scholarly journals The emerging role and targetability of the TCA cycle in cancer metabolism

2017 ◽  
Vol 9 (2) ◽  
pp. 216-237 ◽  
Author(s):  
Nicole M. Anderson ◽  
Patrick Mucka ◽  
Joseph G. Kern ◽  
Hui Feng
Keyword(s):  
Cancer Metabolism ◽  
Tca Cycle ◽  
The Tca Cycle

Metabolic Plasticity drives Development during Mammalian Embryogenesis

2020 ◽  
Author(s):  
Mark S. Sharpley ◽  
Fangtao Chi ◽  
Utpal Banerjee
Keyword(s):  
Cancer Metabolism ◽  
Tca Cycle ◽  
Nutrient Utilization ◽  
Maternal Control ◽  
Metabolic Plasticity ◽  
Preimplantation Mouse Embryos ◽  
The Tca Cycle ◽  
Preimplantation Mouse ◽  
And Function ◽  
Genome Activation

SummaryPreimplantation mouse embryos interact minimally with their environment, and development is largely driven by metabolic processes. During the earliest cleavage stages, metabolism is rigid, with maternal deposits enforcing a redox state that facilitates zygotic genome activation. As maternal control falls, metabolic shuttles are activated, increasing glycolysis and equilibrating the TCA cycle. The resulting flexibility of nutrient utilization and metabolic plasticity facilitates unidirectional developmental progression such that later stage embryos proceed to form blastocysts without any exogenously added nutrients. We explore the mechanisms that govern this choreographed sequence that balances the deposition, degradation, synthesis and function of metabolic enzymes with redox control, bioenergetics and biosynthesis. Cancer cells follow a distinct metabolic strategy from that of the preimplantation embryo. However, important shared features emerge under reductive stress. We conclude that metabolic plasticity drives normal development while stress conditions mimic hallmark events in Cancer Metabolism.

Therapeutic Targeting of Cancer Cell Metabolism in Lymphoid Neoplasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Chi Van Dang
Keyword(s):  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Biomass Accumulation ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Myc Oncogene ◽  
Xenograft Growth ◽  
The Tca Cycle ◽  
Cancer Cell Metabolism ◽  
The Warburg Effect

Abstract Abstract SCI-27 The MYC oncogene plays a pivotal role in human lymphoid neoplasias, specifically in lymphomas and acute leukemias, which are characterized by altered glucose metabolism, termed the Warburg effect. The Warburg effect or elevated conversion glucose to lactate by cancer cells has been a prevailing model of cancer metabolism. Since the 1980’s, genetic alterations of oncogenes and tumor suppressors have provided insights into tumorigenesis. However, whether metabolism contributes to tumorigenesis was highly debated. In 1997, we reported that the MYC oncogene product, the Myc transcription factor, regulates the lactate dehydrogenase A (LDHA)gene. Myc also activates many glycolytic enzymes, mitochondrial biogenesis, and glutamine metabolism by inducing glutaminase (GLS) and glutamine transporters, thereby providing not only ATP through the TCA cycle but also anapleurotic building blocks. Myc also induces biomass accumulation by stimulating ribosomal biogenesis. It stimulates the cell cycle machinery and DNA replication. Deregulated MYC in cancer results in enforced biomass accumulation, such that cell death occurs when bioenergetic demands exceed nutrient availability. In this regard, we have exploited this conceptual framework and targeted LDHA and GLS with small molecular inhibitors as proof-of- concept that altered cancer metabolism could be targeted for cancer therapy. Specifically, we documented that a drug-like inhibitor of LDHA could decreased tumor xenograft growth, providing evidence that metabolic therapy is feasible. We further found in a human Burkitt lymphoma model that Myc induces a genetic program that drives glutamine metabolism both under aerobic and hypoxic conditions. Inhibition of glutaminase, which converts glutamine to glutamate for its catabolism by the TCA cycle, by a drug-like molecule also diminished lymphoma xenograft growth in vivo. These studies indicate that targeting cancer cell metabolism could constitute a novel strategy to treat lymphoid neoplasias. Disclosures: Dang: Agios Pharmaceuticals, Inc.: Consultancy, Honoraria.

Liquid-liquid extraction of succinate using a dicopper cryptate

2020 ◽  
Author(s):  
Riccardo Mobili ◽  
Sonia La Cognata ◽  
Francesca Merlo ◽  
Andrea Speltini ◽  
Massimo Boiocchi ◽  
...  
Keyword(s):  
Aqueous Phase ◽  
Visible Spectrum ◽  
Tca Cycle ◽  
Residual Concentration ◽  
Waste Products ◽  
Liquid Liquid Extraction ◽  
The Tca Cycle ◽  
Quantitative Extraction ◽  
Uv Visible

<div> <p>The extraction of the succinate dianion from a neutral aqueous solution into dichloromethane is obtained using a lipophilic cage-like dicopper(II) complex as the extractant. The quantitative extraction exploits the high affinity of the succinate anion for the cavity of the azacryptate. The anion is effectively transferred from the aqueous phase, buffered at pH 7 with HEPES, into dichloromethane. A 1:1 extractant:anion adduct is obtained. Extraction can be easily monitored by following changes in the UV-visible spectrum of the dicopper complex in dichloromethane, and by measuring the residual concentration of succinate in the aqueous phase by HPLC−UV. Considering i) the relevance of polycarboxylates in biochemistry, as e.g. normal intermediates of the TCA cycle, ii) the relevance of dicarboxylates in the environmental field, as e.g. waste products of industrial processes, and iii) the recently discovered role of succinate and other dicarboxylates in pathophysiological processes including cancer, our results open new perspectives for research in all contexts where selective recognition, trapping and extraction of polycarboxylates is required. </p> </div>

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

scholarly journals Metabolomics of aging in primary fibroblasts from small and large breed dogs

GeroScience ◽  
2021 ◽  
Author(s):  
Paul S. Brookes ◽  
Ana Gabriela Jimenez
Keyword(s):  
Aging Process ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Targeted Metabolomics ◽  
The Tca Cycle ◽  
Age Dependent ◽  
Primary Fibroblasts ◽  
Aging Rates ◽  
Underlying Mechanisms ◽  
Coenzyme A Biosynthesis

AbstractAmong several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

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 Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2634
Author(s):  
Beatriz Soldevilla ◽  
Angeles López-López ◽  
Alberto Lens-Pardo ◽  
Carlos Carretero-Puche ◽  
Angeles Lopez-Gonzalvez ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tca Cycle ◽  
Metabolomic Profile ◽  
Diagnostic Potential ◽  
The Tca Cycle ◽  
Novel Biomarkers ◽  
Potential Methods ◽  
Clinical Potential ◽  
First Time

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

scholarly journals Effects of corn steep liquor on β-poly(l-malic acid) production in Aureobasidium melanogenum

AMB Express ◽  
2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Genan Wang ◽  
Bingyi Shi ◽  
Pan Zhang ◽  
Tingbin Zhao ◽  
Haisong Yin ◽  
...  
Keyword(s):  
Malic Acid ◽  
Low Cost ◽  
Corn Steep Liquor ◽  
Enrichment Analysis ◽  
Tca Cycle ◽  
Water Soluble ◽  
Growth And Yield ◽  
The Tca Cycle ◽  
Steep Liquor ◽  
Aureobasidium Melanogenum

Abstractβ-poly(l-malic acid) (PMLA) is a water-soluble biopolymer used in medicine, food, and other industries. However, the low level of PMLA biosynthesis in microorganisms limits its further application in the biotechnological industry. In this study, corn steep liquor (CSL), which processes high nutritional value and low-cost characteristics, was selected as a growth factor to increase the PMLA production in strain, Aureobasidium melanogenum, and its metabolomics change under the CSL addition was investigated. The results indicated that, with 3 g/L CSL, PMLA production, cell growth, and yield (Yp/x) were increased by 32.76%, 41.82%, and 47.43%, respectively. The intracellular metabolites of A. melanogenum, such as amino acids, organic acids, and key intermediates in the TCA cycle, increased after the addition of CSL, and the enrichment analysis showed that tyrosine may play a major role in the PMLA biosynthesis. The results presented in this study demonstrated that the addition of CSL would be an efficient approach to improve PMLA production.

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