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Review
. 2022 Jul:89:101037.
doi: 10.1016/j.preteyeres.2021.101037. Epub 2021 Dec 29.

Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life

Dominik Lewandowski  1 , Christopher L Sander  2 , Aleksander Tworak  1 , Fangyuan Gao  1 , Qianlan Xu  3 , Dorota Skowronska-Krawczyk  4
Affiliations
Review

Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life

Dominik Lewandowski et al. Prog Retin Eye Res. 2022 Jul.

Abstract

The retinal pigment epithelium-photoreceptor interphase is renewed each day in a stunning display of cellular interdependence. While photoreceptors use photosensitive pigments to convert light into electrical signals, the RPE supports photoreceptors in their function by phagocytizing shed photoreceptor tips, regulating the blood retina barrier, and modulating inflammatory responses, as well as regenerating the 11-cis-retinal chromophore via the classical visual cycle. These processes involve multiple protein complexes, tightly regulated ligand-receptors interactions, and a plethora of lipids and protein-lipids interactions. The role of lipids in maintaining a healthy interplay between the RPE and photoreceptors has not been fully delineated. In recent years, novel technologies have resulted in major advancements in understanding several facets of this interplay, including the involvement of lipids in phagocytosis and phagolysosome function, nutrient recycling, and the metabolic dependence between the two cell types. In this review, we aim to integrate the complex role of lipids in photoreceptor and RPE function, emphasizing the dynamic exchange between the cells as well as discuss how these processes are affected in aging and retinal diseases.

Keywords: Aging; Docosahexaenoic acid (DHA); Membranes; Photoreceptors; Polyunsaturated fatty acid (PUFA); RPE; Rod outer segment; lipids; lipids in eye diseases.

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Figures

Figure 1.
Figure 1.. Lipid environment at the RPE/photoreceptor interface.
The dynamic interplay between photoreceptors and the RPE enables the efficient and necessary recycling and biogenesis of lipid components. Transporters on the basal side of RPE cells bring in several lipid components from circulation while also allowing for cholesterol efflux. The RPE also accepts lipids from photoreceptors from shedding disk tips, which become phagolysosomes in the RPE. The RPE uses both sources of lipid precursors to produced vital components of photoreceptor membranes, which are then transported back to photoreceptors for their incorporation and support of phototransduction.
Figure 2.
Figure 2.. Rod OS disks have regionally distinct microenvironments.
The central region of rod OS disks, rich in rhodopsin (red, PDB: 1F88), has an abundance of long and unsaturated FAs. Rim regions of rod OS disks containing ABCA4 (blue, PDB: 7LKP) and PRPH2/ROM1 (tetramer of human tetraspanin CD81 used as a model in green, PDB: 5TCX) have relatively high amounts of short and saturated FAs. There are many other distinctions in lipid species between the two regions, including relative amounts of PC and PE. ©2021 Sander et al. Adapted from an article originally published in the Journal of Cell Biology. https://doi.org/10.1083/jcb.202101063
Figure 3.
Figure 3.. Major glycerophospholipids – synthesis and potential signaling applications.
(A) Chemical structure of the five major glycerolipids. (B) Major glycerophospholipid pathways. Many enzymes are involved in the interconversion of each lipid species, including (C) Proposed involvement of IP3 and DAG in arrestin 1 translocation. Structures from a recent study of arrestin 1 in complex with IPs showed their ability to displace the arrestin 1 C-terminus, which is essential for inner-segment localization. The combination of a new basal structure, IP-complex structures, and data from Orisme et al. suggest a possible molecular mechanism for arrestin 1 translocation in cases of PLC activity. PLC structures were made from PDB structure 2ZKM (Hicks et al., 2008). PKC structures made from model predicted using AlphaFold, Uniprot identifier P17252 (Jumper et al., 2021). Basal and IP3-bound arrestin-1 structures taken from PDB structures 7JSM and 7JXA (Sander et al., accepted for puvlication).
Figure 4.
Figure 4.. RPE, rods, and cones express select enzymes involved in lipid metabolism.
(A) Heatmaps representing gene expression profiles of genes and pathways involved in lipid uptake, biosynthesis, and metabolism. Data were sourced from the human eye single-cell RNA-seq gene expression database (Lu et al., 2020) and normalized to each cell GAPDH expression level.
Figure 5.
Figure 5.. Metabolic and structural changes in ELOVL2 deficient animals.
Gene set enrichment analysis (GSEA) was performed on RNA-Seq data from the retina of Elovl2C234W and WT mice. A. “Oxidative Phosphorylation” pathway is significantly downregulated, as shown on the enrichment plot. B. Gene sets “Oxidative Phosphorylation” and C. “Oxidative Stress Induced Senescence’’ with genes ranked by WT/Elovl2C234W in mean log2Fold Change of expression level. Color bars indicate row Z-score. In the analysis, we used 4-month-old mice (N=4 for each genotype) and Molecular Signatures Database (MSigDB). D. EM analysis of Bruch’s Membrane (BM). Comparison of 18-month-old WT and Elovl2C234W RPE/BM surfaces show thickening and disorganization of BM (yellow arrows), including accumulation of basal lamina deposits (BLamD - red stars) and distorted RPE infoldings
Figure 6.
Figure 6.. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) signals consistent with localization to photoreceptor and RPE compartments.
(A) Schematic diagram of outer retina and Bruch’s membrane. Blue, pink, yellow, and green bands indicate layers formed by highly compartmentalized and vertically aligned photoreceptors and RPE cells in panels B and C. Layers: OPL, outer plexiform layer; ONL, outer nuclear layer; ELM, external limiting membrane; RPE, retinal pigment epithelium; BrM, Bruch’s membrane; R, Rod; C, cone photoreceptors. (B–F) Overlaid MALDI-MSI images and H&E stained cross-section of the peripheral retina display signals from multiple lipid classes that localize to specific subcellular compartments of the photoreceptor cells and RPE. (B) Overlay showing four separate signals defined in panels C–F, localized to (C) ONL, (D) photoreceptor inner and outer segments, (E) mitochondria-rich photoreceptor inner segments, and (F) RPE apical processes. ©2021 Anderson et al. Reprinted from an article originally published in J. Am. Soc. Mass Spectrom. https://doi.org/10.1021/jasms.0c00119.
Figure 7.
Figure 7.. ELOVL2 and AMD.
(A) RNAscope detection of Elovl2 (red) and Arr3 (green) mRNA shows high expression of Elovl2 in perifoveal cones and low expression in ganglion cells. (B) DNA methylation level of the cg16867657 in ELOVL2 promoter is not increased in samples isolated from AMD donors (GSE102952 (Oliver et al., 2015)); (C) Chromatin accessibility data measured by ATAC-seq (GSE99287 (Wang et al., 2018)) shows significantly decreased signal of ELOVL2 promoter in samples isolated from AMD donors when compared to age-matched healthy donors both in the macula and in the periphery. No change is observed in the intron region.
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