3 years ago

Ablation of the riboflavin-binding protein retbindin reduces flavin levels and leads to progressive and dose-dependent degeneration of rods and cones.

Ryan A Kelley, Muna I Naash, Larissa Ikelle, Ayse M Genc, Tirthankar Sinha, Muayyad R Al-Ubaidi, Mustafa S Makia
The interface between the neural retina and the retinal pigment epithelium (RPE) is critical for several processes, including visual pigment regeneration and retinal attachment to the RPE. One of its most important functions is the exchange of metabolites between the photoreceptors and RPE because photoreceptor cells have very high energy demands, largely satisfied by oxidative metabolism. The riboflavin (RF) cofactors, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are two key cofactors involved in oxidative metabolism. We have previously shown that retbindin is a photoreceptor-specific RF-binding protein exclusively expressed in the rods and present in the inter-photoreceptor matrix at the interface between the RPE and photoreceptor outer segments. Here, we show that retbindin ablation in mice causes a retinal phenotype characterized by time- and dose-dependent declines in rod and cone photoreceptor functions as early as 120 days of age. While minor retinal ultrastructural defects were observed at all ages examined, a significant decline occurred in photoreceptor nuclei at 240 days of age (~36.8% rods and ~19.9% cones). Interestingly, significant reductions in FAD and FMN levels were observed before the onset of degeneration (~46.1% FAD and ~45% FMN). These findings suggest that the reduced levels of these flavins result in the disruption of intracellular mechanisms, leading to photoreceptor cell death. Altogether, our results suggest that retbindin is a key player in the acquisition and retention of flavins in the neural retina, warranting future investigation into retbindin s role in photoreceptor cell death in models of retinal degenerative disorders.

Publisher URL: http://doi.org/10.1074/jbc.M117.785105

DOI: 10.1074/jbc.M117.785105

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