Retinal pigment epithelium lipid metabolic demands and therapeutic restoration

Abstract

One of the defining features of the retina is the tight metabolic coupling between cells such as photoreceptors and the retinal pigment epithelium (RPE). This necessitates the compartmentalization and proper substrate availability required for specialized processes such as photo-transduction. Glucose metabolism is preferential in many human cell types for adenosine triphosphate generation, yet fatty acid β-oxidation generates essential fuel for RPE. Here, we provide a brief overview of metabolic demands in both the healthy and dystrophic RPE with an emphasis on fatty acid oxidation. We outline therapies aimed at renormalizing this metabolism and explore future avenues for therapeutic intervention.

Cell-cell interaction in the pathogenesis of inherited retinal diseases

“…Located juxtaposed to photoreceptors ( Figure 1 ), RPE form the outer retina-blood barrier, with their apical and basal side interfacing with photoreceptors and the Bruch’s membrane, respectively ( Lakkaraju et al, 2020 ). RPE tightly interact with photoreceptors to coordinate metabolism and visual cycle ( Palczewski and Kiser, 2020 ; Hurley, 2021 ; Nolan et al, 2021 ). We will further discuss the interaction between photoreceptors and their interaction partners MG and RPE in the following sections.…”

“…Another approach to inhibit glycolysis in RPE is to activate the Akt pathway by phosphatidylserine on the outer segments ( Viegas and Neuhauss, 2021 ). As photoreceptors are rich in lipids, the remaining products from phagocytosed outer segments contain sufficient phospholipids, fatty acids, cholesterol, and proteins to support the energy demand of RPE ( Nolan et al, 2021 ; Ramachandra Rao and Fliesler, 2021 ; Viegas and Neuhauss, 2021 ). These lipids are broken down into ketone bodies by hydroxymethylglutaryl-coenzyme A (CoA) synthase 2 in RPE through the mitochondrial β-oxidation pathways ( Nolan et al, 2021 ).…”

“…As photoreceptors are rich in lipids, the remaining products from phagocytosed outer segments contain sufficient phospholipids, fatty acids, cholesterol, and proteins to support the energy demand of RPE ( Nolan et al, 2021 ; Ramachandra Rao and Fliesler, 2021 ; Viegas and Neuhauss, 2021 ). These lipids are broken down into ketone bodies by hydroxymethylglutaryl-coenzyme A (CoA) synthase 2 in RPE through the mitochondrial β-oxidation pathways ( Nolan et al, 2021 ). The ketone bodies are released to the apical side of the RPE probably to be taken up by photoreceptors as another source of energy supply ( Nolan et al, 2021 ).…”

“…These lipids are broken down into ketone bodies by hydroxymethylglutaryl-coenzyme A (CoA) synthase 2 in RPE through the mitochondrial β-oxidation pathways ( Nolan et al, 2021 ). The ketone bodies are released to the apical side of the RPE probably to be taken up by photoreceptors as another source of energy supply ( Nolan et al, 2021 ). Approximately 80% of materials in the phagocytosed outer segments are recycled back to photoreceptors or removed to the blood stream as waste, a process regulated by ATP-driven Na + /K + pumps ( Mazzoni et al, 2014 ; Country, 2017 ; Kwon and Freeman, 2020 ).…”

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function

“…A critical aspect of this inter-dependence is the RPE's metabolic flexibility. It relies on oxidative substrates; fatty acids, lactate and amino acids (proline) to provide TCA cycle intermediates thereby sparing glucose for the use by the neural retina (6,(59)(60)(61)(62). Fatty acids are one of these flexible substrates, provided by the daily phagocytosis of lipid-rich OS, they generate fuel for RPE and NR function through fatty acid oxidation (FAO) (13).…”