Mechanisms involved in A2E oxidation

Kim, So Ra; Jockusch, Steffen; Itagaki, Yasuhiro; Turro, Nicholas J.; Sparrow, Janet R.

doi:10.1016/j.exer.2008.03.016

Cited by 41 publications

(42 citation statements)

References 40 publications

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“…Ϫ/Ϫ Abca4 Ϫ/Ϫ and other mice with delayed all-trans-retinal clearance (20,24,28,32,50), and toxicity of A2E/oxidized A2E and ensuing immunoreactivity has been reported as well (10,11,39,53). However, oxidized A2E was not detected in 4-week-and 3-month-old Rdh8…”

Section: Are A2e and Other All-trans-retinal Condensation Products Inmentioning

confidence: 76%

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Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice

Maeda¹,

Maeda²,

Golczak³

et al. 2009

Journal of Biological Chemistry

220

307

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Exposure to bright light can cause visual dysfunction and retinal photoreceptor damage in humans and experimental animals, but the mechanism(s) remain unclear. We investigated whether the retinoid cycle (i.e. the series of biochemical reactions required for vision through continuous generation of 11-cis-retinal and clearance of all-trans-retinal, respectively) might be involved. Previously, we reported that mice lacking two enzymes responsible for clearing all-trans-retinal, namely photoreceptor-specific ABCA4 (ATP-binding cassette transporter 4) and RDH8 (retinol dehydrogenase 8), manifested retinal abnormalities exacerbated by light and associated with accumulation of diretinoid-pyridinium-ethanolamine (A2E), a condensation product of all-trans-retinal and a surrogate marker for toxic retinoids. Now we show that these mice develop an acute, light-induced retinopathy. However, cross-breeding these animals with lecithin:retinol acyltransferase knock-out mice lacking retinoids within the eye produced progeny that did not exhibit such light-induced retinopathy until gavaged with the artificial chromophore, 9-cis-retinal. No significant ocular accumulation of A2E occurred under these conditions. These results indicate that this acute light-induced retinopathy requires the presence of free all-trans-retinal and not, as generally believed, A2E or other retinoid condensation products. Evidence is presented that the mechanism of toxicity may include plasma membrane permeability and mitochondrial poisoning that lead to caspase activation and mitochondria-associated cell death. These findings further understanding of the mechanisms involved in light-induced retinal degeneration.

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Section: Are A2e and Other All-trans-retinal Condensation Products Inmentioning

confidence: 76%

“…2, A-D). Moreover, although production of oxidized A2E from A2E had been reported for in vitro systems (6,10,11,39,42), amounts of A2E did not change after illumination (Fig. 2D), suggesting that neither A2E nor oxidized A2E causes light-induced acute retinal degeneration in Rdh8 Ϫ/Ϫ Abca4 Ϫ/Ϫ mice.…”

Section: Abca4mentioning

confidence: 98%

Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice

Maeda¹,

Maeda²,

Golczak³

et al. 2009

Journal of Biological Chemistry

220

307

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“…5). In addition, because our research indicates that atomic oxygen can also insert at the carbon-carbon double bonds (12,15) (Fig. 3), many of these photo-fragments could carry furanoid or epoxide moieties (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Further evidence comes from the inhibitory effects of known quenchers/ scavengers of singlet oxygen (14). At least in the case of A2E, electron spin resonance spectroscopy indicates that superoxide anion is also generated following 430 nm irradiation of the compound (15). The oxygen-containing moieties ensuing from the photoexcitation of A2E and all-trans-retinal dimer include epoxides, furanoid oxides, and cyclic peroxides (11-13, 16, 17).…”

mentioning

confidence: 99%

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

Yanase

Feng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

130

125

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Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a low molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE.advanced glycation end products | lipofuscin | photofragmentation | photooxidation | retinal pigment epithelial cells F luorescent bisretinoid pigments are amassed as lipofuscin in retinal pigment epithelial (RPE) cells in association with aging although individuals vary with respect to the extent of accumulation (1). The excessive deposition of these compounds in RPE cells is also considered to lead to retinal degeneration in early onset blinding disorders associated with mutations in the genes encoding ABCA4 (ATP-binding cassette subfamily A member 4) (2, 3), ELOVL4 (4), and BEST-1 (5). Moreover, the deposition of these pigments likely also contributes to the etiology of agerelated macular degeneration (AMD) (6, 7). Whereas these bisretinoids constitute a complex mixture, all appear to originate from reactions of all-trans-retinal and some have been identified, including A2E (Fig. 1) and its isomers (8); A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE) and A2-dihydropyridine-ethanolamine (A2-DHP-E) (9); and all-trans-retinal dimer, all-trans-retinal dimer-phosphatidylethanolamine (all-transretinal dimer-PE), and all-trans-retinal dimer-ethanolamine (alltrans-retinal dimer-E) (10, 11). Structural features common to all of these pigments are the alternating single and double carbon...

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“…3 possess fluorescent properties and are the source of fundus autofluorescence (Sparrow et al, 2010b;2010c). Moreover, it seems that these bis-retinoids form by the random condensation reactions of two molecules of all-transretinal, and are highly susceptible to photooxidation Sparrow et al, 2002;Dillon et al, 2004;Fishkin et al, 2005;Jang et al, 2005;Wang et al, 2006;Kim et al, 2008;Wu et al, 2010). RPE cells, different from other types of cells, are constantly exposed to sunlight strongest at 400-700 nm.…”

Section: Structural Features and Propertiesmentioning

confidence: 99%

Structures and biogenetic analysis of lipofuscin bis-retinoids

Yao

2013

J. Zhejiang Univ. Sci. B

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Age-related macular degeneration (AMD) is still an incurable blinding eye disease because of complex pathogenic mechanisms and unusual diseased regions. With the use of chemical biology tools, great progress has been achieved in improving the understanding of AMD pathogenesis. The severity of AMD is, at least in part, linked to the non-degradable lipofuscin bis-retinoids in retinal pigment epithelial (RPE). This material is thought to result from the lifelong accumulation of lysosomal residual bodies containing the end products derived from the daily phagocytosis of rod outer segments by RPE cells. Here, we present previously recognized bis-retinoids with focus on structures and biosynthetic pathways. In addition to a brief discussion on the mutual conversion relationships of bis-retinoids, future perspectives and the medical relevance of such studies on these lipofuscin constituents are also highlighted.

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Mechanisms involved in A2E oxidation

Cited by 41 publications

References 40 publications

Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice

Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice

Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration

Structures and biogenetic analysis of lipofuscin bis-retinoids

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