bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2026–05–31
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Heavy water labeling reveals metabolic flexibility of amino acid and polyamine pathways in mammalian cells.
  2. HMGB1 regulates mitochondrial structure and reactive oxygen species balance during the transition from naïve to primed pluripotency.
  1. Commun Chem. 2026 May 29.
    Heavy water labeling reveals metabolic flexibility of amino acid and polyamine pathways in mammalian cells.
    Alan Gonzalez-Ibarra, Missael Arroyo-Negrete, Wioleta Banaszuk-Krupa, Katarzyna Socała, Nikola Gapińska, Piotr Wlaź, Julio Cesar Torres-Elguera, Tomasz Sawoszczuk, Marek Tchórzewski, Maria Hatzoglou, Dawid Krokowski.
      Amino acid and polyamine metabolism underpins many cellular processes, such as cell growth, stress adaptation, and signaling. However, the usage of specific metabolic pathways is highly context-dependent, and there are many compensatory mechanisms in place for the biosynthesis of amino acids. Here, we establish low-dose heavy water (D₂O) labeling as a tracer to monitor amino acid and polyamine metabolism in mammalian systems. Using targeted HPLC-MS of primary amines, we quantified deuterium incorporation in mouse embryonic fibroblasts, pancreatic β-cell-derived MIN6 cells, and mouse tissues, which we then benchmarked with orthogonal tracers (13C-glucose and 15NH₄⁺). We demonstrated D₂O labels nonessential amino acids and polyamines. We validated specificity, as inhibition of key metabolic steps altered deuterium incorporation into Ala/Ser/Gly and polyamines and revealed differential engagement of branched-chain amino acid metabolism. We found that glutamine starvation induces integrated stress response-linked remodeling, increasing deuterium incorporation into Glu and glycolytic amino acids while identifying changes in amino acids efflux. Finally, in vivo short-term D₂O exposure distinguishes tissue-specific biosynthetic capacities. Collectively, these data challenge the assumption of uniform alanine labeling by D2O and demonstrate that D₂O provides a sensitive readout of metabolic flexibility, transport crosstalk, and pathway regulation across cell types and tissues.
    DOI:  https://doi.org/10.1038/s42004-026-02081-9
  2. Front Cell Dev Biol. 2026 ;14 1807454
    HMGB1 regulates mitochondrial structure and reactive oxygen species balance during the transition from naïve to primed pluripotency.
    Tatiana Y Starkova, Sergey V Ponomartsev, Veniamin S Fishman, Nariman R Battulin, Nikolay D Aksenov, Evgeny I Bakhmet, Andrey A Kuzmin, Dmitry S Bogolyubov, Sergey A Sinenko, Alexey N Tomilin.
       Introduction: Embryo implantation is characterized by the process of naïve-to-primed pluripotency transition in epiblast cells, involving an anabolic boost, mitochondrial remodeling, and increased proliferation. Yet, the molecular mechanisms underlying these extensive changes remain poorly understood. High mobility group box 1 (HMGB1) is a non-histone, redox-sensitive chromatin protein involved in diverse cellular processes, however its role in pluripotency control has not been fully characterized.
    Methods: To determine the function of HMGB1 in mouse embryonic stem cells (ESCs), Hmgb1-knockout (KO) ESCs were generated using CRISPR/Cas9 system. KO ESCs were analyzed for cell proliferation, cell cycle progression, and apoptosis, as well as for levels of active mitochondria, mitochondrial membrane potential, and reactive oxygen species (ROS) using fluorescent-based reagents and flow cytometry. Pluripotency was assessed by analyzing the expression of pluripotency markers with immunocytochemistry, Western blotting, qRT-PCR, as well as by teratoma formation assay. Naïve-to-primed pluripotency transition was investigated by in vitro culture. Molecular analysis was performed with RNA sequencing, bioinformatics, qRT-PCR, and Western blotting. The ultrastructure of mitochondria was examined using transmission electron microscopy.
    Results: We first successfully generated HMGB1 KO in mouse ESCs and showed that HMGB1 function is dispensable for both cell viability and pluripotency maintenance, while it is required for the cell proliferation boost during the naïve-to-primed pluripotency transition. Molecular and transcriptomic analysis identified the involvement of HMGB1 in the regulation of energy metabolism processes by regulating mitochondrial structure and function, as well as ROS homeostasis. Loss of HMGB1 function in mouse ESCs results in altered mitochondrial structure and excessive ROS production. HMGB1-dependent elevated ROS levels negatively regulate cell proliferation during the transition from naïve to primed pluripotency in vitro.
    Conclusion: While HMGB1 deficiency does not impair self-renewal in the naïve state, it causes a marked reduction in proliferation as cells advance to primed pluripotency. Our findings thus identify HMGB1 as a key regulator of mitochondrial integrity and ROS homeostasis during the naïve-to-primed pluripotency transition.
    Keywords:  HMGB1; cell metabolism; differentiation; embryonic stem cells (ESCs); mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcell.2026.1807454
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