ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Non-Neuronal Cells
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1616911
Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach
Provisionally accepted
Farida Tripodi1
Elisa Margherita Maffioli2
Silvia Sacchi3
Valentina Rabattoni3
Zoraide Motta3Claudia Bearzi4
Gabriella Tedeschi2Loredano Pollegioni3
Paola Coccetti1*- 1University of Milano-Bicocca, Department of Biotechnogy and Bioscieneces, Milano, Italy
- 2University of Milano, DIVAS, Department of Veterinary Medicine and Animal Science, Milano, Italy
- 3University of Insubria, Department of Biotechnology and Life Sciences, Varese, Italy
- 4Institute for Biomedical Technologies, National Research Council of Italy, Milano, Italy
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Astrocytes are the major source of L-serine (L-Ser) in the brain: the glycolytic intermediate D-3phosphoglycerate is converted into L-Ser through the phosphorylated pathway (PP) made up of three enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP), recently proposed to generate a metabolic assembly named serinosome. In the central nervous system, L-Ser is used for a number of functions, including the synthesis of glycine (Gly) and D-serine (D-Ser), the two key NMDAR co-agonists. Here, we used iPSC-derived human astrocytes as a cellular model to evaluate the impact on cell metabolism of the overexpression of each of the three enzymes of the PP as GFP-tagged proteins. The subcellular cytosolic localization of PP enzymes remains unchanged compared to endogenous proteins, while the complex formation is increased in all cases. Notably, among the factors involved, the overexpression of PHGDH appears to play a pivotal role in promoting the serinosome assembly and/or stabilization, highlighting the critical importance of this multi-domain protein. Particularly, the overexpression of each enzyme of the PP alters the cellular metabolism in a specific way. The L-Ser and Gly levels increase more in PHGDH overexpressing cells, in agreement with the known kinetics of the PP. A consistent increase in the TCA cycle, as well as in mitochondrial activities, serine-glycine-one carbon pathway, asparagine, arginine, purine and pyrimidines metabolism is also observed. Peculiar alterations are observed when each enzyme of the PP is overexpressed, strongly supporting the use of hiPSC-derived astrocytes overexpressing the PP pathway enzymes as a valuable cellular model for
Keywords: Phosphorylated pathway, human differentiated astrocytes, serinosome, Metabolism, Proteomics, Metabolomics
Received: 23 Apr 2025; Accepted: 27 Jun 2025.
Copyright: © 2025 Tripodi, Maffioli, Sacchi, Rabattoni, Motta, Bearzi, Tedeschi, Pollegioni and Coccetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Paola Coccetti, University of Milano-Bicocca, Department of Biotechnogy and Bioscieneces, Milano, Italy
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