Abstract
The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.
Highlights
All cellular functions rely intimately on energy metabolism
We summarize the current knowledge of the homeostatic metabolism of the outer retina, the metabolism of inflammatory macrophages, and what might be the consequence when chronic inflammatory macrophages disturb the metabolic exchanges of photoreceptors and the retinal pigment epithelium (RPE) in diseases such as age-related macular degeneration (AMD)
Cones rely on the production of rod-derived cone viability factor (RdCVF) by rods and insulin signaling for glucose uptake to meet their demand for carbon for outer segment renewal and energy supply
Summary
All cellular functions rely intimately on energy metabolism. In neurons in particular, this energy demand, in the form of energy-storage adenosine triphosphate (ATP), is met by glucose metabolism. In the mitochondria, acetyl CoA delivers the 2-carbon acetyl to the eight-step tricarboxylic acid cycle (TCA) that produces the gradient of protons across the inner membrane of mitochondria which drives the production of ATP in a process called oxidative phosphorylation (OXPHO). When carbon demand is high to synthesize proteins, carbohydrates, and lipid membranes in growing or proliferating cells (such as cancer cells, and photoreceptors that constantly renew their outer segments) glycolysis exceeds the demand of pyruvate for the TCA in order to produce intermediary metabolites and extra energy in a process called aerobic glycolysis or the Warburg effect [3]. It has become increasingly clear that immune cells and, in particular, inflammatory macrophages undergo profound metabolic reprogramming in which the TCA ceases to produce energy but its intermediary products are used for immunological functions. We summarize the current knowledge of the homeostatic metabolism of the outer retina, the metabolism of inflammatory macrophages, and what might be the consequence when chronic inflammatory macrophages disturb the metabolic exchanges of photoreceptors and the RPE in diseases such as AMD
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