bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–08–10
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach.
  2. Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
  1. Front Cell Neurosci. 2025 ;19 1616911
    Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach.
    Farida Tripodi, Elisa Maffioli, Silvia Sacchi, Valentina Rabattoni, Zoraide Motta, Claudia Bearzi, Gabriella Tedeschi, Loredano Pollegioni, Paola Coccetti.
       Introduction: Astrocytes are the major source of L-serine (L-Ser) in the brain: the glycolytic intermediate D-3-phosphoglycerate 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.
    Methods: 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.
    Results: 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.
    Discussion: Peculiar alterations are observed when each enzyme of the PP is overexpressed, strongly supporting the use of human iPSC-derived astrocytes overexpressing the PP pathway enzymes as a valuable cellular model for understanding how Ser glial metabolism occurs in a non-tumor system under both physiological and pathological conditions.
    Keywords:  human differentiated astrocytes; metabolism; metabolomics; phosphorylated pathway; proteomics; serinosome
    DOI:  https://doi.org/10.3389/fncel.2025.1616911
  2. bioRxiv. 2025 Aug 02. pii: 2025.08.01.668168. [Epub ahead of print]
    Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
    Sherry X Zhou, Benjamin Madden, Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis J Maher.
       BACKGROUND: The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells.
    METHODS: We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition.
    RESULTS: SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
    CONCLUSIONS: SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.
    DOI:  https://doi.org/10.1101/2025.08.01.668168
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