Proline metabolism and transport in retinal health and disease

Abstract

The retina is one of the most energy-demanding tissues in the human body. Photoreceptors in the outer retina rely on nutrient support from the neighboring retinal pigment epithelium (RPE), a monolayer of epithelial cells that separate the retina and choroidal blood supply. RPE dysfunction or cell death can result in photoreceptor degeneration, leading to blindness in retinal degenerative diseases including some inherited retinal degenerations and age-related macular degeneration (AMD). In addition to having ready access to rich nutrients from blood, the RPE is also supplied with lactate from adjacent photoreceptors. Moreover, RPE can phagocytose lipid-rich outer segments for degradation and recycling on a daily basis. Recent studies show RPE cells prefer proline as a major metabolic substrate, and they are highly enriched for the proline transporter, SLC6A20. In contrast, dysfunctional or poorly differentiated RPE fails to utilize proline. RPE uses proline to fuel mitochondrial metabolism, synthesize amino acids, build the extracellular matrix, fight against oxidative stress, and sustain differentiation. Remarkably, the neural retina rarely imports proline directly, but it uptakes and utilizes intermediates and amino acids derived from proline catabolism in the RPE. Mutations of genes in proline metabolism are associated with retinal degenerative diseases, and proline supplementation is reported to improve RPE-initiated vision loss. This review will cover proline metabolism in RPE and highlight the importance of proline transport and utilization in maintaining retinal metabolism and health.

Unique Chemistry, Intake, and Metabolism of Polyamines in the Central Nervous System (CNS) and Its Body

“…This task is fulfilled by regulating biosynthesis (Figure 2) as well as degradation (Figure 3). The amino acids L-arginine, L-ornithine, glycine, L-proline, L-glutamate, and L-methionine [41][42][43] are effective sources. Biosynthesis predominantly follows two different pathways, both producing PUT as starting material for the following reactions (Figure 2).…”

Vitamin B3, nicotinamide, enhances mitochondrial metabolism to promote differentiation of the retinal pigment epithelium

“…The use of well-differentiated RPE cells has been underscored by many studies. Specific to metabolism, studies have shown that, unlike native RPE, poorly differentiated ARPE-19 as well as human telomerase reverse transcriptase RPE-1 cells are incapable of utilizing the amino acid proline as a nutrient source ( 17 , 48 ). Our current study demonstrates a clear link between RPE differentiation and mitochondrial-related metabolism.…”

Metabolic Characterization of Ocular Tissues in Relation to Laser-Induced Choroidal Neovascularization in Rats

“…We also found that proline was decreased along with changes in the glutathione pathway in the plasma of CNV rats. Likewise, previous plasma metabolomics studies of patients with AMD identified significant changes in the proline level . RPE cells prefer proline as a major metabolic substrate. , Proline metabolism is sufficient to fuel mitochondrial metabolism, sustain differentiation, promote GSH synthesis, and protect the RPE against oxidative damage. , Therefore, proline may serve as a protective factor against AMD development.…”

“…Blocking of proline metabolism in RPE impairs glucose metabolism and GSH production, which would lead to oxidative damage to the RPE. 25,26 Under conditions of oxidative stress, plasma GSH concentrations are markedly reduced due to a combination of enhanced degradation and decreased synthesis. 29 Consequentially, dietary proline was found to improve visual function in an RPE-specific oxidative damage mouse model.…”