed.ncbi.nlm.nih.gov/PMC5948992 |
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