scholarly journals Ncl1-mediated metabolic rewiring critical during metabolic stress

2019 ◽  
Vol 2 (4) ◽  
pp. e201900360 ◽  
Author(s):  
Ajay Bhat ◽  
Rahul Chakraborty ◽  
Khushboo Adlakha ◽  
Ganesh Agam ◽  
Kausik Chakraborty ◽  
...  
Keyword(s):  
Amino Acid ◽  
Translational Control ◽  
Acid Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Metabolic Stress ◽  
Protein Translation ◽  
Leucine Supplementation ◽  
Nutritional Limitation ◽  
Amino Acid Levels

Nutritional limitation has been vastly studied; however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in the presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine up-regulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation—events that are rescued by leucine supplementation. Through a comprehensive genetic screen, we show that leucine-mediated effect depends on a transfer RNA methyltransferase (NCL1), absence of which decouples transcription and translation in the cell, inhibits the conversion of leucine to ketoisocaproate, and leads to tricarboxylic acid cycle block. We therefore propose a role of NCL1 in regulating metabolic homeostasis through translational control.

scholarly journals Ncl1 mediated metabolic rewiring critical during metabolic stress

2019 ◽  
Author(s):  
Ajay Bhat ◽  
Rahul Chakraborty ◽  
Khushboo Adlakha ◽  
Ganesh Agam ◽  
Kausik Chakraborty ◽  
...  
Keyword(s):  
Amino Acid ◽  
Translational Control ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
Protein Translation ◽  
Leucine Supplementation ◽  
Nutritional Limitation ◽  
Trna Methyltransferase ◽  
Amino Acid Levels

AbstractNutritional limitation has been vastly studied, however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine upregulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation, events that are rescued by leucine supplementation. Through a comprehensive genetic screen we show that leucine mediated effect depends on a tRNA methyltransferase (Ncl1), absence of which decouples cell’s transcription and translation, inhibits the conversation of leucine to ketoisocaproate and leads to TCA cycle block. We therefore, propose a role of Ncl1 in regulating metabolic homeostasis through translational control.

scholarly journals Amino Acids Promote Mitochondrial-Derived Compartment Formation in Mammalian Cells

2020 ◽  
Author(s):  
Max-Hinderk Schuler ◽  
Alyssa M. English ◽  
Leah VanderMeer ◽  
Janet M. Shaw ◽  
Adam L. Hughes
Keyword(s):  
Amino Acid ◽  
Mammalian Cells ◽  
Metabolic Stress ◽  
Amino Acid Content ◽  
Protein Translation ◽  
Translation Inhibition ◽  
Evolutionarily Conserved ◽  
Amino Acid Levels ◽  
Mitochondrial Remodeling ◽  
Cellular Stressors

SUMMARYWe recently identified a new cellular structure in yeast, called the Mitochondrial-Derived Compartment (MDC), that forms on mitochondria in response to amino acid excess. While emerging evidence supports an important function for MDCs in protecting cells from metabolic stress, whether this system exists beyond yeast remains unclear. Here, we show that MDCs are conserved in mammals, and like their yeast counterparts, are responsive to the intracellular amino acid content. Specifically, we find that inhibition of protein translation stimulates formation of dynamic, micron-sized compartments that associate with the mitochondrial network. These compartments are enriched for the carrier receptor Tomm70A and other select mitochondrial outer and inner membrane cargo, associate with the ER membrane, and require the conserved GTPase Miro1 for formation. Mammalian MDCs are responsive to changes in amino acid levels during translation inhibition, and are not activated by other common cellular stressors. Thus, MDCs represent an evolutionarily conserved nutrient-responsive mitochondrial remodeling system.

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 Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue

GeroScience ◽  
2021 ◽  
Author(s):  
Haihui Zhuang ◽  
Sira Karvinen ◽  
Timo Törmäkangas ◽  
Xiaobo Zhang ◽  
Xiaowei Ojanen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Amino Acid ◽  
White Adipose Tissue ◽  
Aerobic Capacity ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Disease Risk ◽  
Whole Body ◽  
Whole Body Metabolism

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

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.

Purification and properties of glutamate-phenylpyruvate aminotransferase from the ruminal protozoan Entodinium caudatum

2004 ◽  
Vol 55 (9) ◽  
pp. 991
Author(s):  
Md. Ruhul Amin ◽  
Ryoji Onodera ◽  
R. Islam Khan ◽  
R. John Wallace ◽  
C. Jamie Newbold
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Maximum Activity ◽  
Purification And Properties ◽  
Sds Page ◽  
Wide Range ◽  
S 100 ◽  
A Cell

Entodinium species are important in catabolic protein metabolism by the mixed ruminal microbial population. This study was conducted to purify, and investigate properties of one of the enzymes involved in amino acid metabolism by Entodinium caudatum, glutamate-phenylpyruvate aminotransferase (GPA; EC 2.6.1.64). GPA was purified 74-fold from a cell-free extract by ammonium sulfate precipitation and column chromatography with phenyl-superose, DEAE-Toyopearl 650M, Sephacryl S-100 HR, and Sephadex G-100. The molecular mass of GPA was estimated by SDS–PAGE to be 65.0 kDa. The optimum pH was 6.0 and it was found to be reactive over a wide range of pH from 5.0 to 10.5. Maximum activity of GPA occurred at 45°C and the activity declined at temperatures over 55°C. GPA was stable below 60°C. Aminooxyacetate and phenylhydrazine were highly inhibitory, and SDS, EDTA, and some heavy metal ions also inhibited activity. The purification and characterisation of the enzyme will help to isolate the gene and ultimately to understand the role of GPA in both anabolic and catabolic amino acid metabolism by Entodinium caudatum.

HOMOCYSTINURIA, AN ERROR IN THE METABOLISM OF METHIONINE

PEDIATRICS ◽  
1964 ◽  
Vol 33 (3) ◽  
pp. 413-420 ◽  
Author(s):  
Theo Gerritsen ◽  
Harry A. Waisman
Keyword(s):  
Amino Acid ◽  
Acid Metabolism ◽  
Failure To Thrive ◽  
Methionine Metabolism ◽  
Ectopia Lentis ◽  
Metabolic Defect ◽  
Loading Tests ◽  
Amino Acid Levels ◽  
Mentally Retarded Children ◽  
Degrees Of Severity

A new inborn error of metabolism was found in two mentally retarded children. The excretion of homocystine was accompanied in one boy by ectopia lentis, failure to thrive, poor developmental milestones, thrombo embolic phenomena, methioninuria, decreased excretion of taurine, and elevated plasma methionine. The second patient had normal plasma methionine levels, and a nearly normal amino acid pattern in the urine other than homocystine. Loading tests using methionine, serine, and homocystine failed to alter plasma amino acid levels and did not provide any information on the nature of the metabolic defect in sulfur amino acid metabolism. The two children had different abnormalities in methionine metabolism or they had the same metabolic defect but in different degrees of severity.

scholarly journals The role of amino acid metabolism during abiotic stress release

2019 ◽  
Vol 42 (5) ◽  
pp. 1630-1644 ◽  
Author(s):  
Willian Batista‐Silva ◽  
Björn Heinemann ◽  
Nils Rugen ◽  
Adriano Nunes‐Nesi ◽  
Wagner L. Araújo ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Stress Release

scholarly journals Glucagon Receptor Signaling and Glucagon Resistance

2019 ◽  
Vol 20 (13) ◽  
pp. 3314 ◽  
Author(s):  
Janah ◽  
Kjeldsen ◽  
Galsgaard ◽  
Winther-Sørensen ◽  
Stojanovska ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Diseases ◽  
Physiological Role ◽  
Glucagon Receptor ◽  
Metabolomic Profiling ◽  
Hepatic Fat

Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.

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