bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2025–09–14
seventeen papers selected by
Marc Segarra Mondejar
  1. SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
  2. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  3. An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
  4. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  5. Ca2+ Fluxes across Membrane Contact Sites.
  6. Lipid droplets: Open questions and conceptual advances around a unique organelle.
  7. TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
  8. Astrocyte-Neuron Metabolic Synergies in Neurological Homeostasis and Disease.
  9. Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
  10. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  11. Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
  12. Contribution of metabolism-independent glucose sensing to metabolic homeostasis.
  13. Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
  14. Simulated metabolic profiles reveal biases in pathway analysis methods.
  15. HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
  16. Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.
  17. CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
  1. J Cell Biol. 2025 Oct 06. pii: e202406017. [Epub ahead of print]224(10):
    SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission.
    Rachel Shannon, Yadu Balachandran, Xindi Wang, Maxime Boutry, Hong Xie, Peter K Kim, William S Trimble.
      Mitochondria continually undergo fission to maintain their network and health. Nascent fission sites are marked by the ER, which facilitates actin polymerization to drive calcium flux into the mitochondrion and constrict the inner mitochondrial membrane. Septins are a major eukaryotic cytoskeleton component that forms filaments that can both directly and indirectly modulate other cytoskeleton components, including actin. Septins have been implicated in mitochondrial fission; however, a connection between septins and the regulation of cytoskeletal machinery driving fission is not known. We find that SEPTIN9 is present at mitochondrial fission sites from its early stages with the ER and prior to the fission factor dynamin-related protein 1 (DRP1). SEPTIN9 has an isoform-specific role in fission, dependent on its N-terminal interaction to activate a Rho guanine nucleotide exchange factor, ARHGEF18. Without SEPTIN9, mitochondrial calcium influx is impaired, indicating SEPTIN9-containing octamers play a critical role in the early stages of fission.
    DOI:  https://doi.org/10.1083/jcb.202406017
  2. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  3. Nat Metab. 2025 Sep 08.
    An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Rachel 'Rae' J House, Althea Waldhart, Kelly H Sokol, Samuel R Daniels, Cameron J Lee, Joseph Longo, Amy Johnson, Vincent J Sartori, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53-/- pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1038/s42255-025-01366-y
  4. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  5. Cold Spring Harb Perspect Biol. 2025 Sep 09. pii: a041765. [Epub ahead of print]
    Ca2+ Fluxes across Membrane Contact Sites.
    Lucia Barazzuol, Marisa Brini, Tito Calì.
      The calcium ion (Ca2+) is a pivotal second messenger orchestrating diverse cellular functions, including metabolism, signaling, and apoptosis. Membrane contact sites (MCSs) are critical hubs for Ca2+ exchange, enabling rapid and localized signaling across cell compartments. Well-characterized interfaces, such as those between the endoplasmic reticulum (ER) and mitochondria and ER-plasma membrane (PM), mediate Ca2+ flux through specialized channels. Less understood, yet significant, contacts involving Golgi, lysosomes, peroxisomes, and the nucleus further expand the landscape of intracellular Ca2+ signaling. These organelles are engaged in Ca2+ homeostasis mainly through their MCS, but the molecular players and the mechanisms regulating the process of Ca2+ transfer remain incompletely elucidated. This review provides a comprehensive overview of Ca2+ signaling across diverse MCS, emphasizing understudied organelles and the need for further investigation to uncover novel therapeutic opportunities.
    DOI:  https://doi.org/10.1101/cshperspect.a041765
  6. J Cell Biol. 2025 Oct 06. pii: e202406019. [Epub ahead of print]224(10):
    Lipid droplets: Open questions and conceptual advances around a unique organelle.
    W Mike Henne, Emma Reynolds, William A Prinz.
      Once viewed as mere lipid inclusions, the past four decades have witnessed an explosion of research into lipid droplet (LD) biogenesis and function. Pioneering cell biology, biochemical, genetics, and lipidomic studies now reveal LDs as active players in lipid metabolism and cellular homeostasis. Here, we discuss some of the major findings that defined LDs as bona fide organelles. However, despite what is known, much needs to be discovered. We highlight five enduring questions that continue to challenge the LD field and discuss a few misconceptions about this remarkable organelle.
    DOI:  https://doi.org/10.1083/jcb.202406019
  7. J Biomed Sci. 2025 Sep 10. 32(1): 87
    TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
    Shukla Sarkar, Chien-I Chang, Jussekia Jean, Meng-Ju Wu.
      Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.
    Keywords:  2-hydroxyglutarate; Epigenetic regulation; Fumarate; Itaconate; Metabolic reprogramming; Oncometabolites; Succinate; TCA cycle; Tumor immunity; α-ketoglutarate
    DOI:  https://doi.org/10.1186/s12929-025-01186-y
  8. Neurochem Res. 2025 Sep 09. 50(5): 293
    Astrocyte-Neuron Metabolic Synergies in Neurological Homeostasis and Disease.
    Jiahao Dong, Zihan Gao, Mingrui Liu, Binglu Qian, Cheng Yuan, Hui Liu, Ni Rao, Yingjiao Liu.
      Metabolic synergy between astrocytes and neurons is key to maintaining normal brain function. As the main supporting cells in the brain, astrocytes work closely with neurons through intercellular metabolic synergy networks to jointly regulate energy metabolism, lipid metabolism, synaptic transmission, and cerebral blood flow. This important synergy is often disrupted in neurological diseases such as Alzheimer's disease, Parkinson's disease, and stroke. This study systematically explores the physiological basis of this intercellular collaboration and its dysfunctional manifestations in the aforementioned diseases, and provides detailed insights into how abnormalities in specific collaborative pathways (such as impaired lactate transport, disrupted glutamate cycling, or lipid processing defects) significantly contribute to disease progression. By elucidating the molecular mechanisms underlying these collaborative impairments, this study aims to identify potential therapeutic targets, with the core strategy being to restore these critical intercellular collaborative relationships to alleviate neurological diseases.
    Keywords:  Astrocyte-neuron; Intercellular collaboration; Metabolic synergy; Neurological disorders
    DOI:  https://doi.org/10.1007/s11064-025-04548-y
  9. Int J Mol Sci. 2025 Aug 30. pii: 8466. [Epub ahead of print]26(17):
    Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
    Melvin Li, Sarah R Amend, Kenneth J Pienta.
      Metabolism is a tightly controlled, but plastic network of pathways that allow cells to grow and maintain homeostasis. As a normal cell transforms into a malignant cancer cell and proliferates to establish a tumor, it utilizes a variety of metabolic pathways that support growth, proliferation, and survival. Cancer cells alter metabolic pathways in different contexts, leading to complex metabolic heterogeneity within a tumor. There is an unmet need to characterize how cancer cells alter how they use resources from the environment to evolve, spread to other sites of the body, and survive current standard-of-care therapies. We review key techniques and methods that are currently used to study cancer metabolism and provide drawbacks and considerations in using one over another. The goal of this review is to provide a methods' guide to study different aspects of cell and tissue metabolism, how they can be applied to cancer, and discuss future perspectives on advancements in these areas.
    Keywords:  13C-metabolic flux analysis; Seahorse metabolic flux analysis; cancer metabolism; fluorescent probes; genetically encoded fluorescent biosensors; isotope tracing; untargeted metabolomics
    DOI:  https://doi.org/10.3390/ijms26178466
  10. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  11. Biochim Biophys Acta Rev Cancer. 2025 Sep 10. pii: S0304-419X(25)00192-1. [Epub ahead of print] 189450
    Unraveling the role of mitochondrial dynamics in cancer stem cells: Molecular basis and therapeutic implications.
    Gaia Giannitti, Sara Marchesi, Riccardo Garavaglia, Ivan Preosto, Fabrizio Fontana.
      Many tumors consist of heterogeneous cell populations derived from a minority of cancer stem cells (CSCs), which possess distinct metabolic profiles that contribute to resistance against conventional anticancer therapy and increase the risk of tumor relapse. These unique CSC phenotypes are largely supported by altered mitochondrial function and turnover, regulated through continuous cycles of mitochondrial biogenesis, fission, fusion, and mitophagy. Consequently, understanding mitochondrial regulatory mechanisms in CSCs could reveal novel targets for cancer therapy. This article explores how mitochondrial dynamics contribute to CSC metabolic adaptation and drug resistance, alongside recent advances in the development of mitochondria-targeted drugs and their therapeutic usage.
    Keywords:  Cancer stem cells; Cancer therapy; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial fission and fusion; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189450
  12. Trends Endocrinol Metab. 2025 Sep 06. pii: S1043-2760(25)00177-8. [Epub ahead of print]
    Contribution of metabolism-independent glucose sensing to metabolic homeostasis.
    Nadia Rashid, Kavaljit H Chhabra.
      Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.
    Keywords:  G protein-coupled receptors; glucose metabolism; glucose sensing; glucose transporters; sodium-glucose co-transporters
    DOI:  https://doi.org/10.1016/j.tem.2025.08.008
  13. Methods. 2025 Sep 10. pii: S1046-2023(25)00201-4. [Epub ahead of print]
    Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
    Jarrod Laro, Monica Ness, Joseane Godinho, Randy Coats, Laura-Isobel McCall.
      The tricarboxylic acid cycle (TCA), also known as the Krebs Cycle or the citric acid cycle, is an essential metabolic pathway involved in energy production that is often impacted by disease, making it of key interest to identify effective, affordable, and simple ways to monitor the impact of disease on TCA metabolism. 13C-based stable isotope labeling is a useful technique to track pathway alterations in living hosts. However, infusion-based methodologies are slow and expensive despite achieving steady-state labeling. Bolus-based methods are cheaper, faster, and compatible with biohazardous models, but require optimization to achieve maximum labeling. Herein, we performed bolus-based stable isotope labeling experiments in mouse models to identify the optimal dosage amount, label administration length, fast length prior to label administration, 13C-labeled precursor, and route of administration for the TCA cycle in the esophagus, heart, kidney, liver, plasma, and proximal colon. 13C-glucose at a concentration of 4 mg/g administered via intraperitoneal injection followed by a 90 min label incorporation period achieved the best overall TCA labeling. For most organs, a 3 h fast prior to label administration improved labeling, but labeling in the heart was better with no fasting period, showcasing the need to optimize methodology on an organ-by-organ basis. We also identified that bolus administration of glucose provided little impact on metabolism compared to vehicle control. The experiments outlined here provide critical information for designing in vivo stable isotope labeling experiments for the study of the TCA cycle.
    Keywords:  Bolus; Carbon-13; Fasting; Glucose; Labeling; Mice; TCA cycle
    DOI:  https://doi.org/10.1016/j.ymeth.2025.09.004
  14. Metabolomics. 2025 Sep 09. 21(5): 136
    Simulated metabolic profiles reveal biases in pathway analysis methods.
    Juliette Cooke, Cecilia Wieder, Nathalie Poupin, Clément Frainay, Timothy Ebbels, Fabien Jourdan.
       INTRODUCTION: Initially developed for transcriptomics data, pathway analysis (PA) methods can introduce biases when applied to metabolomics data, especially if input parameters are not chosen with care. This is particularly true for exometabolomics data, where there can be many metabolic steps between the measured exported metabolites in the profile and internal disruptions in the organism. However, evaluating PA methods experimentally is practically impossible when the sample's "true" metabolic disruption is unknown.
    OBJECTIVES: This study aims to show that PA can lead to non-specific enrichment, potentially resulting in false assumptions about the true cause of perturbed metabolic states.
    METHODS: Using in silico metabolic modelling, we can create disruptions in metabolic networks. SAMBA, a constraint-based modelling approach, simulates metabolic profiles for entire pathway knockouts, providing both a known disruption site as well as a simulated metabolic profile for PA methods. PA should be able to detect the known disrupted pathway among the significantly enriched pathways for that profile.
    RESULTS: Through network-level statistics, visualisation, and graph-based metrics, we show that even when a given pathway is completely blocked, it may not be significantly enriched when using PA methods with its corresponding simulated metabolic profile. This can be due to various reasons such as the chosen PA method, the initial pathway set definition, or the network's inherent structure.
    CONCLUSION: This work highlights how some metabolomics data may not be suited to typical PA methods, and serves as a benchmark for analysing, improving and potentially developing new PA tools.
    Keywords:  Benchmarking; Constraint-based modelling; Metabolomics; Pathway analysis
    DOI:  https://doi.org/10.1007/s11306-025-02335-y
  15. Cell. 2025 Sep 02. pii: S0092-8674(25)00929-8. [Epub ahead of print]
    HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
    Jeany Delafiori, Mohammed Shahraz, Andreas Eisenbarth, Volker Hilsenstein, Bernhard Drotleff, Alberto Bailoni, Bishoy Wadie, Måns Ekelöf, Alexander Mattausch, Theodore Alexandrov.
      Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses. Profiling HeLa and NIH3T3 cells, we detected 73 small-molecule metabolites validated by bulk liquid chromatography tandem MS (LC-MS/MS), achieving high reproducibility and single-cell resolution. Interrogating nine NCI-60 cancer cell lines and HeLa, we identified cell-type markers in subpopulations and metabolic hubs. Upon inhibiting glycolysis in HeLa cells, we observed emerging glucose-centered metabolic coordination and intra-condition heterogeneity. Overall, we demonstrate how HT SpaceM enables robust, large-scale SCM across over 140,000 cells from 132 samples and provide guidance on how to interpret metabolic insights beyond population averages.
    Keywords:  LC-MS/MS; MALDI-imaging mass spectrometry; NCI-60; SpaceM; co-abundance; heterogeneity; high-throughput; reproducibility; single-cell metabolomics; small-molecule metabolites
    DOI:  https://doi.org/10.1016/j.cell.2025.08.015
  16. Methods Cell Biol. 2025 ;pii: S0091-679X(25)00130-X. [Epub ahead of print]197 275-290
    Assessing mitochondrial number and morphology in a C. elegans model of human tauopathy.
    Eleni Tsakiri, Giorgos Niforos-Garcia, Brian D Ackley, Konstantinos Palikaras.
      Mitochondrial dysfunction is a shared hallmark of neurodegenerative disorders, including Alzheimer's disease (AD) and tauopathies among others. Pathological alterations of the microtubule-associated protein Tau can disrupt mitochondrial dynamics, transport, and function, ultimately leading to neuronal toxicity and synaptic deficits. Understanding these processes is crucial for developing therapeutic interventions. The nematode Caenorhabditis elegans serves as a powerful model to study mitochondrial morphology and Tau-induced neurotoxicity due to its well-characterized nervous system and genetic tractability. Here, we describe a robust methodology for assessing mitochondrial morphology, Tau aggregation, and neuronal integrity in a nematode model of tauopathy. By combining confocal laser scanning microscopy and motility assays, we provide a comprehensive framework for investigating mitochondrial deficits. This approach offers valuable insights into the interplay between Tau pathology and mitochondrial dysfunction, thereby advancing our understanding of neurodegenerative mechanisms and potential therapeutic targets.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Motility; Neurodegeneration; Neurons; Tauopathy
    DOI:  https://doi.org/10.1016/bs.mcb.2025.05.002
  17. EMBO Rep. 2025 Sep 12.
    CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
    Mengting Liu, Aoxing Cheng, Weiyi You, Jiaxin Wu, Chenxu Dai, Ting Wang, Ying Wu, Fumei Zhong, Jue Shi, Yingying Du, Zhonghuai Hou, Ping Gao, Ke Ruan, Yi Yang, Yuzheng Zhao, Kaiguang Zhang, Zhenye Yang, Jing Guo.
      While cancer cells overexpress lactate dehydrogenase A (LDHA) to support glycolytic flux and lactate production, the role of LDHB-which preferentially catalyzes lactate oxidation-remains unclear. Here, we demonstrate that LDHB, but not LDHA, is essential for mitotic progression in cancers. During mitosis, CDK1 phosphorylates LDHA at threonine 18, reducing its incorporation into the lactate dehydrogenase (LDH) tetramer. This results in LDHB-enriched tetramers that shift catalytic activity toward lactate oxidation, converting lactate and NAD⁺ into pyruvate and NADH. The generated NADH fuels oxidative phosphorylation and ATP production, thereby sustaining mitosis. Notably, LDHA-T18 phosphorylation occurs exclusively in tumor tissues. Our findings reveal a tumor-specific mechanism in which CDK1 reprograms LDH isoenzyme composition to direct lactate toward NADH production, ensuring energy homeostasis during mitosis. This underscores the therapeutic necessity of targeting both LDHA and LDHB in cancer.
    Keywords:  ATP; Lactate; Lactate Dehydrogenase; Mitosis; NADH
    DOI:  https://doi.org/10.1038/s44319-025-00573-8
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