The Presence of Pyruvate Carboxylase in the Human Brain and its Role in the Survival of Cultured Human Astrocytes

Gondáš, Eduard; Trančiková, Alžbeta; Šofranko, Jakub; Majerová, Petra; Lucansky, Vincent; Dohál, Matúš; Murín, Radovan

doi:10.33549/physiolres.935026

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…The cell viability was calculated as the ratio of LDH activity in lysates to total LDH activity according to method previosly described [32]. The total LDH activity is the sum of LDH activities estimated in lysates and media.…”

Section: Cell Survivalmentioning

confidence: 99%

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Gondas,

Baranovicova,

Šofranko

et al. 2024

Preprint

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Astrocytes are considered to possess a noticeable role in brain metabolism and as a partners in neuron-glia cooperation contribute to synthesis, bioconversions and regulation of the flux of substrates for neuronal metabolism. With the aim to investigate to which extend are human astrocytes metabolizing amino acids and by which compounds are they enriching their surrounding we employed the metabolomics analysis of their culture media by 1H-NMR. In addition, we compered the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readely dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rate, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. The hyperglycemia suppressed the capacity of astrocytes to release branched-chain amino acids while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in metabolism of several amino acids, and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders.

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Section: Cell Survivalmentioning

confidence: 99%

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Gondas,

Baranovicova,

Šofranko

et al. 2024

Preprint

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Both Enantiomers of 2-Hydroxyglutarate Modulate the Metabolism of Cultured Human Neuroblastoma Cells

Gondáš,

Baranovičová,

Bystrický

et al. 2024

Neurochem Res

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Elevated levels of D-2-hydroxyglutarate (D-2HG) and L-2-hydroxyglutarate (L-2HG) in the brain are associated with various pathological conditions, potentially contributing to neurological symptoms and neurodegeneration. Previous studies on animal models have revealed their capability to interfere with several cellular processes, including mitochondrial metabolism. Both enantiomers competitively inhibit the enzymatic activity of 2-oxoglutarate-dependent dioxygenases. These enzymes also execute several signaling cascades and regulate the level of covalent modifications on nucleic acids or proteins, e.g., methylation, hydroxylation, or ubiquitination, with an effect on epigenetic regulation of gene expression, protein stability, and intracellular signaling. To investigate the potential impact of 2HG enantiomers on human neuronal cells, we utilized the SH-SY5Y human neuroblastoma cell line as a model. We employed proton nuclear magnetic resonance (1H-NMR) spectroscopy of culture media that provided high-resolution insights into the changes in the content of metabolites. Concurrently, we performed biochemical assays to complement the 1H-NMR findings and to estimate the activities of lactate and 3-hydroxybutyrate dehydrogenases. Our results reveal that both 2HG enantiomers can influence the cellular metabolism of human neuroblastoma cells on multiple levels. Specifically, both enantiomers of 2HG comparably stimulate anaerobic metabolism of glucose and inhibit the uptake of several essential amino acids from the culture media. In this respect, both 2HG enantiomers decreased the catabolism capability of cells to incorporate the leucine-derived carbon atoms into their metabolism and to generate the ketone bodies. These results provide evidence that both enantiomers of 2HG have the potential to influence the metabolic and molecular aspects of human cells. Furthermore, we may propose that increased levels of 2HG enantiomers in the brain parenchyma may alter brain metabolism features, potentially contributing to the etiology of neurological symptoms in patients.

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Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives

Chang,

Wu,

Chern

2024

Neurobiology of Disease

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The Presence of Pyruvate Carboxylase in the Human Brain and its Role in the Survival of Cultured Human Astrocytes

Cited by 3 publications

References 48 publications

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Both Enantiomers of 2-Hydroxyglutarate Modulate the Metabolism of Cultured Human Neuroblastoma Cells

Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives

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