Abstract 241: Acetylomic and Metabolomic Alterations in Aged Hearts: Role for Silent Information Regulator (SIRT) 3

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jimmy Zhang ◽  
William R Urciuoli ◽  
Paul S Brookes ◽  
George A Porter ◽  
Sergiy M Nadtochiy
Keyword(s):  
Metabolic Pathways ◽  
Carbon Flux ◽  
Tca Cycle ◽  
Adult Group ◽  
Protein Levels ◽  
Mitochondrial Alterations ◽  
Age Related ◽  
Transport Chain ◽  
Tca Cycle Intermediates ◽  
Substantial Decline

Introduction: SIRT3 is a mitochondrial metabolic regulator, and a decline in function of SIRT3 may play a role in age-related mitochondrial alterations. The aim of this study was to investigate the possible down-regulation of SIRT3 activity in aged hearts, and to identify which metabolic pathways in aged hearts may be impaired due to SIRT3 dysfunction. Methods: Mitochondria were isolated from WT adult (7 mo.), SIRT3 -/- adult (7 mo.) and WT aged (18 mo.) hearts. Acetylated proteins in mitochondrial samples were identified using 2D gels and mass spectrometry. Metabolite concentrations and carbon fluxes through core metabolic pathways were determined using 13 C-labeled substrates and LC-MS/MS. Results: Mitochondrial acetylation patterns in the SIRT3 -/- adult group matched those found in the WT aged group; the level of acetylation was significantly higher than in WT adult. While the SIRT3 -/- samples exhibited zero SIRT3 protein content, no difference in SIRT3 protein level was seen between adult and aged WT hearts. Mechanistically, this suggests that alterations in mitochondrial acetylation during aging were not caused by lower SIRT3 protein levels, but rather by a lower SIRT3 enzymatic activity. Furthermore, aged myocardium exhibited 40% lower NAD + levels, which may underlie compromised SIRT3 activity. ATP levels were decreased in both SIRT3 -/- and WT aged hearts, suggesting possible defects in energy metabolism. Using metabolomics, we demonstrated that alterations of TCA cycle intermediates were similar in SIRT3 -/- and WT aged hearts (relative to WT adult), and included a substantial decline of carbon flux through α-ketoglutarate and malate. Furthermore, regulation of energy production might also be impaired at the level of the electron transport chain, where Complex I was significantly inhibited in both SIRT3 deficient and aged hearts. Conclusions: Collectively these data suggested that acetylomic and metabolomic fingerprints observed in SIRT3 -/- hearts were recapitulated in aged hearts.

Synthesis and Breakdown of the Universal Precursors to Biological Metabolism Promoted by Ferrous Iron

2018 ◽  
Author(s):  
Kamila B. Muchowska ◽  
Sreejith Jayasree VARMA ◽  
Joseph Moran
Keyword(s):  
Amino Acids ◽  
Chemical Reaction ◽  
Metabolic Pathways ◽  
Ferrous Iron ◽  
Reaction Network ◽  
Tca Cycle ◽  
Chemical Reaction Network ◽  
Metabolic Precursors ◽  
Tca Cycle Intermediates

How core biological metabolism initiated and why it uses the intermediates, reactions and pathways that it does remains unclear. Life builds its molecules from CO<sub>2 </sub>and breaks them down to CO<sub>2 </sub>again through the intermediacy of just five metabolites that act as the hubs of biochemistry. Here, we describe a purely chemical reaction network promoted by Fe<sup>2+ </sup>in which aqueous pyruvate and glyoxylate, two products of abiotic CO<sub>2 </sub>reduction, build up nine of the eleven TCA cycle intermediates, including all five universal metabolic precursors. The intermediates simultaneously break down to CO<sub>2 </sub>in a life-like regime resembling biological anabolism and catabolism. Introduction of hydroxylamine and Fe<sup>0 </sup>produces four biological amino acids. The network significantly overlaps the TCA/rTCA and glyoxylate cycles and may represent a prebiotic precursor to these core metabolic pathways.

Synthesis and Breakdown of the Universal Precursors to Biological Metabolism Promoted by Ferrous Iron

2018 ◽  
Author(s):  
Kamila B. Muchowska ◽  
Sreejith Jayasree VARMA ◽  
Joseph Moran
Keyword(s):  
Amino Acids ◽  
Chemical Reaction ◽  
Metabolic Pathways ◽  
Ferrous Iron ◽  
Reaction Network ◽  
Tca Cycle ◽  
Chemical Reaction Network ◽  
Metabolic Precursors ◽  
Tca Cycle Intermediates

How core biological metabolism initiated and why it uses the intermediates, reactions and pathways that it does remains unclear. Life builds its molecules from CO<sub>2 </sub>and breaks them down to CO<sub>2 </sub>again through the intermediacy of just five metabolites that act as the hubs of biochemistry. Here, we describe a purely chemical reaction network promoted by Fe<sup>2+ </sup>in which aqueous pyruvate and glyoxylate, two products of abiotic CO<sub>2 </sub>reduction, build up nine of the eleven TCA cycle intermediates, including all five universal metabolic precursors. The intermediates simultaneously break down to CO<sub>2 </sub>in a life-like regime resembling biological anabolism and catabolism. Introduction of hydroxylamine and Fe<sup>0 </sup>produces four biological amino acids. The network significantly overlaps the TCA/rTCA and glyoxylate cycles and may represent a prebiotic precursor to these core metabolic pathways.

Breath [13CO2] recovery from an oral glucose load during exercise: comparison between [U-13C] and [1,2-13C]glucose

2003 ◽  
Vol 95 (2) ◽  
pp. 477-482 ◽  
Author(s):  
J. Ruzzin ◽  
F. Péronnet ◽  
J. Tremblay ◽  
D. Massicotte ◽  
C. Lavoie
Keyword(s):  
Metabolic Pathways ◽  
Glucose Oxidation ◽  
Tca Cycle ◽  
Significant Loss ◽  
Oral Glucose ◽  
Exogenous Glucose ◽  
The Tca Cycle ◽  
Exercise Period ◽  
Tca Cycle Intermediates ◽  
Male Subjects

The purpose of the present experiment was to compare 13CO2 recovery at the mouth, and the corresponding exogenous glucose oxidation computed, during a 100-min exercise at 63 ± 3% maximal O2 uptake with ingestion of glucose (1.75 g/kg) in six active male subjects, by use of [U-13C] and [1,2-13C]glucose. We hypothesized that 13C recovery and exogenous glucose oxidation could be lower with [1,2-13C] than [U-13C]glucose because both tracers provide [13C]acetate, with possible loss of 13C in the tricarboxylic acid (TCA) cycle, but decarboxylation of pyruvate from [U-13C]glucose also provides 13CO2, which is entirely recovered at the mouth during exercise. The recovery of 13C (25.8 ± 2.3 and 27.4 ± 1.2% over the exercise period) and the amounts of exogenous glucose oxidized computed were not significantly different with [1,2-13C] and [U-13C]glucose (28.9 ± 2.6 and 30.7 ± 1.3 g, between minutes 40 and 100), suggesting that no significant loss of 13C occurred in the TCA cycle. This stems from the fact that, during exercise, the rate of exogenous glucose oxidation is probably much larger than the flux of the metabolic pathways fueled from TCA cycle intermediates. It is thus unlikely that a significant portion of the 13C entering the TCA cycle could be diverted to these pathways. From a methodological standpoint, this result indicates that when a large amount of [13C]glucose is ingested and oxidized during exercise, 13CO2 production at the mouth accurately reflects the rate of glucose entry in the TCA cycle and that no correction factor is needed to compute the oxidative flux of exogenous glucose.

Aminoguanidine pretreatment prevents methotrexate-induced small intestinal injury in the rat by attenuating nitrosative stress and restoring the activities of vital mitochondrial enzymes

2017 ◽  
Vol 28 (3) ◽  
Author(s):  
Kasthuri Natarajan ◽  
Premila Abraham ◽  
Rekha Kota ◽  
Dhayakani Selvakumar
Keyword(s):  
Nitric Oxide ◽  
Body Weight ◽  
Nitrosative Stress ◽  
Tca Cycle ◽  
Mitochondrial Enzymes ◽  
Protein Levels ◽  
Transport Chain ◽  
Small Intestinal Injury ◽  
Inos Inhibitor ◽  
Small Intestines

AbstractBackground:One of the major toxic side effects of methotrexate (MTX) is enterocolitis, for which there is no efficient standard treatment. Nitric oxide overproduction has been reported to play an important role in MTX-induced mucositis. This study was designed to investigate whether pretreatment with aminoguanidine (AG) – a selective iNOS inhibitor – prevents MTX-induced mucositis in rats.Methods:Rats were pretreated with AG (30 and 50 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for 3 consecutive days. After the final dose of MTX, the rats were killed, and the small intestines were used for analysis.Results:The small intestines of MTX-treated rats showed moderate to severe injury. Pretreatment with AG had a dose-dependent protective effect on MTX-induced mucositis. AG pretreatment reduced iNOS protein levels, mucosal nitric oxide levels, and protein tyrosine nitration. AG pretreatment also restored the activities of electron transport chain (ETC) complexes, vital tricarboxylic acid (TCA cycle) enzymes, and mitochondrial antioxidant enzymes.Conclusions:These findings suggest that AG is beneficial in ameliorating MTX-induced enteritis in rats.

Age-Related Mitochondrial Alterations without Neuronal Loss in the Hippocampus of a Transgenic Model of Alzheimer's Disease

2013 ◽  
Vol 10 (4) ◽  
pp. 390-405 ◽  
Author(s):  
Mar Cuadrado-Tejedor ◽  
Jesus Felipe Cabodevilla ◽  
Marta Zamarbide ◽  
Teresa Gomez-Isla ◽  
Rafael Franco ◽  
...  
Keyword(s):  
Neuronal Loss ◽  
Transgenic Model ◽  
Mitochondrial Alterations ◽  
Age Related

scholarly journals Profiles of Secondary Metabolites (Phenolic Acids, Carotenoids, Anthocyanins, and Galantamine) and Primary Metabolites (Carbohydrates, Amino Acids, and Organic Acids) during Flower Development in Lycoris radiata

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 248
Author(s):  
Chang Ha Park ◽  
Hyeon Ji Yeo ◽  
Ye Jin Kim ◽  
Bao Van Nguyen ◽  
Ye Eun Park ◽  
...  
Keyword(s):  
Amino Acids ◽  
Secondary Metabolites ◽  
Organic Acids ◽  
Phenolic Acids ◽  
Flower Development ◽  
Developmental Stages ◽  
Tca Cycle ◽  
Primary And Secondary Metabolites ◽  
Hydrophilic Compounds ◽  
Tca Cycle Intermediates

This study aimed to elucidate the variations in primary and secondary metabolites during Lycorisradiata flower development using high performance liquid chromatography (HPLC) and gas chromatography time-of-flight mass spectrometry (GC-TOFMS). The result showed that seven carotenoids, seven phenolic acids, three anthocyanins, and galantamine were identified in the L. radiata flowers. Most secondary metabolite levels gradually decreased according to the flower developmental stages. A total of 51 metabolites, including amines, sugars, sugar intermediates, sugar alcohols, amino acids, organic acids, phenolic acids, and tricarboxylic acid (TCA) cycle intermediates, were identified and quantified using GC-TOFMS. Among the hydrophilic compounds, most amino acids increased during flower development; in contrast, TCA cycle intermediates and sugars decreased. In particular, glutamine, asparagine, glutamic acid, and aspartic acid, which represent the main inter- and intracellular nitrogen carriers, were positively correlated with the other amino acids and were negatively correlated with the TCA cycle intermediates. Furthermore, quantitation data of the 51 hydrophilic compounds were subjected to partial least-squares discriminant analyses (PLS-DA) to assess significant differences in the metabolites of L. radiata flowers from stages 1 to 4. Therefore, this study will serve as the foundation for a biochemical approach to understand both primary and secondary metabolism in L. radiata flower development.

scholarly journals The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 762
Author(s):  
Edward V. Prochownik ◽  
Huabo Wang
Keyword(s):  
Metabolic Pathways ◽  
Redox State ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Vascular Supply ◽  
Extrinsic Factors ◽  
The Tca Cycle ◽  
Initial Substrate ◽  
Numerous Cell ◽  
Bio Synthesis

Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

scholarly journals Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex II and Methylmalonyl-CoA Mutase

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 117
Author(s):  
Thekla Cordes ◽  
Christian M. Metallo
Keyword(s):  
Amino Acid ◽  
Metabolic Pathways ◽  
Mammalian Cells ◽  
Coenzyme A ◽  
Cultured Cells ◽  
Tca Cycle ◽  
Regulatory Function ◽  
Reversible Inhibitor ◽  
Complex Ii ◽  
Branched Chain

Itaconate is a small molecule metabolite that is endogenously produced by cis-aconitate decarboxylase-1 (ACOD1) in mammalian cells and influences numerous cellular processes. The metabolic consequences of itaconate in cells are diverse and contribute to its regulatory function. Here, we have applied isotope tracing and mass spectrometry approaches to explore how itaconate impacts various metabolic pathways in cultured cells. Itaconate is a competitive and reversible inhibitor of Complex II/succinate dehydrogenase (SDH) that alters tricarboxylic acid (TCA) cycle metabolism leading to succinate accumulation. Upon activation with coenzyme A (CoA), itaconyl-CoA inhibits adenosylcobalamin-mediated methylmalonyl-CoA (MUT) activity and, thus, indirectly impacts branched-chain amino acid (BCAA) metabolism and fatty acid diversity. Itaconate, therefore, alters the balance of CoA species in mitochondria through its impacts on TCA, amino acid, vitamin B12, and CoA metabolism. Our results highlight the diverse metabolic pathways regulated by itaconate and provide a roadmap to link these metabolites to potential downstream biological functions.

scholarly journals Cytochrome c Deficiency Differentially Affects the In Vivo Mitochondrial Electron Partitioning and Primary Metabolism Depending on the Photoperiod

Plants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 444
Author(s):  
Igor Florez-Sarasa ◽  
Elina Welchen ◽  
Sofia Racca ◽  
Daniel H. Gonzalez ◽  
José G. Vallarino ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Tca Cycle ◽  
Day Length ◽  
Primary Metabolism ◽  
Stress Signaling ◽  
Alternative Pathways ◽  
Tca Cycle Intermediates ◽  
Growth Adaptation ◽  
Plant Respiration

Plant respiration provides metabolic flexibility under changing environmental conditions by modulating the activity of the nonphosphorylating alternative pathways from the mitochondrial electron transport chain, which bypass the main energy-producing components of the cytochrome oxidase pathway (COP). While adjustments in leaf primary metabolism induced by changes in day length are well studied, possible differences in the in vivo contribution of the COP and the alternative oxidase pathway (AOP) between different photoperiods remain unknown. In our study, in vivo electron partitioning between AOP and COP and expression analysis of respiratory components, photosynthesis, and the levels of primary metabolites were studied in leaves of wild-type (WT) plants and cytochrome c (CYTc) mutants, with reduced levels of COP components, under short- and long-day photoperiods. Our results clearly show that differences in AOP and COP in vivo activities between WT and cytc mutants depend on the photoperiod likely due to energy and stress signaling constraints. Parallel responses observed between in vivo respiratory activities, TCA cycle intermediates, amino acids, and stress signaling metabolites indicate the coordination of different pathways of primary metabolism to support growth adaptation under different photoperiods.

scholarly journals Formaldehyde and De/Methylation in Age-Related Cognitive Impairment

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 913
Author(s):  
Ting Li ◽  
Yan Wei ◽  
Meihua Qu ◽  
Lixian Mou ◽  
Junye Miao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cell Proliferation ◽  
Cognitive Impairment ◽  
Metabolic Pathways ◽  
Memory Formation ◽  
Epigenetic Alterations ◽  
Diagnostic Biomarker ◽  
Reactive Substance ◽  
Age Related ◽  
Novel Therapeutic

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis and modification of bio-compounds, such as DNA, RNA, and amino acids. Endogenous FA plays a role in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA. Recently, epigenetic alterations associated with FA dysmetabolism have been considered as one of the important features in age-related cognitive impairment (ARCI), suggesting the potential of using FA as a diagnostic biomarker of ARCI. Notably, FA plays multifaceted roles, and, at certain concentrations, it promotes cell proliferation, enhances memory formation, and elongates life span, effects that could also be involved in the aetiology of ARCI. Further investigation of and the regulation of the epigenetics landscape may provide new insights about the aetiology of ARCI and provide novel therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document