Eye on the horizon: The metabolic landscape of the RPE in aging and disease

Abstract

To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.

Keywords: Age-related macular degeneration; Metabolic ecosystem; RPE aging; RPE metabolism; Retina inflammation; Retina metabolism; Retinal pigment epithelium.

Fig. 1.

Figure 1. The roles of the RPE in maintaining retinal homeostasis. The RPE is a monolayer of cells that occupies an anatomical niche between the photoreceptors and the main vascular layer of the eye, called the choroid. The choroid consists of three main layers: the choriocapillaris, Sattler’s layer, and Haller’s layer, each containing progressively larger blood vessels. The choroid is home to several different cell types including melanocytes, fibroblasts, pericytes, and immune cells such as macrophages. The RPE fulfills several essential roles that maintain retinal homeostasis, including the phagocytosis of photoreceptor outer segments, participation in the visual cycle, and the bidirectional transport of nutrients and waste products between circulation and the outer retina. Cell types in the diagram are not drawn to scale. Abbreviations: atROL = all-trans retinol, 11cRAL = 11-cis retinal.

Fig. 2.

Figure 2. Metabolism in the RPE. Most of the glucose taken up by the RPE from the choroid is transported to the apical side of the RPE monolayer to fuel the photoreceptors. However, some of the glucose undergoes glycolysis in the RPE to provide precursors for the pentose phosphate pathway and serine/glycine biosynthesis. Lactate produced as a byproduct of photoreceptor metabolism is imported into the RPE through MCT1 transporters and can either be exported to the basal side through MCT3 transporters or be converted to pyruvate to provide a substrate for OXPHOS. OXPHOS is a highly efficient means of energy production, generating 30-36 moles of ATP per mole of glucose, compared to 2 moles of ATP generated by glycolysis. Another important fuel for RPE cells are fatty acids which can originate from endocytosed LDL particles or phagocytosed photoreceptor outer segments. Fatty acids undergo β-oxidation in the RPE to generate acetyl-CoA which can enter the TCA cycle or be used for the synthesis of ketone bodies or cholesterol. Ketone bodies can be exported to the apical side of the RPE to support photoreceptor metabolism, while cholesterol can be exported via the formation of HDL-like particles. Proline and glutamine may also be consumed by the RPE, providing carbon and nitrogen for the synthesis of TCA intermediates and other amino acids. Fumarate and malate may be exported from the RPE to the photoreceptors where they are converted into succinate. The succinate is then taken up by the RPE, shuttling reducing power from the oxygen-poor retina to the oxygen-rich RPE. Abbreviations: α-KG, alpha ketoglutarate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; ETC, electron transport chain, FADH₂, flavin adenine dinucleotide (reduced); Fum, fumarate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Glu, glutamate; GLUT1, glucose transporter 1; HDL, high-density lipoprotein; HK, hexokinase; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; Mal, malate; MCT1, monocarboxylate transporter 1; MCT3, monocarboxylate transporter 3; NAD⁺, nicotinamide adenine dinucleotide (oxidised); NADH, nicotinamide adenine dinucleotide (reduced); OXPHOS, oxidative phosphorylation; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PKM, pyruvate kinase muscle isotype; POS, photoreceptor outer segment; RPE, retinal pigment epithelium; Succ, succinate; TCA, tricarboxylic acid.

Fig. 3.

Figure 3. RPE metabolic dysregulation in AMD. Blue boxes indicate decreases and pink boxes indicate increases. Decreased fatty acid oxidation and OXPHOS arise from mtDNA damage, mitochondrial dysfunction, and decreased PGC-1α activity. This causes bioenergetic stress, forcing RPE cells to compensate by increasing glycolysis, potentially restricting glucose supply to the photoreceptors. AMD risk genes contribute to dysregulated cholesterol metabolism, decreasing cholesterol efflux through HDL-like particles and promoting drusen formation. Abbreviations: ABCA1, ATP-binding cassette A1; ADP, adenosine diphosphate; APOE, apolipo-protein E; ATP, adenosine triphosphate; CETP, cholesterol ester transfer protein; ETC, electron transport chain; FADH₂, flavin adenine dinucleotide; Fum, fumarate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LIPC, hepatic lipase; Mal, malate; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide (reduced); OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; RPE, retinal pigment epithelium; Succ, succinate; TCA, tricarboxylic acid.

Fig. 4.

Figure 4. The effects of TNFα on metabolism. Summary of the effects of TNFα on glucose (purple), mitochondrial (green), lipid (beige), and amino acid (blue) metabolism in various cell types. Numbers in top left corner of boxes indicate differing effects depending on cell type. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 5.

Figure 5. The effects of TGF-β on metabolism. Summary of the effects of TGF-β on glucose (purple), mitochondrial (green), lipid (beige), and amino acid (blue) metabolism in various cell types. Numbers in top left corner of boxes indicate differing effects depending on cell type. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 6.

Figure 6. The effects of IL-6 on metabolism. Summary of the effects of IL-6 on glucose (purple), mitochondrial (green), lipid (beige) metabolism in various cell types. Numbers in top left corner of boxes indicate differing effects depending on cell type. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 7.

Figure 7. The effects of IL-1β on metabolism. Summary of the effects of IL-1β on glucose (purple), mitochondrial (green), lipid (beige) metabolism in various cell types. Numbers in top left corner of boxes indicate differing effects depending on cell type. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 8.

Figure 8. The sources of oxidative stress in the RPE and their effects on metabolism. Multiple intrinsic and age-related factors contribute to severe oxidative stress in the RPE. Reactive oxygen species may influence metabolism through direct modification of metabolic enzymes or through oxidative stress sensitive pathways. This results in dysregulated glucose (pink), mitochondrial (green), and lipid (beige) metabolism. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 9.

Figure 9. The effects of EGF on metabolism. EGF is expressed in the RPE, can be released from heparin by MMP cleavage, and is upregulated in several eye diseases. EGF acts on several intracellular signalling pathways, influencing metabolic gene/protein expression and activity, and ultimately affecting multiple aspects of glucose, mitochondrial, lipid, and amino acid metabolism. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 10.

Figure 10. The effects of FGF on metabolism. FGF is expressed in the RPE, can be released from heparin by MMP cleavage, and is upregulated in several eye diseases. EGF acts on several intracellular signalling pathways, influencing metabolic gene/protein expression and activity, and ultimately affecting multiple aspects of glucose, mitochondrial, and lipid metabolism. ↑ indicates an increase and ↓ indicates a decrease.

Fig. 11.

The effects of IGF-1 on metabolism. IGF-1 can be released from heparin by MMP cleavage and is upregulated in several eye diseases. EGF acts on several intracellular signalling pathways, influencing metabolic gene/protein expression and activity, and ultimately affecting multiple aspects of glucose, mitochondrial, lipid, and amino acid metabolism. ↑ indicates an increase and ↓ indicates a decrease.