The work thus far implicates the mitochondria, and overall alterations to bioenergetics in RPE, as a potential mechanism driving AMD pathology. Recent publications by the laboratories of Hurley et al.
47 and Philp
7 have promoted the idea of metabolic coupling between the RPE and retina. This concept provides a potential explanation for how reduced RPE mitochondrial function could have a global effect on the retina. Based on a series of elegant studies, Kanow and colleagues
48 propose that the neural retina and RPE are part of a “metabolic ecosystem,” whereby each cell is co-dependent on the other cell for survival. In this working model (
Fig. 2), glucose from the blood is largely unused by the RPE and is transported to the photoreceptors.
48 Photoreceptors use glucose through glycolysis to produce energy and the by-product lactate, which is transported to the RPE where it is used for OxPhos. An important part of this highly regulated process is the suppression of glycolysis in the RPE by lactate, thereby preserving glucose as an energy source for the photoreceptors.
48 Photoreceptors also supply the RPE with a large amount of lipids through daily phagocytosis and digestion of the photoreceptor outer segments. These lipids are substrates for β-oxidation, which produces acetyl CoA, feeding into the TCA and producing β-hydroxybutarate, an alternative energy source for the retina.
7,49 Although other energy sources, such as glutamine,
50 proline,
51 and glycogen
52 are not specifically mentioned here, they would likely contribute to the flow of energy substrates between the retina and RPE.
AMD disrupts this metabolic ecosystem. As mitochondria are the site of OxPhos and β-oxidation, damage to this organelle in the RPE would reduce ATP production. RPE would begin to rely on glycolysis to maintain the cell's energy requirement, thereby reducing the flow of glucose to the photoreceptors. Decreased photoreceptor glycolysis could have multiple effects, including reduced production of lactate for RPE to use as an energy source. Limited suppression of glycolysis due to decreased lactate promotes glucose utilization by the RPE, starving photoreceptors, leading to degeneration and cell death. It has been well documented in AMD that rod death precedes the loss of cones.
40,53,54 This observation is relevant to the metabolic co-dependence that cones have with rods. Rods secrete an inactive thioredoxin, coined rod-derived cone viability factor, which promotes glucose uptake by the cones and stimulates glycolysis.
55 In the context of changes in RPE metabolism due to AMD-induced mitochondrial damage, the reduced flow of glucose to the photoreceptors coupled with rod death would accelerate the loss of macular cones, a hallmark of advanced AMD.