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Proline generates GSH and NADPH to counter oxidative stress. Proline can shuttle between the mitochondria and cytosol to form the proline cycle, which transfers electrons from NADPH into the mitochondria and stimulate flux of the pentose phosphate pathway. Proline catabolism can stimulate NADPH formation by driving malic enzymes, folate cycle and reductive carboxylation through IDH1/2. Glutamate, cysteine and glycine forms the tripeptide GSH, which is used by antioxidant enzymes to scavenge reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Oxidized glutathione (GSSG) is then reduced back to GSH by NADPH-dependent glutathione reductase, thereby consuming NADPH. 3PG 3-phosphoglycerate, αKG alpha-ketoglutarate, Asp aspartate, IDH isocitrate dehydrogenase (isoforms 1,2), GSH glutathione, GSSG oxidized GSH, ME malic enzyme (isoforms 1,3), OAA oxaloacetate, P5C pyrroline-5-carboxylate, ROS reactive oxygen species
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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, lead...
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... The low levels of Figure 2. Breakdown of amino acids for consumption in the mitochondrial TCA cycle, and extramitochondrial metabolite flux from urea cycle and glycolysis towards heme biosynthesis in wildtype cells. The scheme was modified from the biochemistry textbook Stryer and from [71]. The well-established Shemin pathway of heme biosynthesis is highlighted in an ellipse with a gray background. ...
... Breakdown of amino acids for consumption in the mitochondrial TCA cycle, and extramitochondrial metabolite flux from urea cycle and glycolysis towards heme biosynthesis in wildtype cells. The scheme was modified from the biochemistry textbook Stryer and from[71]. The wellestablished Shemin pathway of heme biosynthesis is highlighted in an ellipse with a gray background. ...
The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-aminolevulinic acid synthase (ALAS) to promote pyridoxal phosphate (PLP) binding. CLPX may also influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted a reduction in arginine/histidine levels. In Mus musculus cerebellum, reductions in arginine/histidine and citrulline occurred with a concomitant accumulation of the heme precursor protoporphyrin IX. This suggests that the increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA and C1 glycine but also specific C5 delta amino acids. As enzymes responsible for these effects, the elevated abundance of CLPX and ALAS is paralleled by increased OAT (PLP-dependent, ornithine delta-aminotransferase) levels. Possibly as a consequence of altered C1 metabolism, the proteome profiles of P. anserina CLPP-null cells showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. The reduced histidine levels may explain the previously observed metal interaction problems. As the main nitrogen-storing metabolite, a deficiency in arginine would affect the urea cycle and polyamine synthesis. Supplementation of arginine and histidine might rescue the growth deficits of CLPP-mutant patients.
... 8 Figure 2. Breakdown of amino acids for consumption in the mitochondrial TCA cycle, and extramitochondrial metabolite flux from urea cycle and glycolysis towards heme biosynthesis in wildtype cells. The scheme was modified from the biochemistry textbook Stryer and from [62]. The wellestablished Shemin pathway of heme biosynthesis is highlighted in an ellipse with a gray background. ...
Serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome with growth deficit, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP-loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-amino-levulinic-acid synthase (ALAS) to promote pyridoxal-phosphate (PLP) binding. CLPX may influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted arginine/histidine reduction. In Mus musculus cerebellum, reductions of Arginine/Histidine and Citrulline occurred with concomitant accumulation of heme-precursor protoporphyrin-IX. This suggests that increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA with C1 glycine but also specific C5 delta amino-acids. As responsible enzymes for these converse effects, elevated abundance of CLPX and ALAS is paralleled by elevation of OAT (PLP-dependent, ornithine-delta-aminotransferase). Possibly as consequence of altered C1 metabolism, CLPP-null cells in P. anserina proteome profiles showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. Reduced Histidine levels may explain previously observed metal interaction problems. As main nitrogen-storing metabolite, deficient Arginine would affect the urea cycle and polyamine synthesis. Supplementation of Arginine and Histidine might rescue growth deficits of CLPP-mutant patients.
... Mutations in genes related to proline metabolism are associated with retinal degenerative diseases (100). Additionally, proline supplementation has been shown to improve the alleviation of RPE-induced vision loss (100,101). Further research is needed to understand the underlying reasons and mechanisms behind the detrimental effects of elevated lactate levels on the RPE. ...
The Warburg effect, which was first described a century ago, asserts that mitotic tumor cells generate higher quantities of lactate. Intriguingly, even in typical physiological circumstances, postmitotic retinal photoreceptor cells also produce elevated levels of lactate. Initially classified as metabolic waste, lactate has since gained recognition as a significant intracellular signaling mediator and extracellular ligand. This current review endeavors to provide a concise overview and discourse on the following topics: the localization of lactate-producing enzymes, the functional significance of these enzymes, the signaling functions of lactate, and its impact on the gene expression of photoreceptors in retinal cells.
... The rich proline content conduces to the medicinal effects of SFM to a certain extent. It has been proven to promote fetus and placenta development in vitro (Hussain et al., 2020), regulate oocyte cytoplasm maturation, and GSH-related redox homeostasis (Du, Zhu, Lim, & Chao, 2021). Additionally, thiazole has been found to improve the taste of meat (Yeo, Balagiannis, Koek, & Parker, 2022). ...
Silky fowl is a highly valued breed of chicken with both culinary and medicinal significance. We conducted a comprehensive and integrated proteomic, transcriptomic, and metabolomic analysis to compare silky fowl meat (SFM) with Leghorn chicken meat (LCM). In SFM, 262 differentially expressed proteins (48 up-regulated, 214 down-regulated), 2577 differentially expressed genes (949 up-regulated, 1628 down-regulated), and 198 differentially abundant metabolites (52 up-regulated, 146 down-regulated) were identified. Our studies underscore the notable involvement of SFM in essential amino acid biosynthesis, accompanied by the up-regulation of genes associated with melanogenesis. Several genes exhibited consistent expression patterns with the results derived from real-time quantitative polymerase chain reaction (RT-qPCR). SFM contained higher levels of flavor-enhancing factors (glutathione, glycine, serine) relative to LCM. Moreover, it harbored the presence of pharmacologically significant metabolites alongside up-regulated genes related to vitamin E metabolism. These multi-omics differences provide a comprehensive framework that lays the groundwork for future investigations into the biological, nutritional, and pharmacological applications of silky fowl.
... Genetic defects in proline synthesis lead to retinal pigment epithelium (RPE) dysfunction and retinal degeneration in humans. 61 Proline is a key and favorable nutrient to support the TCA cycle in RPE. 62 Dietary proline improves visual function and decreases photoreceptor death after sodium-iodate-induced RPE damage in mice. ...
Nutritional deprivation occurring in most preterm infants postnatally can induce hyperglycemia, a significant and independent risk factor for suppressing physiological retinal vascularization (Phase I retinopathy of prematurity (ROP)), leading to compensatory but pathological neovascularization. Amino acid supplementation reduces retinal neovascularization in mice. Little is known about amino acid contribution to Phase I ROP. In mice modeling hyperglycemia-associated Phase I ROP, we found significant changes in retinal amino acids (including most decreased L-leucine, L-isoleucine, and L-valine). Parenteral L-isoleucine suppressed physiological retinal vascularization. In premature infants, severe ROP was associated with a higher mean intake of parenteral versus enteral amino acids in the first two weeks of life after adjustment for treatment group, gestational age at birth, birth weight, and sex. The number of days with parenteral amino acids support independently predicted severe ROP. Further understanding and modulating amino acids may help improve nutritional intervention and prevent Phase I ROP.
... Aside from being provided by diet, proline can be produced from ornithine, glutamate, or from collagen degradation. Mutations of enzymes in these pathways are known to cause RPE cell death and retinal degeneration (8,9). For example, mutations of ornithine aminotransferase (OAT) cause gyrate atrophy, an ocular disease characterized by progressive loss of the RPE/ choroid (Cho), leading to retinal degeneration. ...
... There are multiple lines of evidence that proline metabolism is uniquely important in retinal health and disease. First, proline is the only amino acid whose consumption is linked to RPE differentiation (7,9). Proline stimulates RPE mitochondrial function. ...
... Proline, along with its derivatives such as hydroxyproline and glycine, constitutes the primary components of the extracellular matrix. Both mitochondrial function and extracellular matrix turnover play crucial roles in RPE function and the pathogenesis of AMD (9,24). Second, mutations of multiple genes involved in proline metabolism, including OAT, P5C dehydrogenase, and P5C reductase, cause inherited retinal degenerations and RPE atrophy in patients and animal models (9,(25)(26)(27). ...
It is known that metabolic defects in the retinal pigment epithelium (RPE) can cause degeneration of its neighboring photoreceptors in the retina, leading to retinal degenerative diseases such as age-related macular degeneration. However, how RPE metabolism supports the health of the neural retina remains unclear. The retina requires exogenous nitrogen sources for protein synthesis, neurotransmission, and energy metabolism. Using ¹⁵N tracing coupled with mass spectrometry, we found human RPE can utilize the nitrogen in proline to produce and export 13 amino acids, including glutamate, aspartate, glutamine, alanine, and serine. Similarly, we found this proline nitrogen utilization in the mouse RPE/choroid but not in the neural retina of explant cultures. Coculture of human RPE with the retina showed that the retina can take up the amino acids, especially glutamate, aspartate, and glutamine, generated from proline nitrogen in the RPE. Intravenous delivery of ¹⁵N proline in vivo demonstrated ¹⁵N-derived amino acids appear earlier in the RPE before the retina. We also found proline dehydrogenase, the key enzyme in proline catabolism is highly enriched in the RPE but not the retina. The deletion of proline dehydrogenase blocks proline nitrogen utilization in RPE and the import of proline nitrogen–derived amino acids in the retina. Our findings highlight the importance of RPE metabolism in supporting nitrogen sources for the retina, providing insight into understanding the mechanisms of the retinal metabolic ecosystem and RPE-initiated retinal degenerative diseases.
... RPE cells are a polarized monolayer of cells between the photoreceptors and the choriocapillaris. Deregulated RPE cell metabolism [1][2][3] and bioenergetics [4][5][6] has been proposed as an important aspect of AMD pathology. Metabolic profiling of biofluids (serum, plasma, urine, and aqueous humor) and isolated primary human RPE cells have shown differential metabolism in regard to sources of ATP between AMD patients and control groups. ...
Age‐related macular degeneration (AMD) is associated with formation of drusen, clusters of lipids, and oxidized lipid products under the retinal pigment epithelium (RPE). 7‐Ketocholesterol (7KC) is a form of oxidized cholesterol present in drusen and is hypothesized to play a role in AMD pathogenesis. The association of 7KC with cellular toxicity and inflammation, key elements of AMD pathology, has been demonstrated. However, the effects of 7KC on altering RPE bioenergetics, a potentially important pathologic process in AMD, are unclear. Herein, we describe the effects of non‐lethal doses of 7KC on the bioenergetics and phenotype of RPE cells in culture. Metabolic analysis demonstrated a significant dose‐dependent increase in total ATP production rates that was driven primarily by an increase in glycolysis. The increase in glycolysis was accompanied by an increase in glucose uptake and increased expression of hexokinase 1. Increased levels of Translocase of Outer Mitochondrial Membrane 20 and NADH:Ubiquinone Oxidoreductase Core Subunit S1, Succinate dehydrogenase, Ubiquinol‐Cytochrome C Reductase Core Protein 2, Cytochrome C Oxidase II, and ATP synthase subunit beta, proteins involved in oxidative phosphorylation (OXPHOS), were also seen. However, specific electron transport chain activity remained unchanged. 7KC‐treated cells also demonstrated a change in cellular morphology with decreased expression of epithelial markers. In summary, 7KC has significant effects on the bioenergetics and morphology of RPE cells reflective of findings seen in clinical AMD.
... [24] Dietary proline protects retinas from degeneration induced by the oxidative damage in the retinal pigment epithelium. [25] Accumulating in several plant species in response to environmental stress, proline plays a key rolein plant recovery from stress. [26] Improving cardiovascular function and enhancing lean tissue mass, arginine is widely used as dietary supplement also to reduce obesity. ...
The analysis via GC‐MS of the amino acids present in AnchoisFert, a new organic fertilizer co‐product of fish oil extraction from anchovy fillet leftovers using limonene, unveils the presence of 16 amino acids, essential, quasi‐essential and non‐essential. Leucine, glycine, glutamic acid and alanine are the most abundant AAs. Proline, aspartic acid, arginine, serine, lysine and phenylalanine are also relatively plentiful. Alongside the results of the techno‐economic and life cycle assessment analyses, these outcomes suggest that the “LimoFish” circular economy process is highly effective in recovering valued AAs that otherwise would be lost in the environment. This greatly improves the sustainability of anchovy fishing, processing and consumption, further supporting the scale‐up and industrialization of the process.
... [24] Dietary proline protects retinas from degeneration induced by the oxidative damage in the retinal pigment epithelium. [25] Accumulating in several plant species in response to environmental stress, proline plays a key rolein plant recovery from stress. [26] Improving cardiovascular function and enhancing lean tissue mass, arginine is widely used as dietary supplement also to reduce obesity. ...
The analysis via GC-MS of the amino acids present in AnchoisFert, a new organic fertilizer co-product of fish oil extraction from anchovy fillet leftovers using limonene, unveils the presence of 16 amino acids, essential, quasi-essential and non-essential. Leucine, glycine, glutamic acid and alanine are the most abundant AAs. Proline, aspartic acid, arginine, serine, lysine and phenylalanine are also relatively plentiful. Alongside the results of the techno-economic and life cycle assessment analyses, these outcomes suggest that the “LimoFish” circular economy process is highly effective in recovering valued AAs that otherwise would be lost in the environment. This greatly improves the sustainability of anchovy fishing, processing and consumption, further supporting the scale-up and industrialization of the process.
... 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. ...
In the mammalian retina, a metabolic ecosystem exists in which photoreceptors acquire glucose from the choriocapillaris with the help of the retinal pigment epithelium (RPE). While the photoreceptor cells are primarily glycolytic, exhibiting Warburg-like metabolism, the RPE is reliant on mitochondrial respiration. However, the ways in which mitochondrial metabolism affect RPE cellular functions are not clear. We first used the human RPE cell line, ARPE-19, to examine mitochondrial metabolism in the context of cellular differentiation. We show that nicotinamide induced rapid differentiation of ARPE-19 cells, which was reversed by removal of supplemental nicotinamide. During the nicotinamide-induced differentiation, we observed using quantitative PCR, western blotting, electron microscopy, and metabolic respiration and tracing assays that (1) mitochondrial gene and protein expression increased, (2) mitochondria became larger with more tightly-folded cristae, and (3) mitochondrial metabolism was enhanced. Additionally, we show primary cultures of human fetal RPE cells responded similarly in the presence of nicotinamide. Furthermore, disruption of mitochondrial oxidation of pyruvate attenuated the nicotinamide-induced differentiation of the RPE cells. Together, our results demonstrate a remarkable effect of nicotinamide on RPE metabolism. We also identify mitochondrial respiration as a key contributor to the differentiated state of the RPE, and thus to many of the RPE functions that are essential for retinal health and photoreception.
