The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected

Abstract

Defects in energy metabolism in either the retina or the immediately adjacent retinal pigment epithelium (RPE) underlie retinal degeneration, but the metabolic dependence between retina and RPE remains unclear. Nitrogen-containing metabolites such as amino acids are essential for energy metabolism. Here, we found that 15N-labeled ammonium is predominantly assimilated into glutamine in both the retina and RPE/choroid ex vivo. [15N]Ammonium tracing in vivo show that, like the brain, the retina can synthesize asparagine from ammonium, but RPE/choroid and the liver cannot. However, unless present at toxic concentrations, ammonium cannot be recycled into glutamate in the retina and RPE/choroid. Tracing with 15N-labeled amino acids show that the retina predominantly uses aspartate transaminase for de novo synthesis of glutamate, glutamine, and aspartate, whereas RPE uses multiple transaminases to utilize and synthesize amino acids. Retina consumes more leucine than RPE, but little leucine is catabolized. The synthesis of serine and glycine is active in RPE but limited in the retina. RPE, but not the retina, uses alanine as mitochondrial substrates through mitochondrial pyruvate carrier. However, when the mitochondrial pyruvate carrier is inhibited, alanine may directly enter the retinal mitochondria but not those of RPE. In conclusion, our results demonstrate that the retina and RPE differ in nitrogen metabolism and highlight that the RPE supports retinal metabolism through active amino acid metabolism.

Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

“…Fig 6). We recently also reported that aspartate transamination is the primary pathway for the catabolism of aspartate and glutamate in mouse neural retinas 35 . As a major neurotransmitter, glutamate is the most abundant amino acid in the retina 36,37 .…”

“…Retinal cells with the highest glutamate levels also have the highest aspartate levels 37 . We have previously reported that aspartate is utilized robustly to provide both carbons and nitrogen groups for glutamate synthesis 8,35,38 . Notably, aspartate transamination also generates oxaloacetate (OAA) which can be converted to malate by cytosolic malate dehydrogenase (MDH1) to carry electrons into mitochondria through the malate-aspartate shuttle (Fig 6).…”

“…The RPE is closely coupled with photoreceptors in nutrient utilization 20,22,23,35 . In agreement with other studies of RPE cells 28,35,47 , we found that human RPE/choroid explants consumed glucose, proline, nicotinamide and BCAAs, and released plenty of 3-HB, citrate and cholesterol. All these released metabolites are made from acetyl-CoA, indicating that RPE mitochondria function like mitochondria in the liver that oxidize nutrients to support other tissues.…”

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications

“…Nearby MGCs and RPE provide much of the glutamine 62 , 157 , which when converted to glutamate via glutaminase (GLS) can either enter the catabolic TCA cycle or contribute to GSH generation (Fig. 6 ) 46 .…”

Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

“…These tissue layers exhibit metabolic synergy in numerous ways. For example, the rods and cones of the photoreceptor layer perform aerobic glycolysis and provide the adjacent retinal pigment epithelium (RPE) with lactate [ 89 , 90 ], and the RPE synthesizes amino acids, such as glutamine and glutamate, to support photoreceptor metabolism and function [ 91 ]. Interestingly, although retinal pyruvate oxidation is minimal [ 89 , 90 ], the MPC appears to be essential for photoreceptor integrity and visual function [ 92 ].…”