Involvement of all-trans-retinal in acute light-induced retinopathy of mice.
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.
Maeda
Akiko
A
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Maeda
Tadao
T
Golczak
Marcin
M
Chou
Steven
S
Desai
Amar
A
Hoppel
Charles L
CL
Matsuyama
Shigemi
S
Palczewski
Krzysztof
K
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000208:Acute Disease; D000375:Aging / Q000473:pathology; D000429:Alcohol Oxidoreductases / Q000172:deficiency; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004224:Diterpenes; D019856:Ethanolamine / Q000378:metabolism; D006801:Humans; D008027:Light; D013058:Mass Spectrometry; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats; D012160:Retina / Q000201:enzymology / Q000473:pathology; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D012172:Retinaldehyde / Q000378:metabolism*; D000084562:Retinyl Esters; D012243:Rhodopsin / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D020169:Caspases; D004224:Diterpenes; D019856:Ethanolamine; D012172:Retinaldehyde; D000084562:Retinyl Esters; D012243:Rhodopsin; D014801:Vitamin A; D051028:bcl-2-Associated X Protein; C512841:Abca4 protein, mouse; C042882:isorhodopsin; C009166:retinol acetate; C525880:HSD17B6 protein, mouse