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

Abstract

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.

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

“…atRAL along with its derivative products likely are the initiators of photoreceptor cell pathology for several reasons: (i) phototransduction is the only light-sensitive pathway in ROS and this process involves the conversion of retinoids and generation of atRAL (62,63); (ii) such light-induced degeneration can be prevented by pretreatment with retinoid cycle inhibitors (Fig. S3); and (iii) both retinoids and their condensation products are known to produce cellular toxicity and death (12,18,31,64,65). Retinal pathology could also result from mitochondrial dysfunction, because lipophilic unsaturated compounds such as retinoids can also act as electron acceptors that compromise ATP production (66)(67)(68)(69).…”

“…The primary cause of acute retinal degeneration after bright light exposure in Abca4 −/− Rdh8 −/− mice is the delayed clearance of atRAL from photoreceptors (18). Moreover, light-induced retinal degeneration in Abca4 −/− Rdh8 −/− mice can be prevented by pharmacological interventions such as the retinoid cycle inhibitor with a primary amino group, retinylamine (12,30), and the NAPDH oxidase inhibitor, apocynin (31,(47)(48)(49) (Fig.…”

“…Brief exposure of Abca4 −/− Rdh8 −/− mice to intense light results in acute retinal degeneration, which allows investigators to follow the precise sequence of degenerative events at both a cellular and molecular level (18,29). Notably, such retinal degeneration can be prevented by inhibition of atRAL production with retinylamine, a retinoid cycle inhibitor (30), or by sequestration of atRAL by producing Schiff-base adducts of atRAL with drugs containing a primary amine group (12,29).…”

“…Both proteins are involved in the retinoid cycle, a metabolic sequence of chemical transformations needed to maintain continuous regeneration of the visual chromophore, 11−cis−retinal (11cRAL) from all-trans-retinal (atRAL), and both are also required for efficient clearance of atRAL upon its liberation from activated rhodopsin (13)(14)(15)(16)(17). Impaired clearance of atRAL is detrimental to retinal cells due to the high toxicity of this reactive aldehyde to all cell types (18). Clearance of atRAL is achieved by ABCA4, which transports atRAL from the disk lumen to the cytoplasmic space of photoreceptor outer segments (19) where RDHs, including RDH8, then reduce atRAL to ROL (11,20).…”

Serum levels of lipid metabolites in age‐related macular degeneration

“…Abca4 2/2 Rdh8 2/2 mice were generated as described previously (34,35). Such mice used in this study were homozygous for the Leu450 allele of Rpe65 as determined by a published genotyping protocol (36) and free of the Crb1/rd8 (37) and rd/rd (38) mutations.…”