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

2020 ◽  
Author(s):  
Bo Li ◽  
Ting Zhang ◽  
Wei Liu ◽  
Yekai Wang ◽  
Rong Xu ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Lipid Synthesis ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
High Energy ◽  
Metabolic Dysfunction ◽  
Metabolic Demand ◽  
Energy Demands

AbstractPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

scholarly journals Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1217 ◽  
Author(s):  
C. Henrique Alves ◽  
Rosa Fernandes ◽  
Ana Raquel Santiago ◽  
António Francisco Ambrósio
Keyword(s):  
Macular Degeneration ◽  
Vascular System ◽  
Current Knowledge ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Microglial Cells ◽  
Endothelial Cell Proliferation ◽  
Metabolic Demand ◽  
Age Related

The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina and the choriocapillaris that supplies the outer retina and retinal pigment epithelium (RPE). Pathological neovascularization, characterized by endothelial cell proliferation and new vessel formation, is a common hallmark in several retinal degenerative diseases, including age-related macular degeneration (AMD). A limited number of studies have suggested that microglia, the resident immune cells of the retina, have an important role not only in the pathology but also in the formation and physiology of the retinal vascular system. Here, we review the current knowledge on microglial interaction with the retinal vascular system under physiological and pathological conditions. To do so, we first highlight the role of microglial cells in the formation and maintenance of the retinal vasculature system. Thereafter, we discuss the molecular signaling mechanisms through which microglial cells contribute to the alterations in retinal and choroidal vasculatures and to the neovascularization in AMD.

Modification of leucine transport across bovine pigment epithelium by metabolic stress

1989 ◽  
Vol 257 (5) ◽  
pp. C940-C947 ◽  
Author(s):  
E. L. Pautler ◽  
C. Tengerdy ◽  
J. Beyer ◽  
D. Beezley
Keyword(s):  
Transport System ◽  
Opposite Direction ◽  
Competitive Inhibition ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Metabolic Stress ◽  
Temperature Sensitive ◽  
Sodium Dependence ◽  
L System ◽  
Leucine Transport

The transport of leucine in the apical-to-basal (retina to choroid) direction across the isolated bovine retinal pigment epithelium is mediated predominantly by the L amino transport system at low carrier (10 microns) concentrations. There is no evidence of an active or facilitated transport system operating in the opposite direction. The identification of the L system is based on the lack of sodium dependence, specific inhibition of leucine transport by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), and the demonstration of trans-stimulation. Lysine, glutamate, and 2-methylaminoisobutyric acid (MeAIB) did not provide any competitive inhibition. Ouabain and iodoacetate were also ineffective in modifying leucine transport. The transport mediated by the L system was markedly temperature sensitive, whereas no temperature dependence was apparent in the transport of leucine in the basal-to-apical direction (choroid to retina). When treated with dinitrophenol (DNP), the transport of leucine in the apical-to-basal direction was greatly enhanced, but no effect was observed on the leucine movement in the opposite direction. Azide and rotenone had an effect similar to DNP, as did reducing the partial pressure of O2 to less than 40 Torr. The enhancement of transport appeared to be mediated by the activation of an ancillary system, since it was susceptible to different classes of metabolic and competitive inhibitors as well as the observed ionic dependency. After DNP treatment, the transport of leucine was inhibited by lysine and BCH, revealed a sodium dependence, and could be inhibited by iodoacetate. The characteristics of the enhanced transport appear to be similar to those of the recently described G system(s) of amino acid transport.

scholarly journals The Role of MicroRNAs in Mitochondria-Mediated Eye Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Sabrina Carrella ◽  
Filomena Massa ◽  
Alessia Indrieri
Keyword(s):  
Current Knowledge ◽  
Expression Profiles ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
High Energy ◽  
Light Signal ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Mitochondrial Functions

The retina is among the most metabolically active tissues with high-energy demands. The peculiar distribution of mitochondria in cells of retinal layers is necessary to assure the appropriate energy supply for the transmission of the light signal. Photoreceptor cells (PRs), retinal pigment epithelium (RPE), and retinal ganglion cells (RGCs) present a great concentration of mitochondria, which makes them particularly sensitive to mitochondrial dysfunction. To date, visual loss has been extensively correlated to defective mitochondrial functions. Many mitochondrial diseases (MDs) show indeed neuro-ophthalmic manifestations, including retinal and optic nerve phenotypes. Moreover, abnormal mitochondrial functions are frequently found in the most common retinal pathologies, i.e., glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), that share clinical similarities with the hereditary primary MDs. MicroRNAs (miRNAs) are established as key regulators of several developmental, physiological, and pathological processes. Dysregulated miRNA expression profiles in retinal degeneration models and in patients underline the potentiality of miRNA modulation as a possible gene/mutation-independent strategy in retinal diseases and highlight their promising role as disease predictive or prognostic biomarkers. In this review, we will summarize the current knowledge about the participation of miRNAs in both rare and common mitochondria-mediated eye diseases. Definitely, given the involvement of miRNAs in retina pathologies and therapy as well as their use as molecular biomarkers, they represent a determining target for clinical applications.

scholarly journals Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors

2021 ◽  
Author(s):  
Louis M Scott ◽  
Emma E Vincent ◽  
Natalie Hudson ◽  
Chris Neal ◽  
Nicholas Jones ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Metabolic Reprogramming ◽  
Mitochondrial Morphology ◽  
Interleukin 33 ◽  
Stress Signals

SummaryIt remains unresolved how retinal pigment epithelial (RPE) cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed RPE to several stress signals, particularly toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonises the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular “alarmin” activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declines and resultant bioenergetic switching is aligned with altered mitochondrial morphology. Our data not only sheds new light in the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors, but also uncovers a novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.

scholarly journals Slow TCA flux implies low ATP production in tumors

2021 ◽  
Author(s):  
Caroline R. Bartman ◽  
Yihui Shen ◽  
Won Dong Lee ◽  
Tara TeSlaa ◽  
Connor S.R. Jankowski ◽  
...  
Keyword(s):  
Electron Transport ◽  
Warburg Effect ◽  
Electron Transport Chain ◽  
Aerobic Glycolysis ◽  
Tca Cycle ◽  
High Energy ◽  
Glycolytic Flux ◽  
Atp Production ◽  
Transport Chain ◽  
The Warburg Effect

SummaryThe tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain1–6. Recent studies have measured which nutrients contribute carbon to the tumor TCA metabolites7,8, but not tumor TCA flux: how fast the cycle turns. Here, we develop and validate an in vivo dynamic isotope tracing-mass spectrometry strategy for TCA flux quantitation, which we apply to all major mouse organs and to five tumor models. We show that, compared to the tissue of origin, tumor TCA flux is markedly suppressed. Complementary glycolytic flux measurements confirm tumor glycolysis acceleration, but the majority of tumor ATP is nevertheless made aerobically, and total tumor ATP production is suppressed compared to healthy tissues. In murine pancreatic cancer, this is accommodated by downregulation of the major energy-using pathway in the healthy exocrine pancreas, protein synthesis. Thus, instead of being hypermetabolic as commonly assumed, tumors apparently make ATP at a lower than normal rate. We propose that, as cells de-differentiate into cancer, they eschew ATP-intensive processes characteristic of the host tissue, and that the resulting suppressed ATP demand contributes to the Warburg effect and facilitates cancer growth in the nutrient-poor tumor microenvironment.

scholarly journals Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Toshihide Kurihara ◽  
Peter D Westenskow ◽  
Marin L Gantner ◽  
Yoshihiko Usui ◽  
Andrew Schultz ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Metabolic Stress ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Photoreceptor Degeneration ◽  
Rpe Cells ◽  
Glucose And Lipid Metabolism ◽  
Age Related ◽  
Cellular Stresses

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

scholarly journals RNA-Seq reveals differential expression profiles and functional annotation of genes involved in retinal degeneration in Pde6c mutant Danio rerio

2019 ◽  
Author(s):  
Madhu Sudhana Saddala ◽  
Anton Lennikov ◽  
Adam Bouras ◽  
Hu Huang
Keyword(s):  
Gene Expression ◽  
Retinal Degeneration ◽  
Calcium Binding ◽  
Vision Loss ◽  
Gene Annotation ◽  
Expression Profiles ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Tca Cycle ◽  
Kegg Pathways

Abstract Retinal degenerative diseases affect millions of people and represent the leading cause of vision loss around the world. Retinal degeneration has been attributed to a wide variety of causes, such as disruption of genes involved in phototransduction, biosynthesis, folding of the rhodopsin molecule, and the structural support of the retina. The molecular pathogenesis of the biological events in retinal degeneration is unclear; however, the molecular basis of the retinal pathological defect can be potentially determined by gene-expression profiling of the whole retina. In the present study, we analyzed the differential gene expression profile of the retina from a wild-type zebrafish and phosphodiesterase 6C (pde6c) mutant. The datasets were downloaded from the Sequence Read Archive (SRA), and adaptors and unbiased bases were removed, and sequences were checked to ensure the quality. The reads were further aligned to the reference genome of zebrafish, and the gene expression was calculated. The differentially expressed genes (DEGs) were filtered based on the false discovery rate (FDR) (±4) and p-values (p < 0.001). We performed gene annotation (molecular function [MF], biological process [BP], cellular component [CC]) and determined the functional pathways Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for the DEGs. Our result showed 216 upregulated and 3,527 downregulated genes between normal and pde6c mutant zebrafish. These DEGs are involved in various KEGG pathways, such as the phototransduction (12 genes), mRNA surveillance (17 genes), phagosome (25 genes), glycolysis/gluconeogenesis (15 genes), adrenergic signaling in cardiomyocytes (29 genes), ribosome (20 genes), the citrate cycle (TCA cycle; 8 genes), insulin signaling (24 genes), oxidative phosphorylation (20 genes), and RNA transport (22 genes) pathways. Many more of all the pathway genes were downregulated, while fewer were upregulated in the retina of mutant zebrafish. Our data strongly indicate that, among these genes, the abovementioned pathways’ genes—as well as calcium-binding, neural damage, peptidase, immunological, and apoptosis proteins—are mostly involved in the retinal and neural degeneration that cause abnormalities in photoreceptors or retinal pigment epithelium (RPE) cells.

scholarly journals Mitochondrial Dysfunction in the Aging Retina

Biology ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 31 ◽  
Author(s):  
Janis T. Eells
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cell Function ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
High Energy ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Ros Generation ◽  
Mtdna Mutations ◽  
Age Related

Mitochondria are central in retinal cell function and survival and they perform functions that are critical to cell function. Retinal neurons have high energy requirements, since large amounts of ATP are needed to generate membrane potentials and power membrane pumps. Mitochondria over the course of aging undergo a number of changes. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation and increased numbers of mtDNA mutations. Mitochondria in the neural retina and the retinal pigment epithelium are particularly susceptible to oxidative damage with aging. Many age-related retinal diseases, including glaucoma and age-related macular degeneration, have been associated with mitochondrial dysfunction. Therefore, mitochondria are a promising therapeutic target for the treatment of retinal disease.

scholarly journals RNA-Seq reveals differential expression profiles and functional annotation of genes involved in retinal degeneration in Pde6c mutant Danio rerio

2020 ◽  
Author(s):  
Madhu Sudhana Saddala ◽  
Anton Lennikov ◽  
Adam Bouras ◽  
Hu Huang
Keyword(s):  
Gene Expression ◽  
Retinal Degeneration ◽  
Calcium Binding ◽  
Vision Loss ◽  
Gene Annotation ◽  
Expression Profiles ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Tca Cycle ◽  
Kegg Pathways

Abstract Background Retinal degenerative diseases affect millions of people and represent the leading cause of vision loss around the world. Retinal degeneration has been attributed to a wide variety of causes, such as disruption of genes involved in phototransduction, biosynthesis, folding of the rhodopsin molecule, and the structural support of the retina. The molecular pathogenesis of the biological events in retinal degeneration is unclear; however, the molecular basis of the retinal pathological defect can be potentially determined by gene-expression profiling of the whole retina. In the present study, we analyzed the differential gene expression profile of the retina from a wild-type zebrafish and phosphodiesterase 6c (pde6c) mutant. Results The datasets were downloaded from the Sequence Read Archive (SRA), and adaptors and unbiased bases were removed, and sequences were checked to ensure the quality. The reads were further aligned to the reference genome of zebrafish, and the gene expression was calculated. The differentially expressed genes (DEGs) were filtered based on the false discovery rate (FDR) (±4) and p-values (p < 0.001). We performed gene annotation (molecular function [MF], biological process [BP], cellular component [CC]), and determined the functional pathways Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for the DEGs. Our result showed 216 upregulated and 3,527 downregulated genes between normal and pde6c mutant zebrafish. These DEGs are involved in various KEGG pathways, such as the phototransduction (12 genes), mRNA surveillance (17 genes), phagosome (25 genes), glycolysis/gluconeogenesis (15 genes), adrenergic signaling in cardiomyocytes (29 genes), ribosome (20 genes), the citrate cycle (TCA cycle; 8 genes), insulin signaling (24 genes), oxidative phosphorylation (20 genes), and RNA transport (22 genes) pathways. Many more of all the pathway genes were downregulated, while fewer were upregulated in the retina of mutant zebrafish. Conclusions Our data strongly indicate that, among these genes, the above-mentioned pathways’ genes as well as calcium-binding, neural damage, peptidase, immunological, and apoptosis proteins are mostly involved in the retinal and neural degeneration that cause abnormalities in photoreceptors or retinal pigment epithelium (RPE) cells.

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