Proline mediates metabolic communication between retinal pigment epithelial cells and the retina

Yam, Michelle; Engel, Abbi; Wang, Yekai; Zhu, Siyan; Hauer, Allison; Zhang, Rui; Lohner, Daniel; Huang, Jiancheng; Dinterman, Marlee; Zhao, Chen; Chao, Jennifer R.; Du, Jianhai

doi:10.1074/jbc.ra119.007983

Cited by 76 publications

(121 citation statements)

References 66 publications

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“…These observations about retinal metabolism prompted us to explore the role of succinate in the overall metabolic ecosystem of the eye. The RPE relies on its mitochondria to oxidize diverse fuels including lactate, fatty acids, glutamine and proline, and some of these fuels can be supplied to the RPE by the retina (Adijanto et al, 2014;Du et al, 2016;Kanow et al, 2017;Reyes-Reveles et al, 2017;Yam et al, 2019). In this report we show that the RPE/choroid complex has an extraordinary capacity to oxidize succinate.…”

Section: Introductionmentioning

confidence: 49%

“…The RPE consumes mitochondrial fuels, and RPE cells are in direct contact with the retina and metabolites exchange between these tissues within an eye (Adijanto et al, 2014;Du et al, 2016;Kanow et al, 2017;Nickla and Wallman, 2010;Reyes-Reveles et al, 2017;Swarup et al, 2019;Yam et al, 2019;Young and Bok, 1969). For these reasons, we tested the capacity of RPE cells to consume succinate.…”

Section: Retinas Release Succinate Which Can Fuel O2 Consumption In Ementioning

confidence: 99%

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Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium

Bisbach

Hass

Robbings

et al. 2020

Preprint

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AbstractWhen O2 is plentiful, the mitochondrial electron transport chain uses it as a terminal electron acceptor. However, the mammalian retina thrives within a hypoxic niche in the eye. We find that mitochondria in retinas adapt to their hypoxic environment by relying on the “reverse” succinate dehydrogenase reaction, where fumarate accepts electrons instead of O2. Reverse succinate dehydrogenase activity produces succinate and is enhanced by down-regulation of cytochrome oxidase subunits. Retinas can export the succinate to the neighboring retinal pigment epithelium/choroid complex. There, succinate stimulates O2 consumption several fold and enhances synthesis and release of malate. Malate released from the pigment epithelium can be imported into the retina, where it is converted to fumarate and again used to accept electrons in the reverse succinate dehydrogenase reaction. Our findings show how a malate/succinate shuttle can sustain these two tissues by transferring reducing power from an O2-poor tissue (retina) to an O2-rich one (retinal pigment epithelium/choroid).

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Section: Introductionmentioning

confidence: 49%

Section: Retinas Release Succinate Which Can Fuel O2 Consumption In Ementioning

confidence: 99%

Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium

Bisbach

Hass

Robbings

et al. 2020

Preprint

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“…Further experiments verified that the neural retina possess an efficient system for serine uptake. [15].…”

Section: Why Is Serine Important To the Entire Retina?mentioning

confidence: 99%

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

Sinha

Ikelle

Naash

et al. 2020

Cells

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In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid–ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argument for the exploration of serine-based clinical interventions for retinal pathologies.

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“…In these cells, the Krebs cycle mitochondrial metabolites derived from the proline metabolism were found to be actively transported to the apical retinal side for retina energetic supply. By using 13 C-proline, the same team confirmed in vivo in mice this active flow of energetic proline-derived metabolites toward the retina [16]. They also showed, in an acute mice model of RPE-induced retinal degeneration, that dietary proline was able to protect RPE from oxidative damage, improving the visual function.…”

Section: Discussionmentioning

confidence: 82%

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

Barca

Rondet-Courbis

Ferré

et al. 2020

JCM

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To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini–Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria; proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.

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Proline mediates metabolic communication between retinal pigment epithelial cells and the retina

Cited by 76 publications

References 66 publications

Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium

Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

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Proline mediates metabolic communication between retinal pigment epithelial cells and the retina

Cited by 76 publications

References 66 publications

Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium

Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

Contact Info

Product

Resources

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Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium

Succinate can shuttle reducing power from the hypoxic retina to the O₂-rich pigment epithelium