Dyslipidemia in retinal metabolic disorders

Abstract

The light-sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid-rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.

Keywords: FGF21; dyslipidemia; photoreceptor; retinal metabolism; β-oxidation.

Figure 1. β‐oxidation pathway in peroxisome and mitochondria

Figure 2. Schematics of photoreceptor and retinal structure

(A) Schematics of rod and cone structure. (B) Schematics of retinal neuronal and vascular arrangement. RPE, retinal pigment epithelium; OS/IS, outer segments/inner segments; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.

Figure 3. Cell‐specific transcriptional regulation of retinal functions

Adapted from Macosko et al, Cell 2015. (A) Retinal cell types can be identified using single‐cell RNAseq based on cell‐specific expression of genes markers. OPN1MW, Opsin 1, medium wave sensitive; RHO, rhodopsin; GABRA1, gamma‐aminobutyric acid type A receptor alpha1 subunit; OTOR, otoraplin; VSX2, visual system homeobox 2; OTX2, orthodenticle homeobox 2; SLC6A9, solute carrier family 6 member 9; SLC6A1, solute carrier family 6 member 1; NEFL, neurofilament light; SLC5A7, solute carrier family 5 member 7; NHLH2, nescient helix‐loop‐helix 2; PAX6, paired box 6; SLC4A3, solute carrier family 4 member 3; CX3CR1, C‐X3‐C motif chemokine receptor 1; RGS5, regulator Of G protein signaling 5; CLDN5, claudin 5; GFAP, glial fibrillary acidic protein; RLBP1, retinaldehyde binding protein 1. (B) Transcriptomic enrichment for specific pathway such as the phototransduction pathways can be scored using gene set variation analysis based on highly variable genes between retinal cell types.

Figure 4. Schematics of electron transport chain (ETC)

The ETC passes electrons from NADH and FADH ₂ to protein complexes (I to V) and mobile electron carriers coenzyme Q (CoQ) and cytochrome c (Cyt c). Oxygen (O₂) is the final electron recipient. The transfer of electrons generates energy to pump protons (H⁺) from the mitochondrial matrix into the intermembrane space. An electrochemical proton gradient is created across the inner mitochondrial membrane, allowing the protons to pass through complex V (ATP synthase) to generate adenosine triphosphate (ATP) from adenosine diphosphate (ADP). Complex I, NADH coenzyme Q reductase, complex II, succinate dehydrogenase, complex III, cytochrome bc ₁ complex, complex IV, cytochrome c oxidase. Complex I and complex III are the main sites for superoxide (ROS) formation.