scholarly journals Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Dylan Gerard Ryan ◽  
Ming Yang ◽  
Hiran A Prag ◽  
Giovanny Rodriguez Blanco ◽  
Efterpi Nikitopoulou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Response ◽  
Tricarboxylic Acid Cycle ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Comparative Approach ◽  
Redox Biology ◽  
The Tca Cycle

The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

scholarly journals Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism

2021 ◽  
Author(s):  
Dylan Gerard Ryan ◽  
Ming Yang ◽  
Hiran A Prag ◽  
Giovanny Rodriguez Blanco ◽  
Efterpi Nikitopoulou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Response ◽  
Tricarboxylic Acid Cycle ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Comparative Approach ◽  
Redox Biology ◽  
The Tca Cycle

The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

scholarly journals Metabolomics Analysis in Different Development Stages on SP0 Generation of Rice Seeds After Spaceflight

2021 ◽  
Vol 12 ◽  
Author(s):  
Deyong Zeng ◽  
Jie Cui ◽  
YiShu Yin ◽  
Yi Xiong ◽  
Mengyao Liu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Stress Response ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Cycle Rate ◽  
Development Stages ◽  
The Tca Cycle ◽  
Rice Seeds

Spaceflight is a special abiotic stress condition. In recent years, it has been confirmed that the spaceflight caused the stress response of rice seeds, and the protein level, transcription level, and methylation level will change during the planting process after returning to the ground. However, the changes at the metabolome level are not very clear. In this study, two kinds of rice seeds, Dongnong423 (DN3) and Dongnong416 (DN6), were carried on the ShiJian-10 retractable satellite (SJ-10) for 12.5 days in orbit, returned to the ground and planted in the field until the three-leaf (TLP) and tillering stage (TS). The results of antioxidant enzyme activity, soluble sugar, and electron leakage rate revealed that the spaceflight caused the stress response of rice. The TLP and TS of DN3 identified 110 and 57 different metabolites, respectively, while the TLP and TS of DN6 identified 104 and 74 different metabolites, respectively. These metabolites included amino acids, sugars, fatty acids, organic acids and secondary metabolites. We used qRT-PCR technology to explore the changes of enzyme genes in the tricarboxylic acid cycle (TCA) and amino acid metabolism pathway. Combined with the results of metabolomics, we determined that during the TLP, the TCA cycle rate of DN3 was inhibited and amino acid metabolism was activated, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. In TS, the TCA cycle rate of DN3 was inhibited, and amino acid metabolism was not significantly changed, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. These results suggested that the response mechanisms of the two different rice strains to spaceflight stress are different, and these differences may be reflected in energy consumption and compound biosynthesis of rice in different growth and development stages. This study provided new insights for further exploring the effects of spaceflight.

scholarly journals Effect of Huangqin Tang on Urine Metabolic Profile in Rats with Ulcerative Colitis Based on UPLC-Q-Exactive Orbitrap MS

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Dunfang Wang ◽  
Xuran Ma ◽  
Shanshan Guo ◽  
Yanli Wang ◽  
Tao Li ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Fatty Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Unsaturated Fatty Acids ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Q Exactive ◽  
Therapeutic Mechanisms

As a classic prescription, Huangqin Tang (HQT) has been widely applied to treat ulcerative colitis (UC), although its pharmacological mechanisms are not clear. In this study, urine metabolomics was first analysed to explore the therapeutic mechanisms of HQT in UC rats induced by TNBS. We identified 28 potential biomarkers affected by HQT that might cause changes in urine metabolism in UC rats, mapped the network of metabolic pathways, and revealed how HQT affects metabolism of UC rats. The results showed that UC affects amino acid metabolism and biosynthesis of unsaturated fatty acids and impairs the tricarboxylic acid cycle (TCA cycle). UC induced inflammatory and gastrointestinal reactions by inhibiting the transport of fatty acids and disrupting amino acid metabolism. HQT plays key roles via regulating the level of biomarkers in the metabolism of amino acids, lipids, and so on, normalizing metabolic disorders. In addition, histopathology and other bioinformatics analysis further confirm that HQT altered UC rat physiology and pathology, ultimately affecting metabolic function of UC rats.

scholarly journals Metabolomics reveals the defense mechanism of different rice under space flight stress

2021 ◽  
Author(s):  
Deyong Zeng ◽  
Jie Cui ◽  
Yishu Yin ◽  
Yi Xiong ◽  
Mengyao Liu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Stress Response ◽  
Space Flight ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Tca Cycle ◽  
Mutation Breeding ◽  
Space Environment ◽  
Cycle Rate ◽  
The Tca Cycle

Abstract BackgroundSpace flight is a special abiotic stress condition. Due to the development of space technology, its potential value has received widespread attention. Space mutation breeding is one of the important methods for human beings to solve food security. However, the molecular mechanism of space mutagenesis is still not very clear.ResultIn this study, two kinds of rice, Dongnong423 (DN3) and Dongnong416 (DN6), were carried on the SJ-10 retractable satellite for 12.5 days in orbit, returned to the ground and planted in the field until the three-leaf (TLP) and tillering stage (TS). The results of antioxidant enzyme activity, soluble sugar, and electron leakage rate revealed that the space environment caused the stress response of rice. The TLP and TS of DN3 identified 113 and 58 different metabolites, respectively. The TLP and TS of DN6 identified 107 and 77 different metabolites, respectively. These metabolites include amino acids, sugars, fatty acids, organic acids and secondary metabolites. We used qRT-PCR technology to explore the changes of enzyme genes in the TCA cycle and amino acid metabolism pathway. Combined with the results of metabolomics, we determined that during the TLP, the TCA cycle rate of DN3 was inhibited and amino acid metabolism was activated, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. In TS, the TCA cycle rate of DN3 was inhibited, and amino acid metabolism was not significantly changed, while the TCA cycle rate of DN6 was activated and amino acid metabolism was inhibited. These results suggest that the space environment has different stress response mechanisms to the two rice varieties, and these differences may be reflected in energy consumption and compound biosynthesis.ConclusionsThis research uses metabolomics for the first time to explore the effects of space flight team rice. This research provides new insights for further exploring the effects of space biology and space mutation breeding.

scholarly journals Involvement of enzymes of amino acid metabolism and tricarboxylic acid cycle in bovine oocyte maturation in vitro

Reproduction ◽  
2003 ◽  
pp. 753-763 ◽  
Author(s):  
P Cetica ◽  
L Pintos ◽  
G Dalvit ◽  
M Beconi
Keyword(s):  
Amino Acid ◽  
Isocitrate Dehydrogenase ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Cumulus Cells ◽  
Tricarboxylic Acid ◽  
Maturation In Vitro

Few studies demonstrate at a biochemical level the metabolic profile of both cumulus cells and the oocyte during maturation. The aim of the present study was to investigate the differential participation of enzymatic activity in cumulus cells and in the oocyte during in vitro maturation (IVM) by studying the activity of enzymes involved in the control of amino acid metabolism, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and the tricarboxylic acid (TCA) cycle, isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH). No NAD-dependent isocitrate dehydrogenase (NAD-IDH) activity was recorded in cumulus-oocyte complexes (COCs). ALT, AST, NADP-dependent isocitrate dehydrogenase (NADP-IDH) and MDH enzymatic units remained constant in cumulus cells and oocytes during IVM. Specific activities increased in oocytes and decreased in cumulus cells as a result of IVM (P<0.05). Similar activity of both transaminases was detected in cumulus cells, unlike in the oocyte, in which activity of AST was 4.4 times greater than that of ALT (P<0.05). High NADP-IDH and MDH activity was detected in the oocyte. Addition of alanine, aspartate, isocitrate + NADP, oxaloacetate or malate + NAD to maturation media increased the percentage of denuded oocytes reaching maturation (P<0.05), in contrast to COCs in which differences were not observed by addition of these substrates and co-enzymes. The activity of studied enzymes and the use of oxidative substrates denotes a major participation of transaminations and the TCA cycle in the process of gamete maturation. The oocyte thus seems versatile in the use of several oxidative substrates depending on the redox state.

scholarly journals Blood Metabolite Signature of Metabolic Syndrome Implicates Alterations in Amino Acid Metabolism: Findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS)

2020 ◽  
Vol 21 (4) ◽  
pp. 1249 ◽  
Author(s):  
Jackson A. Roberts ◽  
Vijay R. Varma ◽  
Chiung-Wei Huang ◽  
Yang An ◽  
Anup Oommen ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Cohort Study ◽  
Longitudinal Study ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
P Value ◽  
Biochemical Pathways ◽  
Baltimore Longitudinal Study

Rapid lifestyle and dietary changes have contributed to a rise in the global prevalence of metabolic syndrome (MetS), which presents a potential healthcare crisis, owing to its association with an increased burden of multiple cardiovascular and neurological diseases. Prior work has identified the role that genetic, lifestyle, and environmental factors can play in the prevalence of MetS. Metabolomics is an important tool to study alterations in biochemical pathways intrinsic to the pathophysiology of MetS. We undertook a metabolomic study of MetS in serum samples from two ethnically distinct, well-characterized cohorts—the Baltimore Longitudinal Study of Aging (BLSA) from the U.S. and the Tsuruoka Metabolomics Cohort Study (TMCS) from Japan. We used multivariate logistic regression to identify metabolites that were associated with MetS in both cohorts. Among the top 25 most significant (lowest p-value) metabolite associations with MetS in each cohort, we identified 18 metabolites that were shared between TMCS and BLSA, the majority of which were classified as amino acids. These associations implicate multiple biochemical pathways in MetS, including branched-chain amino acid metabolism, glutathione production, aromatic amino acid metabolism, gluconeogenesis, and the tricarboxylic acid cycle. Our results suggest that fundamental alterations in amino acid metabolism may be central features of MetS.

scholarly journals Metabolic Activity Related to the Potassium Pump in the Midgut of Bombyx Mori Larvae

1985 ◽  
Vol 116 (1) ◽  
pp. 69-78
Author(s):  
P. PARENTI ◽  
B. GIORDANA ◽  
V. F. SACCHI ◽  
G. M. HANOZET ◽  
A. GUERRITORE
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamic Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Electrical Potential ◽  
Tricarboxylic Acid ◽  
Electrical Potential Difference ◽  
Acid Cycle

The transepithelial electrical potential difference across the isolated midgut of Bombyx mori larvae is dependent on the presence of potassium and is unaffected by the addition of hexoses to perfusion media, whereas it is enhanced by alanine, aspartic acid, glutamic acid and the corresponding 2- oxoacids, glutamine and malate. The midgut enzyme profile indicates that the substrates for the tricarboxylic acid cycle are supplied mainly by amino acid metabolism via transaminases. Accordingly, aminoxyacetate drastically reduces the intestinal transepithelial electrical potential difference stimulated by amino acids. Measurement of the free amino acid concentration in the lumen content, intestinal cells and haemolymph shows that glutamic acid, asparagine and glutamine are accumulated in the cell, whilst the haemolymph is enriched with basic amino acids and with glycine, alanine, serine and tyrosine, the major components of the silk fibroin. Therefore, amino acid metabolism directly related to the tricarboxylic acid cycle seems to be the primary source of energy for the potassium pump activity in B. mori midgut.

scholarly journals TCA Cycle Defects and Cancer: When Metabolism Tunes Redox State

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Simone Cardaci ◽  
Maria Rosa Ciriolo
Keyword(s):  
Redox State ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Cellular Redox ◽  
Redox Biology ◽  
Recessive Mutations ◽  
Tca Cycle Enzymes ◽  
The Tca Cycle ◽  
Inborn Defects

Inborn defects of the tricarboxylic acid (TCA) cycle enzymes have been known for more than twenty years. Until recently, only recessive mutations were described which, although resulted in severe multisystem syndromes, did not predispose to cancer onset. In the last ten years, a causal role in carcinogenesis has been documented for inherited and acquired alterations in three TCA cycle enzymes, succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH), pointing towards metabolic alterations as the underlying hallmark of cancer. This paper summarizes the neoplastic alterations of the TCA cycle enzymes focusing on the generation of pseudohypoxic phenotype and the alteration of epigenetic homeostasis as the main tumor-promoting effects of the TCA cycle affecting defects. Moreover, we debate on the ability of these mutations to affect cellular redox state and to promote carcinogenesis by impacting on redox biology.

scholarly journals CsrA Regulates Swarming Motility and Carbohydrate and Amino Acid Metabolism in Vibrio alginolyticus

2021 ◽  
Vol 9 (11) ◽  
pp. 2383
Author(s):  
Bing Liu ◽  
Qian Gao ◽  
Xin Zhang ◽  
Huizhen Chen ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Metabolic Flux ◽  
Acid Metabolism ◽  
Rna Binding ◽  
Environmental Changes ◽  
Nitrogen Sources ◽  
Tca Cycle ◽  
Vibrio Alginolyticus ◽  
Carbon And Nitrogen

Vibrio alginolyticus, like other vibrio species, is a widely distributed marine bacterium that is able to outcompete other species in variable niches where diverse organic matters are supplied. However, it remains unclear how these cells sense and adjust metabolic flux in response to the changing environment. CsrA is a conserved RNA-binding protein that modulates critical cellular processes such as growth ability, central metabolism, virulence, and the stress response in gamma-proteobacteria. Here, we first characterize the csrA homolog in V. alginolyticus. The results show that CsrA activates swarming but not swimming motility, possibly by enhancing the expression of lateral flagellar associated genes. It is also revealed that CsrA modulates the carbon and nitrogen metabolism of V. alginolyticus, as evidenced by a change in the growth kinetics of various carbon and nitrogen sources when CsrA is altered. Quantitative RT-PCR shows that the transcripts of the genes encoding key enzymes involved in the TCA cycle and amino acid metabolism change significantly, which is probably due to the variation in mRNA stability given by CsrA binding. This may suggest that CsrA plays an important role in sensing and responding to environmental changes.

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