Riboflavin and the Riboflavin Binding Protein, Retbindin, are Essential for the Metabolic Homeostasis of the Retina



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Retbindin is a novel retina specific riboflavin binding protein, ablation of which leads to degeneration. Using a combination of untargeted steady state metabolomics and targeted flux metabolomics, we here investigated the mechanism behind this degeneration. Furthermore, the neural retina (NR) and retinal pigment epithelium (RPE) maintain a symbiotic metabolic relationship, disruption of which leads to debilitating vision loss. In the current study we have identified the differences in the steady state metabolite levels and the pathways functioning between bona fide NR and RPE. Moreover, involvement of key metabolic cofactors, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) in cellular homeostasis has been well established for tissues other than the retina. Here, we present an optimized method to effectively extract and quantify FAD and FMN from a single neural retina and its corresponding RPE. We also show that in absence of retbindin there is significant reduction of flavins in both the neural retina and RPE, causing an imbalance in their symbiosis. However, there is no report on how the retina responds to riboflavin deficiency. Thus, here we developed a diet induced model of riboflavin deficiency and identified how that results in metabolic dysfunction in both the neural retina and RPE. We have further shown that these metabolic abnormalities can eventually compromise the electrophysiological response of both the neural retina and the RPE. Thus, we provide evidence how riboflavin and its binding protein retbindin can help in regulating retinal homeostasis.



retina, metabolism, neural retina, RPE, retinal pigment epithelium, riboflavin, FAD, FMN, HPLC, metabolomics, age related macular degeneration (AMD), diabetic retinopathy (DR), MacTel, serine, PHGDH, serine biosynthesis, glucose metabolism, fatty acid metabolism, sphingolipid, ceramide, retbindin, Pkm2, mitochondria, Retinitis Pigmentosa, Inherited retinal disorders, BVVLS, Fazio-Londe Syndrome, Ariboflavinosis, flavins, riboflavin binding protein, riboflavin carrier protein, neurodegeneration, retinal degeneration, machine learning, omics


Portions of this document appear in: Sinha, Tirthankar, Mustafa Makia, Jianhai Du, Muna I. Naash, and Muayyad R. Al-Ubaidi. "Flavin homeostasis in the mouse retina during aging and degeneration." The Journal of nutritional biochemistry 62 (2018): 123-133. And in: Sinha, Tirthankar, Muayyad R. Al-Ubaidi, and Muna I. Naash. "Flavin Imbalance as an Important Player in Diabetic Retinopathy." In Retinal Degenerative Diseases, pp. 575-579. Springer, Cham, 2019. And in: Sinha, Tirthankar, Muna I. Naash, and Muayyad R. Al-Ubaidi. "The symbiotic relationship between the neural retina and retinal pigment epithelium is supported by utilizing differential metabolic pathways." Iscience (2020): 101004.