bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–05–03
eleven papers selected by
Marc Segarra Mondejar, AINA
  1. Microfluidic compartmentalization reveals that ferrostatin-1 restores directional mitochondrial transport in Aβ-challenged neurons.
  2. Elevating levels of neuronal MCU in the hippocampus enhances mitochondrial calcium uptake and respiratory efficiency proportional to demand.
  3. Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG.
  4. Dicyanoisophorone-based fluorescent probe for detecting H2S and monitoring nitroprusside metabolism.
  5. TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
  6. Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
  7. Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.
  8. Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice.
  9. MechFind: a computational framework for de novo prediction of enzyme mechanisms.
  10. SLC33A1-mediated glutathione transport regulates ER redox balance and function.
  11. BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.
  1. Lab Chip. 2026 Apr 29.
    Microfluidic compartmentalization reveals that ferrostatin-1 restores directional mitochondrial transport in Aβ-challenged neurons.
    Nad'a Majerníková, Beatrice Corci, Yuequ Zhang, Tingting Chen, Maaike van Koeveringe, Denice Mensinga, Patty P M F A Mulder, Elisabeth Verpoorte, Andrea Mattarei, Diana Pendin, Cristina Mammucari, Christoffer Åberg, Wilfred den Dunnen, Amalia M Dolga.
      Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). While ferroptosis has been implicated in AD through iron accumulation and amyloid β (Aβ)-mediated toxicity, its role in mitochondrial regulation remains unclear. Here, we examined whether mitochondrial dysfunction in AD increases neuronal vulnerability to ferroptosis and whether ferroptosis inhibition can preserve mitochondrial network integrity. Primary cortical neurons were cultured in a multi-compartment microfluidic platform that facilitated high-resolution tracking of mitochondrial dynamics using time-lapse microscopy. Prolonged exposure to the ferroptosis inducer erastin disrupted neuronal networks, whereas acute exposure to erastin or Aβ significantly enhanced retrograde mitochondrial transport. These effects were blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Using a novel mitochondrial calcium probe (mt-Fura 2.3 AM), we further demonstrated that Aβ acutely increased mitochondrial calcium, which was ameliorated by Fer-1 and by inhibition of the mitochondrial calcium uniporter with MCUi4. In contrast, Aβ-induced hyperactivity recorded on a microelectrode array was prevented by MCUi4, but not Fer-1. Together, these results show that ferroptotic stress profoundly impacts mitochondrial movement and calcium regulation in neurons. Our multimodal microfluidic approach establishes a direct mechanistic link between ferroptosis, mitochondrial dysfunction, and neuronal vulnerability in AD, offering new insights into therapeutic targeting of ferroptosis in neurodegeneration.
    DOI:  https://doi.org/10.1039/d5lc00834d
  2. bioRxiv. 2026 Apr 16. pii: 2026.04.13.718264. [Epub ahead of print]
    Elevating levels of neuronal MCU in the hippocampus enhances mitochondrial calcium uptake and respiratory efficiency proportional to demand.
    Mikel L Cawley, Ryan N Montalvo, Mason L Wheeler, Lucy L Turner, Jessica Pfleger, Zhen Yan, Shannon Farris.
      Mitochondrial calcium signaling integrates energy needs with energy production, amplifying or suppressing mitochondrial respiration in response to activity demand. Neuronal activity is tightly ATPcoupled to increases in mitochondrial calcium uptake, which stimulate the tricarboxylic acid cycle (TCA) and activate calcium-dependent enzymes important for ATP production via oxidative phosphorylation. The mitochondrial calcium uniporter (MCU) is the predominant source of matrix calcium and is differentially expressed across neuronal cell types, suggesting cell-type-specific differences in the coupling of activity-driven calcium levels and mitochondrial respiration. Here, we investigated whether elevating MCU expression enhances mitochondrial calcium uptake and oxidative phosphorylation in the hippocampus. We report that hippocampal mitochondria overexpressing MCU take up calcium at a faster rate without increased sensitivity to calcium overload. By modeling in vivo supply and demand, we found that hippocampal mitochondria overexpressing MCU are more efficient than control mitochondria at responding to increased bioenergetic demand. These findings reveal a role for MCU in modulating mitochondrial calcium uptake and boosting mitochondrial respiration under increasing demand, which contributes to our understanding of how specific cell types may adapt to different bioenergetic demands.
    DOI:  https://doi.org/10.64898/2026.04.13.718264
  3. bioRxiv. 2026 Apr 14. pii: 2026.04.11.717872. [Epub ahead of print]
    Label free multimodal optical imaging of metabolic heterogeneity in aging by integrating SRS, MPF, FLIM, and SHG.
    Hongje Jang, Shuang Wu, Hyehyun Kim, Tong-You Wade Wei, Jian Kang, Anahita Ataran, Fangyuan Gao, Dorota Skowronska-Krawczyk, Kenneth B Margulies, Ali Javaheri, Wei Sun, John Y-J Shyy, Erkin Seker, Lingyan Shi.
      Cellular metabolism is governed by the coordinated organization of macromolecules, including lipids and proteins, together with redox-active cofactors such as NADH and FAD. However, resolving these biochemical features quantitatively and spatially at subcellular resolution remains challenging because no single imaging modality can capture molecular composition, redox state, and tissue architecture simultaneously without labeling. Here, we present MANIFEST ( M ulti-mod A l N onlinear I maging with F luorescence E xcitation and S tatistical T emporal-resolved spectroscopy), a label-free imaging platform that integrates stimulated Raman scattering (SRS), second harmonic generation (SHG), multiphoton fluorescence (MPF), and fluorescence lifetime imaging microscopy (FLIM). The MANIFEST combines chemical imaging of lipids with autofluorescence- and lifetime-based quantification of NADH and FAD metabolism, enabling spatially resolved analysis of metabolic heterogeneity at organelle and tissue-compartment levels. We apply this framework to four distinct aging or disease models: amyloid-beta-treated tri-cultured brain cells, high-fat diet mouse liver, human non-ischemic cardiomyopathy tissue, and aging mouse retina. Across these systems, MANIFEST reveals disease-associated lipid remodeling, redox imbalance, disrupted metabolic zonation, collagen reorganization, and layer-specific metabolic changes. By integrating complementary nonlinear optical modalities into a single label-free platform, MANIFEST provides a generalizable approach for high-resolution metabolic phenotyping in complex biological systems and offers new opportunities for studying disease mechanisms, aging biology, and metabolism-driven tissue pathology.
    DOI:  https://doi.org/10.64898/2026.04.11.717872
  4. Spectrochim Acta A Mol Biomol Spectrosc. 2026 Apr 25. pii: S1386-1425(26)00526-3. [Epub ahead of print]359 127955
    Dicyanoisophorone-based fluorescent probe for detecting H2S and monitoring nitroprusside metabolism.
    Linping Zhang, Xiaorui Cui, Zhihua Rao, You Xu, Jinghan Li, Wentai Zhang, Qin Tu, Jinyi Wang, Mao-Sen Yuan.
      Hydrogen sulfide (H2S) is an important multifunctional gasotransmitter that plays a pivotal role in regulating various physiological processes. Recent studies have shown that sodium nitroprusside (SNP), a commonly used drug for treating hypertension and angiectasis, will produce H2S during its metabolism. Thus, real-time monitoring of H2S can track the metabolic processes of SNP in vivo. In this study, we designed and synthesized a novel near-infrared (NIR) fluorescent probe, RM, based on the mechanism of excited-state intramolecular proton transfer (ESIPT). The probe features dicyanoisophorone as the fluorophore and a 2,4-dinitrobenzene structure as the recognition group for H2S detection. Upon reaction with H2S, RM exhibited a 11.6-fold fluorescence enhancement at 688 nm, with a detection limit of 0.83 μM, demonstrating good selectivity for H2S. Cellular imaging studies revealed that RM can visualize both endogenous and exogenous H2S, offering a promising approach for monitoring SNP metabolism in biological systems.
    Keywords:  Dicyanoisophorone; Fluorescent probe; Hydrogen sulfide; Metabolism of nitroprusside; Near infrared
    DOI:  https://doi.org/10.1016/j.saa.2026.127955
  5. Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]
    TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
    Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.
      Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.
    Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2026.04.004
  6. J Vis Exp. 2026 Apr 10.
    Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
    Aysika Das, Deepak K Kaushik.
      Microglia, the resident macrophage cells of the central nervous system, dynamically alter their metabolic programs in response to physiological and pathological cues. Understanding these metabolic shifts is crucial for elucidating their roles in inflammation. Here, we present a detailed protocol for assessing the glycolytic profile of primary microglia isolated from neonatal mouse brain cortices using a glycolysis stress test on an extracellular flux analyzer. This assay enables real-time measurement of ECAR, an indicator of glycolytic activity associated with low pH, such as lactate. Our approach involves treating cultured microglia under different conditions to examine how metabolic pathways are altered in response to various stimuli, including pro-inflammatory stimuli. Uniquely, our lab prepares fresh stock solutions of different reagents, including glucose, oligomycin, and 2-deoxyglucose (2DG), to target the different aspects of the pathway, with careful adjustment of pH for each reagent to ensure experimental accuracy and reproducibility. This method provides a robust platform for investigating glycolysis in primary microglia and offers insight into their functional states under inflammatory or disease-relevant conditions.
    DOI:  https://doi.org/10.3791/69638
  7. Mol Biol Rep. 2026 Apr 25. pii: 662. [Epub ahead of print]53(1):
    Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.
    Satyam Yadav, Gautam Kumar, Sumit Kumar, Khadga Raj Aran, Sourabh Kosey.
      Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic syndrome characterized by chronic hyperglycemia, progressive pancreatic β-cell malfunction, and peripheral insulin resistance. There is growing evidence suggesting that mitochondrial dysfunction and apoptosis play a critical role in the development and advancement of T2DM. Mitochondria are essential for cellular energy metabolism and redox homeostasis. It is the metabolic stress and apoptotic cell death in insulin-producing β-cells and insulin-sensitive tissues induced by mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) production, imbalanced mitochondrial dynamics, impaired mitophagy, mitochondrial fission-fusion imbalance, and defective biogenesis. This review summarizes the molecular pathways by which mitochondrial dysfunction triggers inflammatory responses, such as activation of NLRP3 inflammasomes, cytokine release, and mitochondria-mediated intrinsic apoptotic signaling. We describe the role of these pathways in insulin resistance and in the emergence of diabetic complications like neuropathy, nephropathy, myopathy, and hepatopathy. New treatment approaches aimed at mitochondrial integrity and apoptotic signaling are promising. These are AMPK/PGC-1α pathway activators, mitochondria-targeted antioxidants (MitoQ, SS-31), and mitophagy and ferroptosis modulators. But poor tissue specificity, poor bioavailability, and patient-to-patient variability are limitations in clinical translation. Lastly, the review highlights the possibilities of personalized medicine strategies that incorporate the use of mitochondrial profiling to maximize therapeutic outcomes. Collectively, available evidence suggests that therapeutic strategies restoring mitochondrial quality control in β-cells may offer greater disease-modifying potential than glucose-centric interventions alone.
    Keywords:  Apoptosis; Mitochondrial Dysfunction; Oxidative Stress; Type 2 Diabetes Mellitus; β-cell Failure
    DOI:  https://doi.org/10.1007/s11033-026-11851-6
  8. Nat Commun. 2026 Apr 30.
    Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice.
    Elizabeth Haythorne, Matthew Lloyd, Chris A Smith, Martijn van de Bunt, Maria Rohm, Alice Elphick, Malgorzata Cyranka, Fiona M Gribble, Frank Reimann, Frances M Ashcroft.
      Severe chronic hyperglycaemia ( > 15 mM) causes impaired glycolytic and mitochondrial metabolism in pancreatic β-cells, leading to dramatically reduced insulin secretion and content. However, patients with type 2 diabetes often experience many years of reduced β-cell function and impaired glucose tolerance preceding diabetes diagnosis. It is postulated that β-cell function may be compromised by relatively small changes in glycaemia, initiating a gradual decline that underlies diabetes progression. We therefore investigated the extent to which impaired glucose tolerance and chronic mild hyperglycaemia are detrimental to β-cells. We show that chronic elevation of blood glucose of just 2-3 mM is sufficient to impair β-cell function, causing marked changes in metabolic gene expression and reducing insulin content, metabolic enzyme activity, mitochondrial oxidative phosphorylation and insulin secretion. Smaller but significant changes are produced by impaired glucose tolerance. These findings demonstrate that altered β-cell metabolism is an early event in type 2 diabetes development and highlight a need for therapeutic intervention during prediabetes.
    DOI:  https://doi.org/10.1038/s41467-026-71528-3
  9. Nat Commun. 2026 04 29. pii: 3903. [Epub ahead of print]17(1):
    MechFind: a computational framework for de novo prediction of enzyme mechanisms.
    Austin D Hartley, Vikas Upadhyay, Veda Sheersh Boorla, Costas D Maranas.
      Fewer than one thousand cataloged mechanistic annotations can be found in the open literature and databases. Here, we introduce MechFind, a computational tool that generates element and charge-balanced putative enzyme mechanisms using only the reaction stoichiometry. Unlike methods requiring structural data, MechFind abstracts reaction steps as changes in chemical moieties. It identifies the most parsimonious mechanistic descriptions and re-ranks them based on similarity to known mechanisms. MechFind recovers the validated mechanism for 72% of a curated training dataset within the top ten predictions and is indirectly validated on enzymes absent from the training set. When applied on 14,931 reactions from the Rhea database, MechFind identifies plausible mechanisms for 57% of all entries, generating over 18,000 hypotheses. This resource significantly expands mechanistic annotation and provides detailed reaction steps to support de novo enzyme design and engineering. All codes, curated datasets, and results are available at https://github.com/maranasgroup/MechFind.git (Commit Hash: fcc0896).
    DOI:  https://doi.org/10.1038/s41467-026-71957-0
  10. Nat Cell Biol. 2026 May 01.
    SLC33A1-mediated glutathione transport regulates ER redox balance and function.
      
    DOI:  https://doi.org/10.1038/s41556-026-01929-5
  11. Cell Rep Med. 2026 Apr 29. pii: S2666-3791(26)00201-6. [Epub ahead of print] 102784
    BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.
    Misty Shuo Zhang, Kenneth Kin-Leung Kwan, Aki Pui-Wah Tse, Gengchao Wang, Larry Lai Wei, Kejie Sun, Noreen Nog-Qin Chui, Derek Lee, Macus Hao-Ran Bao, Xiaoxuan Pang, Zhenqi Wu, Yanyan Chen, Yangyang Wang, Zifan Yang, Xue Jiang, Qidong Li, Yan Zhang, Yajie Zhong, Jacinth Wing-Sum Cheu, Yiling Chen, Weixing Li, Chun-Ming Wong, Jianing Wang, Zongwei Cai, Qi Zhang, Tingbo Liang, Irene Oi-Lin Ng, Adonia E Papathanassiu, Carmen Chak-Lui Wong.
      Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.
    Keywords:  EGR245; branched-chain amino transferase 1; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor; metabolic reprogramming; prolyl hydroxylase-domain protein; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102784
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