Autophagy in age-related macular degeneration using Vldlr KO mouse model of retinopathy

Autophagy plays vital housekeeping neuronal functions but is not believed to fuel energy metabolism. Autophagy regulation by lipids nutrient sensors have not been identified. Cone photoreceptors' very-low-density lipoprotein receptor (Vldlr) expression facilitates the uptake of triglyceride-derived fatty acid. In Vldlr-/- mice, we identify free fatty acid receptor 1 (Ffar1) as a suppressor of transcription factor EB (Tfeb), a master regulator of autophagy. Tfeb, in turn, governs the expression of PGC1?? and Sirtuin-3, leading to reduced ?-ketoglutarate (?-KG). We recently showed that low ?-KG in Vldlr-/- photoreceptors drives Vegfa expression and neovascularization reminiscent of a subset of age-related macular degeneration (AMD). Metabolomics of human AMD vitreous and Vldlr-/- retinas identified a similar Krebs cycle metabolite signature. Improving autophagy in AMD-like mice rescued the neovascular phenotype and vision. Dysregulated autophagy may therefore compound the energy failure of photoreceptors contributing to neovascular AMD and could be a driving force in other neovascular diseases. Overall design: Dissociated cells from 1 C57B6 WT P14 mouse retina and 3 Vldlr KO mouse retina were processed by single cell RNAseq using the DROPseq technology. UMI count matrix data for cells from 2 C57B6 WT P14 retina replicates from Macosko et al, Cell 2015 (replicate 5 and 8, 3000 cells per replicate) were used as reference for DROPseq validation protocol and then conjugated with our the in-house WT replicate.