scholarly journals Mitochondria Contribute to NADPH Generation in Mouse Rod Photoreceptors

2013 ◽  
Vol 289 (3) ◽  
pp. 1519-1528 ◽  
Author(s):  
Leopold Adler ◽  
Chunhe Chen ◽  
Yiannis Koutalos
Keyword(s):  
Single Cell ◽  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Cell Function ◽  
Primary Source ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Cell Type ◽  
Rod Photoreceptors ◽  
Substrate Concentrations

NADPH is the primary source of reducing equivalents in the cytosol. Its major source is considered to be the pentose phosphate pathway, but cytosolic NADP+-dependent dehydrogenases using intermediates of mitochondrial pathways for substrates have been known to contribute. Photoreceptors, a nonproliferating cell type, provide a unique model for measuring the functional utilization of NADPH at the single cell level. In these cells, NADPH availability can be monitored from the reduction of the all-trans-retinal generated by light to all-trans-retinol using single cell fluorescence imaging. We have used mouse rod photoreceptors to investigate the generation of NADPH by different metabolic pathways. In the absence of extracellular metabolic substrates, NADPH generation was severely compromised. Extracellular glutamine supported NADPH generation to levels comparable to those of glucose, but pyruvate and lactate were relatively ineffective. At low extracellular substrate concentrations, partial inhibition of ATP synthesis lowered, whereas suppression of ATP consumption augmented NADPH availability. Blocking pyruvate transport into mitochondria decreased NADPH availability, and addition of glutamine restored it. Our findings demonstrate that in a nonproliferating cell type, mitochondria-linked pathways can generate substantial amounts of NADPH and do so even when the pentose phosphate pathway is operational. Competing demands for ATP and NADPH at low metabolic substrate concentrations indicate a vulnerability to nutrient shortages. By supporting substantial NADPH generation, mitochondria provide alternative metabolic pathways that may support cell function and maintain viability under transient nutrient shortages. Such pathways may play an important role in protecting against retinal degeneration.

scholarly journals Activity of Energy and Carbohydrate Metabolism Enzymes in the Juvenile Pink Salmon Oncorhynchus gorbuscha (Walb.) during the Transition from Freshwater to a Marine Environment

2021 ◽  
Vol 48 (5) ◽  
pp. 546-554
Author(s):  
M. V. Churova ◽  
N. S. Shulgina ◽  
M. Yu. Krupnova ◽  
D. A. Efremov ◽  
N. N. Nemova
Keyword(s):  
Carbohydrate Metabolism ◽  
Marine Environment ◽  
Pentose Phosphate Pathway ◽  
Anaerobic Metabolism ◽  
Pink Salmon ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Oncorhynchus Gorbuscha ◽  
Biochemical Adaptation ◽  
Metabolism Enzymes

Abstract Biochemical adaptations of energy metabolism and some pathways of glucose oxidation during a change in salinity of the environment in larvae and smolts of the pink salmon Oncorhynchus gorbuscha (Walb.) inhabiting the White Sea were studied. We assayed the activity of energy and carbohydrate metabolism enzymes (cytochrome c oxidase (COХ), lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G6PDH), 1-glycerophosphate dehydrogenase (1-GPDH), and aldolase) in pink salmon larvae in a short-term aquarium experiment and in pink salmon smolts in a long-term cage experiment simulating the transition of juveniles from freshwater to a marine environment. A decrease in the activity of COX, LDH, 1‑GPDH, and aldolase already in the first hour after the transfer of larvae to seawater was shown. Smolts kept in the estuary and in the sea had low levels of activity of 1-GPDH and aldolase in comparison with individuals from the river. Most likely, in the salmon juveniles studied, there was a redistribution of carbohydrates between the reactions of aerobic and anaerobic metabolism in favor of anaerobic ATP synthesis. No changes in the enzyme activity of the pentose phosphate pathway, G-6-PDH, were found in either larvae or smolts compared with the individuals kept in freshwater. Maintenance of the required levels of anaerobic metabolism and of the pentose phosphate pathway is probably one of the mechanisms of biochemical adaptation of pink salmon to changes in salinity.

scholarly journals Palbociclib and fulvestrant act in synergy to modulate central carbon metabolism in breast cancer cells

2018 ◽  
Author(s):  
Benedikt Warth ◽  
Amelia Palermo ◽  
Nicholas J.W. Rattray ◽  
Nathan V Lee ◽  
Zhou Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Breast Cancer Cells ◽  
Pentose Phosphate ◽  
List Type ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

SummaryPalbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6 and used as a first-line treatment for patients with estrogen receptor positive breast cancer. It has been shown that patients have improved progression-free survival when treated in combination with fulvestrant, an estrogen receptor antagonist. However, the mechanisms for this survival advantage are not known. We sought to analyze metabolic and transcriptomic changes in MCF-7 adenocarcinoma breast cancer cells following single and combined treatments to determine if selective metabolic pathways are targeted during combination therapy. Our results showed that individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy′s synergism in the cell model. This study highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.Highlights○First study employing multi-omics to investigate combined therapy on breast cancer cells○Fulvestrant attenuates the pentose phosphate pathway and coenzyme production○Synergism of palbociclib and fulvestrant was confirmed in vitro○Altered key pathways have been identifiedeTOC BlurbJohnson et al. applied an innovative multi-omics approach to decipher metabolic pathways affected by single versus combination dosing of palbociclib and fulvestrant in estrogen receptor positive breast cancer. Key metabolites and genes were correlated within metabolic pathways and shown to be involved in the drugs′ synergism.

scholarly journals The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

2021 ◽  
Vol 17 (8) ◽  
pp. e1009326
Author(s):  
Héloise Rytter ◽  
Anne Jamet ◽  
Jason Ziveri ◽  
Elodie Ramond ◽  
Mathieu Coureuil ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Pathogenic Bacteria ◽  
Metabolic Networks ◽  
Tricarboxylic Acid Cycle ◽  
Sulfur Metabolism ◽  
Time Lapse ◽  
Pentose Phosphate ◽  
Francisella Novicida

Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.

scholarly journals Single amino acid-promoted reactions link a non-enzymatic chemical network to the early evolution of enzymatic pentose phosphate pathway

2020 ◽  
Author(s):  
Gabriel Piedrafita ◽  
Sreejith Varma ◽  
Cecilia Castro ◽  
Christoph Messner ◽  
Lukasz Szyrwiel ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Metal Ion ◽  
Enzymatic Reaction ◽  
Pentose Phosphate ◽  
Early Evolution ◽  
Environmental Chemical ◽  
Rna Backbone

AbstractHow metabolic pathways emerged in early evolution remains largely unknown. Recently discovered chemical networks driven by iron and sulfur resemble reaction sequences found within glycolysis, gluconeogenesis, the oxidative and reductive Krebs cycle, the Wood Ljungdahl as well as the S-adenosylmethionine pathways, components of the core cellular metabolic network. These findings suggest that the evolution of central metabolism was primed by environmental chemical reactions, implying that non-enzymatic reaction networks served as a “template” in the evolution of enzymatic activities. We speculated that the turning point for this transition would depend on the catalytic properties of the simplest structural components of proteins, single amino acids. Here, we systematically combine constituents of Fe(II)-driven non-enzymatic reactions resembling glycolysis and pentose phosphate pathway (PPP), with single proteinogenic amino acids. Multiple reaction rates are enhanced by amino acids. In particular, cysteine is able to replace (and/or complement) the metal ion Fe(II) in driving the non-enzymatic formation of the RNA-backbone metabolite ribose 5-phosphate from 6-phosphogluconate, a rate-limiting reaction of the oxidative PPP. In the presence of both Fe(II) and cysteine, a complex is formed, enabling the non-enzymatic reaction to proceed at a wide range of temperatures. At mundane temperatures, this ‘minimal enzyme-like complex’ achieves a much higher specificity in the formation of ribose 5-phosphate than the Fe(II)-driven reaction at high temperatures. Hence, simple amino acids can accelerate key steps within metal-promoted metabolism-like chemical networks. Our results imply a stepwise scenario, in which environmental chemical networks served as primers in the early evolution of the metabolic network structure.Significance StatementThe evolutionary roots of metabolic pathways are barely understood. Here we show results consistent with a stepwise scenario during the evolution of (enzymatic) metabolism, starting from non-enzymatic chemical networks. By systematic screening of metabolic-like reactivities in vitro, and using high-throughput analytical techniques, we identify an iron/cysteine complex to act as a ‘minimal enzymelike complex’, which consists of a metal ion, an amino acid, and a sugar phosphate ligand. Integrated in a metal-driven, non-enzymatic pentose phosphate pathway, it promotes the formation of the RNA-backbone precursor ribose 5-phosphate at ambient temperature.

scholarly journals Enhanced glucose metabolism through activation of HIF-1α covers the energy demand in a rat embryonic heart primordium after heartbeat initiation

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Tatsuya Sato ◽  
Nobutoshi Ichise ◽  
Takeshi Kobayashi ◽  
Hiroyori Fusagawa ◽  
Hiroya Yamazaki ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Energy Demand ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Atp Synthesis ◽  
Pentose Phosphate ◽  
Metabolome Analysis ◽  
Nucleotide Biosynthesis ◽  
Metabolic Characteristics ◽  
Before And After

AbstractThe initiation of heartbeat is an essential step in cardiogenesis in the heart primordium, but it remains unclear how intracellular metabolism responds to increased energy demands after heartbeat initiation. In this study, embryos in Wistar rats at embryonic day 10, at which heartbeat begins in rats, were divided into two groups by the heart primordium before and after heartbeat initiation and their metabolic characteristics were assessed. Metabolome analysis revealed that increased levels of ATP, a main product of glucose catabolism, and reduced glutathione, a by-product of the pentose phosphate pathway, were the major determinants in the heart primordium after heartbeat initiation. Glycolytic capacity and ATP synthesis-linked mitochondrial respiration were significantly increased, but subunits in complexes of mitochondrial oxidative phosphorylation were not upregulated in the heart primordium after heartbeat initiation. Hypoxia-inducible factor (HIF)-1α was activated and a glucose transporter and rate-limiting enzymes of the glycolytic and pentose phosphate pathways, which are HIF-1α-downstream targets, were upregulated in the heart primordium after heartbeat initiation. These results suggest that the HIF-1α-mediated enhancement of glycolysis with activation of the pentose phosphate pathway, potentially leading to antioxidant defense and nucleotide biosynthesis, covers the increased energy demand in the beating and developing heart primordium.

scholarly journals Flux Balance Analysis Identifies Distinct NADPH Production Strategies Across NCI 60 Cancer Cell Lines

2018 ◽  
Author(s):  
Zaid Ahmad
Keyword(s):  
Cell Lines ◽  
Pentose Phosphate Pathway ◽  
Malic Enzyme ◽  
Pentose Phosphate ◽  
Cell Type ◽  
Flux Balance ◽  
Production Strategies ◽  
Balance Analysis ◽  
Cell Type Specific ◽  
Folate Cycle

AbstractFlux Balance Analysis is a linear mathematical procedure which determines the set of reaction fluxes to produce a maximum flux of a reaction of interest. In this study, a core cancer model developed by Zielinski et al. 2017 is constrained by a set of 59 cancer cell type specific uptake and secretion rates. Optimizing for cell type specific biomass objective reactions and examining serine flux distributions reveals variability in production of NADPH. In many cell lines, production of NADPH is correlated to biosynthetic demand, however, outliers exist that produce excess NADPH beyond that of biomass demand. These outliers are first characterized by their NADPH production strategy (pentose phosphate pathway or a combination of One Folate Cycle and Malic Enzyme) and then the factors responsible for the different NADPH production strategies are identified. Results indicate that pentose phosphate pathway (PPP) producing NADPH cell lines had reprogrammed tricarboxylic acid cycle metabolism to meet the demand for decreased flux through glycolytic enzymes, while one folate cycle and malic enzyme (OFC + ME) producing NADPH cell lines had higher threonine, tyrosine and serine uptake.

scholarly journals The effect of quercetin on endothelial cells is modified by heterocellular interactions

2020 ◽  
Vol 11 (5) ◽  
pp. 3916-3925
Author(s):  
Sarka Tumova ◽  
Michael J. Houghton ◽  
Gary Williamson
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Single Cell ◽  
Cell Function ◽  
Cell Interactions ◽  
Cell Type ◽  
Endothelial Cell Function ◽  
Single Cell Type ◽  
Cell Cell

Single cell-type models are useful for determining mechanisms, but in vivo, cell–cell interactions are important, and neighbouring cells can impact endothelial cell function.

scholarly journals Accelerated Metabolite Levels of Aerobic Glycolysis and the Pentose Phosphate Pathway Are Required for Efficient Replication of Infectious Spleen and Kidney Necrosis Virus in Chinese Perch Brain Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 440
Author(s):  
Xixi Guo ◽  
Shiwei Wu ◽  
Ningqiu Li ◽  
Qiang Lin ◽  
Lihui Liu ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Late Stage ◽  
Metabolic Pathways ◽  
Aerobic Glycolysis ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Infection Cycle ◽  
Necrosis Virus ◽  
The Tca Cycle ◽  
Chinese Perch

Glucose is a main carbon and energy source for virus proliferation and is usually involved in the glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA cycle) pathways. In this study, we investigated the roles of glucose-related metabolic pathways during the replication of infectious spleen and kidney necrosis virus (ISKNV), which has caused serious economic losses in the cultured Chinese perch (Siniperca chuatsi) industry. We found that ISKNV infection enhanced the metabolic pathways of the PPP and the TCA cycle at the early stage of the ISKNV infection cycle and enhanced the glycolysis pathway at the late stage of the ISKNV infection cycle though the comprehensive analysis of transcriptomics, proteomics, and metabolomics. The advanced results proved that ISKNV replication induced upregulation of aerobic glycolysis at the late stage of ISKNV infection cycle and aerobic glycolysis were required for ISKNV multiplication. In addition, the PPP, providing nucleotide biosynthesis, was also required for ISKNV multiplication. However, the TCA cycle involving glucose was not important and necessary for ISKNV multiplication. The results reported here provide new insights into viral pathogenesis mechanism of metabolic shift, as well as antiviral treatment strategies.

scholarly journals The Pentose Phosphate Pathway constitutes a major metabolic hub in pathogenic Francisella

2021 ◽  
Author(s):  
Héloise Rytter ◽  
Anne Jamet ◽  
Jason Ziveri ◽  
Elodie Ramond ◽  
Mathieu Coureuil ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Metabolic Pathways ◽  
Pathogenic Bacteria ◽  
Metabolic Networks ◽  
Tricarboxylic Acid Cycle ◽  
Sulfur Metabolism ◽  
Time Lapse ◽  
Pentose Phosphate ◽  
Francisella Novicida

AbstractMetabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in Francisella intracellular life cycle was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation of tktA, rpiA or rpe genes, severely impaired intramacrophagic multiplication during the first 24 hours. Time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how the PPP is instrumental to Francisella pathogenesis and growth in its intracellular niche.

Sign in / Sign up

Export Citation Format

Share Document