Metabolic and redox signaling in the retina

Abstract

Visual perception by photoreceptors relies on the interaction of incident photons from light with a derivative of vitamin A that is covalently linked to an opsin molecule located in a special subcellular structure, the photoreceptor outer segment. The photochemical reaction produced by the photon is optimal when the opsin molecule, a seven-transmembrane protein, is embedded in a lipid bilayer of optimal fluidity. This is achieved in vertebrate photoreceptors by a high proportion of lipids made with polyunsaturated fatty acids, which have the detrimental property of being oxidized and damaged by light. Photoreceptors cannot divide, but regenerate their outer segments. This is an enormous energetic challenge that explains why photoreceptors metabolize glucose through aerobic glycolysis, as cancer cells do. Uptaken glucose produces metabolites to renew that outer segment as well as reducing power through the pentose phosphate pathway to protect photoreceptors against oxidative damage.

Keywords: Aerobic glycolysis; Cone photoreceptor; Glucose transporter; Nucleoredoxin-like genes; Pentose phosphate pathway; Retinal degeneration; Rod-derived cone viability factor; Thioredoxin.

Fig. 1

Architecture of the retina of vertebrates. a Mouse adult retinal section with nuclei labeled with 4′,6-diamidino-2-phenylindole (DAPI). OS outers segment, ONL outer nuclear layer, INL inner nuclear layer, GCL ganglion cell layer. b Schematic drawing of the retinal cells and their functional relations. RPE retinal pigmented epithelium, BC bipolar cell, GC ganglion cell, M Muller glial cell

Fig. 2

Lipid peroxidation chain reaction. a Chemical structure of 4-hydroxy-2-nonenal (HNE). The carbon at position C3 targets cysteine modification. The aldehydes group targets lysine and histidine modifications. b Modification of a cysteine residue (SH) in a protein by HNE through thiol Michael addition at position C3

Fig. 3

Exchanges between the retina and the blood circulation. Blood circulation is controlled at two levels (red arrows): a blood-retinal barrier in the inner retina and an outer retinal barrier, which is constituted by the RPE. RPE retinal pigmented epithelium, BC bipolar cell, GC ganglion cell, M Muller glial cell, AJ adherent junction, OLM outer limiting membrane, P pericyte

Fig. 4

Transport of essential fatty acids from the blood circulation to photoreceptors. RPE retinal pigmented epithelium, ABL albumin, ADIPOR1 adiponectin receptor 1, MFSD2A fatty acid transporter, IPM inter-photoreceptor matrix, FABP fatty acid-binding protein, IRBP inter-photoreceptor retinoid-binding protein

Fig. 5

Recycling of saturated fatty acids by photoreceptors. RPE retinal pigmented epithelium, SFA saturated fatty acid, HMGCS2 mitochondrial HMG-coenzyme A (CoA)-synthase 2, SLC16A1 monocarboxylate transporter isoform 1, SLC16A6 monocarboxylate transporter isoform 7, TCA tricarboxylic acid, E glutamic acid

Fig. 6

Genomic organization of the bifunctional gene nucleoredoxin-like 1. NXNL1 nucleoredoxin-like 1, RdCVFL the thioredoxin enzyme rod-derived cone viability factor long, RdCVF the trophic factor rod-derived cone viability factor, TGA stop codon

Fig. 7

Metabolic signaling regulated by rod-derived cone viability factor. Top-to-bottom RdCVF rod-derived cone viability factor, BSG1 basigin-1, GLUT1 glucose transporter SLC2A1, Glc glucose, G6P glucose-6-phosphate, FBP fructose biphosphate, DHAP dihydroxyacetone phosphate, PEP phosphoenol pyruvate, PYR pyruvate, LACT lactate, MPC mitochondrial pyruvate carrier, HK hexokinase, GPI glucose-6-phosphate isomerase, PFK phosphofructokinase, ALDO aldolase, TPI triosephosphate isomerase, PGK phosphoglycerate kinase, PGM phosphoglycerate mutase, ENO enolase, PKM pyruvate kinase M, LDH lactate dehydrogenase, MCT1 lactate transporter SLC16A, NADPH nicotinamide adenine dinucleotide phosphate, G6PDH glucose-6-phosphate dehydrogenase, 6PDG 6-phosphogluconate dehydrogenase, OXPHO oxidative phosphorylation, ROS reactive oxygen species

Fig. 8

Thioredoxin/glutaredoxin system. a The oxidoreduction reaction between the thioredoxin (TXN) and its substrate (X protein). Reduced thioredoxin TXN-SH₂ binds to a target protein X via its hydrophobic surface area. Nucleophilic attack by the thiolate of Cys₃₂ results in the formation of a transient mixed disulfide, which is followed by a nucleophilic attack of the deprotonated Cys₃₅ generating oxidized TXN-S2 and the reduced protein, X-SH₂. b Deglutathionylation reaction by glutaredoxin (GLRX). c The oxidation of methionine generates a diastereomeric mixture of two stereoisomers methionine S-sulfoxide and methionine R-sulfoxide. Met-SO methionine sulfoxide MSRA and MSRB methionine sulfoxide reductase A and B, ROS reactive oxygen species. d Methionine sulfoxide reductase A reaction. MSRA methionine sulfoxide reductase A, TXN thioredoxin, GLRX glutaredoxin reductase, GSH glutathione

Fig. 9

Redox power is regulated by the production of NADPH by the pentose phosphate pathway. a Oxidoreduction of NADP⁺ and NADPH. b Schematic drawing of the thioredoxin/glutaredoxin system. TXNRD thioredoxin reductase, GSR glutathione reductase, GSH glutathione, TXN thioredoxin, Cys cysteine, MSR methionine sulfoxide reductase, GLRX glutaredoxin, PRDX peroxiredoxin, GPX glutathione peroxidase. The suffix ox and rd represent the oxidized and reduced forms, respectively

Fig. 10

Metabolic and redox signaling of the NXNL1 gene products. Rods produce the thioredoxin RdCVFL and the trophic factor RdCVF by alternative splicing. Cones exclusively produce the thioredoxin RdCVFL. RPE: retinal pigmented epithelium. Left to right RHO rhodopsin, PUFA polyunsaturated fatty acid, TAU microtubule-associated protein TAU, BSG1 basigin-1, GLUT1 glucose transporter SLC2A1, Glc glucose, G6P glucose-6-phsphate, DHAP dihydroxyacetone phosphate, PYR pyruvate, LACT lactate, PFK phosphofructokinase, PKM pyruvate kinase M, GAPDH glyceraldehyde-3-phosphate dehydrogenase, ROS reactive oxygen species, NADPH nicotinamide adenine dinucleotide phosphate, TXNRD thioredoxin reductase, GSR glutathione reductase, TXN thioredoxin, GSH glutathione, MCT1 lactate transporter 1 (SLC16A1), MCT3 lactate transporter 3 (SLC16A8). The suffix p and a. represent, respectively, the phosphorylated and the aggregated forms. Framing the coding intron I of the NXNL1 genes, GU.. and ..AG, is the splicing donor and acceptor sites, respectively. The suffix ox and suffix rd represent the oxidized and reduced forms, respectively