bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2023–07–16
two papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium
  1. Isotopic Tracing of Nucleotide Sugar Metabolism in Human Pluripotent Stem Cells.
  2. Metabolic flux in the driver's seat during cardiac health and disease.
  1. Cells. 2023 Jul 03. pii: 1765. [Epub ahead of print]12(13):
    Isotopic Tracing of Nucleotide Sugar Metabolism in Human Pluripotent Stem Cells.
    Federica Conte, Marek J Noga, Monique van Scherpenzeel, Raisa Veizaj, Rik Scharn, Juda-El Sam, Chiara Palumbo, Frans C A van den Brandt, Christian Freund, Eduardo Soares, Huiqing Zhou, Dirk J Lefeber.
      Metabolism not only produces energy necessary for the cell but is also a key regulator of several cellular functions, including pluripotency and self-renewal. Nucleotide sugars (NSs) are activated sugars that link glucose metabolism with cellular functions via protein N-glycosylation and O-GlcNAcylation. Thus, understanding how different metabolic pathways converge in the synthesis of NSs is critical to explore new opportunities for metabolic interference and modulation of stem cell functions. Tracer-based metabolomics is suited for this challenge, however chemically-defined, customizable media for stem cell culture in which nutrients can be replaced with isotopically labeled analogs are scarcely available. Here, we established a customizable flux-conditioned E8 (FC-E8) medium that enables stem cell culture with stable isotopes for metabolic tracing, and a dedicated liquid chromatography mass-spectrometry (LC-MS/MS) method targeting metabolic pathways converging in NS biosynthesis. By 13C6-glucose feeding, we successfully traced the time-course of carbon incorporation into NSs directly via glucose, and indirectly via other pathways, such as glycolysis and pentose phosphate pathways, in induced pluripotent stem cells (hiPSCs) and embryonic stem cells. Then, we applied these tools to investigate the NS biosynthesis in hiPSC lines from a patient affected by deficiency of phosphoglucomutase 1 (PGM1), an enzyme regulating the synthesis of the two most abundant NSs, UDP-glucose and UDP-galactose.
    Keywords:  O-GlcNAcylation; PGM1 deficiency; glycosylation; induced pluripotent stem cells; mass spectrometry-based isotopic tracing; nucleotide sugar metabolism
    DOI:  https://doi.org/10.3390/cells12131765
  2. J Mol Cell Cardiol. 2023 Jul 12. pii: S0022-2828(23)00110-4. [Epub ahead of print]182 15-24
    Metabolic flux in the driver's seat during cardiac health and disease.
    E Douglas Lewandowski.
      Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges. Any inability of metabolic flux to keep pace with the demands of the cardiomyocyte results in progressive dysfunction that contributes to cardiac disease. Thus, the priority in maintaining and regulating flux through metabolic pathways in the cardiomyocyte cannot be understated. Great potential exists in current efforts to elucidate metabolic mechanisms as therapeutic targets for the diseased heart. As a consequence, detecting metabolic flux in the functioning myocardium of the heart, under normal and diseased conditions, is essential in elucidating the metabolic basis of contractile dysfunction. As a companion to the 2022 ISHR Research Achievement Award lecture, this review examines the use and applications of stable isotope kinetics to quantify metabolic flux through intermediary pathways and the exchange and transport of intermediates across the mitochondrial membrane and sarcolemma of intact functioning hearts in determining how these intracellular events are coordinated to support cardiac function and health. Finally, this work reviews recently demonstrated metabolic defects in diseased hearts and the potential for metabolic alleviation of heart disease.
    Keywords:  Fatty acids; Glucose; Heart failure; Ischemia/Reperfusion; Isotopes; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.yjmcc.2023.07.004
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