bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–03–22
24 papers selected by
Marc Segarra Mondejar, AINA
  1. Lactate metabolism and protein lactylation in colorectal cancer: from metabolic reprogramming to epigenetic regulation.
  2. Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
  3. Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.
  4. Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
  5. SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
  6. Accurate prediction of flux distributions compatible with metabolite concentration effects in genome-scale metabolic networks.
  7. Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.
  8. Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis.
  9. Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.
  10. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  11. Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
  12. Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
  13. MFF budding from mitochondria regulates melanosome size and maturation.
  14. Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling.
  15. Lactate and cognition: a dual modulator.
  16. A fluorogenic and ultrabright probe for imaging of lipid droplets in live and fixed cells.
  17. Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.
  18. Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells.
  19. Application of spectral flow cytometry for comprehensive detection of immune metabolism in patient-derived microsamples.
  20. Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
  21. TREM1-NLRP3-driven pyroptosis in sepsis-associated acute kidney injury (AKI) with parallel autophagy changes.
  22. Do metabolic fluxes change with age?
  23. Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
  24. Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.
  1. Front Oncol. 2026 ;16 1741782
    Lactate metabolism and protein lactylation in colorectal cancer: from metabolic reprogramming to epigenetic regulation.
    Yulan Song, Mingyang Zou, Shaobo Wu, Rongwei Ren, Shundong Yuan, Yixin Pan, Jiebin Pan.
      Colorectal cancer (CRC) exhibits profound metabolic reprogramming, in which excessive lactate accumulation remodels the tumor microenvironment and promotes immune suppression, angiogenesis, and therapeutic resistance. Recent studies reveal that lactate also serves as a substrate for lysine lactylation (Kla), linking metabolic overflow to epigenetic regulation. This review focuses on CRC but also incorporates mechanistic data from other tumor models when CRC-specific evidence is limited, synthesizing lactate metabolism, transport, and lactylation into a unified lactate-lactylation axis. Mechanistic analyses highlight the roles of glycolytic enzymes, monocarboxylate transporters (MCT1/4-CD147), and Kla writers, erasers, and readers in driving malignant progression. Based on these insights, a three-step therapeutic framework is proposed: lowering lactate production, blocking lactate shuttling, and restraining Kla-mediated transcriptional reprogramming. Biomarker-guided evaluation using serum lactate dehydrogenase (LDH), tissue Kla immunohistochemistry, and hyperpolarized [1-^13C]-pyruvate MRI provides translational feasibility. This axis offers a mechanistic basis and actionable targets for metabolism-driven precision therapy, particularly in microsatellite-stable CRC (MSS CRC).
    Keywords:  biomarkers; colorectal cancer; immunotherapy; lactate metabolism; lactylation; monocarboxylate transporters; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1741782
  2. Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096
    Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
    Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.
      Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.
    Keywords:  CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117096
  3. Oncogene. 2026 Mar 21.
    Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.
    Jessamy Adams, Caterina M Suelzu, Gabriele Strusi, Justin Stebbing.
      Alterations in metabolism are recognised as a hallmark of cancer, allowing for rapid proliferation in an environment often hypoxic and short of nutrients. Cells within the tumour microenvironment (TME) often undergo metabolic alterations to adapt to these conditions, and this can also contribute to tumour progression. Cancer associated fibroblasts (CAFs) are amongst the most abundant non-cancerous cells in the TME and the main cells responsible for production and maintenance of the extracellular matrix. However, CAF subtypes can impact tumours in different ways and have been shown to play a role in alterations to lipid metabolism within tumours, being able to produce and secrete lipids, internalise them from the surrounding environment, and undergo fatty acid oxidation. Whilst this is still an emerging area of research, it appears that CAFs can have opposing roles in lipid metabolism in different types of cancer. Understanding the different metabolic pathways utilised in both CAFs and cancer cells and how external factors such as obesity and high fat diets influence them, could provide novel treatment avenues in the future. This review explores the literature surrounding lipid metabolism in CAFs and how this influences tumour progression and treatment resistance.
    DOI:  https://doi.org/10.1038/s41388-026-03733-9
  4. Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00037-1. [Epub ahead of print]89 102147
    Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
    Steffen Pöschel, Michael Müller.
      Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.
    Keywords:  2-photon microscopy; Aging; Hypoxia; Mitochondria; Reactive oxygen species; Redox imaging; roGFP
    DOI:  https://doi.org/10.1016/j.mito.2026.102147
  5. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529914123
    SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER-mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L-HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD-autophagy crosstalk.
    Keywords:  3D FIB-SEM; ER–mitochondrial contacts; brown adipocytes; megamitochondria; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2529914123
  6. PLoS Comput Biol. 2026 Mar 16. 22(3): e1014066
    Accurate prediction of flux distributions compatible with metabolite concentration effects in genome-scale metabolic networks.
    Fayaz Soleymani, Zahra Razaghi-Moghadam, Zoran Nikoloski.
      Intracellular fluxes shape all cellular functions, and understanding how they are shaped by the joint effects of enzyme abundances and metabolite concentrations in vivo currently requires gathering matched quantitative proteomic and metabolomic data sets from resource-intensive experiments. Here, we present KineFlux, a hybrid approach that combines machine learning with enzyme-constrained metabolic models to accurately predict steady-state flux distributions using only quantitative proteomic data. KineFlux builds machine learning models for metabolite concentration effects on reaction fluxes, obtained by using fluxomics and proteomics data from a training set of experiments. Using fluxomic and proteomic data sets of Escherichia coli and Saccharomyces cerevisiae, we show that the steady-state flux distributions predicted by KineFlux are in line with fluxes estimated by classical approaches. We also demonstrate that the machine learning models embedded in KineFlux are transferrable at marginal loss of accuracy using independent testing data from E. coli. Therefore, KineFlux expands the usability of enzyme-constrained models towards accurate prediction of genome-scale flux distributions compatible with metabolite concentration effects without knowledge of enzyme kinetics.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014066
  7. Cell Death Dis. 2026 Mar 19.
    Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.
    Sisi Chen, Xiaowei Fu, Tianyue Zhang, Rui Zhou, Long Liu, Liuhai Zeng, Bin Xu, Hengqing Zhu, Zhiyu Li.
      Metabolic reprogramming has garnered significant attention in recent years due to its therapeutic potential in cancer treatment. However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.
    DOI:  https://doi.org/10.1038/s41419-026-08573-9
  8. Nat Commun. 2026 Mar 15.
    Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis.
    Anna Cetnarowska, Mette Hyldahl, Marcus Nygård, Hesam Dashti, Bo Vagner Hansen, Laura Kristine Holm, Kaja Madsen, Maria Stahl Madsen, Vallari Shukla, Esra Durmaz Mitchell, Alexander Rauch, Jesper Grud Skat Madsen, Melina Claussnitzer, Susanne Mandrup.
      Transcriptional master regulators drive cell fate transitions. Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis, and its expression must therefore be tightly regulated and efficiently induced in response to adipogenic cues. Here we decipher the regulatory mechanisms of the highly connected enhancer community driving activation of the PPARG locus during adipocyte differentiation of human mesenchymal stem cells. By systematically deleting nine individual enhancers, spanning upstream, promoter-proximal, and downstream super-enhancer constituents, we demonstrate elaborate enhancer crosstalk in cis involving stabilization of C/EBPβ recruitment prior to chromatin remodeling. We show that the super-enhancer constituent E + 102 plays a dual role in cis crosstalk and feedback activation and is obligate for activation of PPARG expression. Non-coding genetic variants associated with cardiometabolic traits and predicted to regulate PPARG expression map to E + 102 and other essential enhancers in the community, thereby supporting the importance of these enhancers in human physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-026-70401-7
  9. Acta Pharmacol Sin. 2026 Mar 16.
    Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.
    Xing-Xian Zhang, Jia-Min Du, Shen-Zhan Wang, Xin-Lei Mo, Xiang-Nan Zhang.
      Mitochondrial dynamics - processes that include fission, fusion, transport, and mitophagy - are essential for shaping mitochondrial form and function to meet neuronal homeostatic demands. Growing evidence links imbalances in these processes to the pathogenesis of multiple brain disorders. In this review we comprehensively summarize the molecular mechanisms that govern mitochondrial dynamics and clarify their roles in key neuronal functions, including synaptic transmission, vesicle recycling, and calcium buffering. We also examine how disruptions in mitochondrial dynamics drive synaptic dysfunction and neuronal injury, with specific implications for neurodegenerative and psychiatric disorders. Finally, we evaluate emerging therapeutic strategies that target mitochondrial dynamics - both pharmacological and genetic - and highlight their promise as novel therapies for brain disorders. This synthesis provides an in-depth perspective on mitochondrial dynamics in brain health and disease and aims to guide future research and drug development.
    Keywords:  mitochondrial dynamics; neurodegenerations; neuron; neuropsychiatric disorders; therapeutic strategy
    DOI:  https://doi.org/10.1038/s41401-025-01746-w
  10. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  11. iScience. 2026 Mar 20. 29(3): 115068
    Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
    Wenli Zhao, Yangguang Bao, Lei Liu, Yixin Gu, Xuran Liu, Óscar Monroig, Tingting Zhu, Peng Sun, Douglas R Tocher, Qicun Zhou, Min Jin.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), contact sites between the endoplasmic reticulum (ER) and mitochondria, are critical for calcium signaling and lipid metabolism. However, how MAMs contribute to mitochondrial dysfunction in lipid overload-induced fatty liver remains unclear. Here, using teleost fish as a model, we showed that high-fat diets promoted the aggregation of PERK and ALCAT1 at MAMs, causing mitochondrial calcium overload and membrane depolarization, and impairing PINK1/Parkin-dependent mitophagy. Acetylation of PERK at lysine 388 facilitated its binding to ALCAT1, while activation of SIRT1 by resveratrol induced site-specific deacetylation of PERK, disrupted PERK-ALCAT1 interaction, and restored mitophagy and mitochondrial integrity. These findings revealed a conserved SIRT1-PERK-ALCAT1 signaling axis linking ER stress to mitophagy failure and identified a potential nutritional intervention to alleviate lipid-induced hepatic injury. This mechanism is conserved across species and offers a basis for controlling metabolic dysfunction-associated steatotic liver disease (MASLD) in teleosts and potentially other vertebrate systems.
    Keywords:  Lipid; Metabolic flux analysis; Molecular network
    DOI:  https://doi.org/10.1016/j.isci.2026.115068
  12. Nat Commun. 2026 03 14. pii: 2487. [Epub ahead of print]17(1):
    Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
    Valentin Duhay, Miaomiao Tian, Klaudia Kosieradzka, Michael Ebner, Wen-Ting Lo, Michael Krauss, Henner-Linus Sprengel, Matthias Voss, Mara Riechmann, Jeffrey N Savas, Michael Schwake, Volker Haucke, Markus Damme.
      Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.
    DOI:  https://doi.org/10.1038/s41467-026-70345-y
  13. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  14. iScience. 2026 Mar 20. 29(3): 115157
    Peripheral amylin modulation rebalances brain glycolysis and Tau-Ser214 phosphorylation via cAMP-PKA signaling.
    Ravichandra S Davargaon, Nirmal Verma, Deepak Kotiya, Noah Leibold, Gopal Viswanathan Velmurugan, Han Coburn, Kuey C Chen, Daniel Ruiz, Victor Corces, Huazhen Liu, Pradeep Kachroo, Pankaj K Singh, Matthew S Gentry, Sanda Despa, Florin Despa.
      Brain glucose dysregulation is shared by Alzheimer's disease (AD) and diabetes, but whether it arises from central or peripheral mechanisms remains unclear. Amylin, a pancreatic hormone, normally supports CNS cAMP-PKA signaling, metabolism and memory; however, prediabetes-associated hypersecretion disrupts this balance. Using human amylin-inducible mice, we show that toggling amylin secretion during metabolic stress bidirectionally regulates brain glycolysis and function. Excess amylin overactivates cAMP-PKA signaling, suppressing glycolysis and inducing Tau-Ser214 phosphorylation, two core features of AD pathology. This state is accompanied by activation of the amino acid starvation response, Tau-T231 hyperphosphorylation, pTau-Aβ coupling, neuroinflammation and memory deficit. In contrast, reducing amylin in prediabetes preserves glycolysis, ATF4-dependent proteostasis and cognition. Astrocytes emerge as primary targets, as amylin receptor blockade prevents glycolytic deficits ex vivo, and amylin accumulates in GFAP-enriched regions in vivo. Together, these results define prediabetic hyperamylinemia as an upstream, modifiable driver of PKA-mediated tau pathology linking metabolic dysfunction to AD.
    Keywords:  behavioral neuroscience; endocrinology; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.115157
  15. Front Mol Neurosci. 2026 ;19 1742681
    Lactate and cognition: a dual modulator.
    Wen Yang, Yu Xu, Kunhua Wang.
      Lactate, traditionally regarded as a byproduct of glycolysis, has emerged as a key metabolic substrate and signaling molecule in the brain. Through the astrocyte-neuron lactate shuttle, lactate provides an essential link between energy metabolism and neuronal function. Beyond its metabolic role, lactate influences synaptic plasticity, neuroinflammation, mitochondrial dynamics, and epigenetic regulation, thereby exerting multifaceted effects on cognitive processes. Accumulating evidence demonstrates that lactate acts as a double-edged regulator: under certain conditions, it promotes neuronal resilience and cognitive enhancement, whereas excessive accumulation or impaired transport may contribute to dysfunction. This review synthesizes current knowledge of lactate metabolism in the central nervous system, highlighting its physiological functions, bidirectional impact on cognition, and emerging role as both a biomarker and therapeutic target. A deeper understanding of lactate-mediated mechanisms may pave the way for novel strategies in the prevention and intervention of cognitive impairment. Clinically, lactate is best interpreted as a context-sensitive metabolic readout rather than a standalone disease-specific biomarker.
    Keywords:  astrocyte–neuron lactate shuttle; cognition; epigenetic regulation; lactate; neuroinflammation; synaptic plasticity
    DOI:  https://doi.org/10.3389/fnmol.2026.1742681
  16. Anal Methods. 2026 Mar 16.
    A fluorogenic and ultrabright probe for imaging of lipid droplets in live and fixed cells.
    Guorui Zhao, Guanchang Ji, Dongdong Song, Yarong Ma, Guanzheng Tian, Guizhen Zhang.
      Lipid droplets (LDs) play a vital role in energy homeostasis and cellular signaling. Therefore, the visualization of LDs is very important. To this end, a new LD-specific fluorescent probe, TPE-Q, was developed based on the aggregation-induced emission (AIE) strategy. TPE-Q features facile synthesis and good biocompatibility. It demonstrates robust performance in labeling LDs in live and fixed cells, characterized by good photostability, a high signal-to-noise ratio, and compatibility with three-dimensional imaging. TPE-Q provides an effective approach for detecting LDs and shows considerable promise for applications in disease diagnosis, pathological investigation, and biomedical research.
    DOI:  https://doi.org/10.1039/d6ay00188b
  17. Sci Adv. 2026 Mar 20. 12(12): eadx8715
    Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.
    Aleksandra Dagunts, Hayden Adoff, Brandon Novy, Lamya Ben Ameur, Monica De Maria, Arpiar Saunders, Braden T Lobingier.
      A critical homeostatic mechanism for regulating G protein-coupled receptor (GPCR) activity is agonist-induced GPCR endocytosis and trafficking to the lysosome for proteolytic down-regulation. The mu opioid receptor (MOR) is a notable example of this type of cellular regulation, where prolonged exposure to high-efficacy opioid drugs causes MOR to traffic to the lysosome. Here, we used functional genomics to identify cellular proteins that control MOR lysosomal down-regulation. We found that the central regulator of MOR postendocytic trafficking is the Retromer complex, which rescues MOR from opioid-induced down-regulation by promoting MOR recycling from endosomes to the plasma membrane. Critically, MOR accesses the Retromer recycling pathway through its noncanonical bileucine recycling motif, and this mechanism controls how MOR is regulated following chronic exposure to opioid drugs. Additionally, we show that this bileucine pathway for Retromer-based recycling is present in other classes of membrane proteins including the glucose transporter GLUT4.
    DOI:  https://doi.org/10.1126/sciadv.adx8715
  18. Sci Rep. 2026 Mar 18.
    Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells.
    Bobak Parang, Liron Yoffe, Rabia Khan, Zhongchi Li, Michal J Nagiec, Eric E Gardner, Yiwey Shieh, Rachel S Heise, Ashish Saxena, Nasser Altorki, John Blenis.
      
    Keywords:  Drug-tolerant persister; EGFR-mutant; Lung cancer; Propionate metabolism
    DOI:  https://doi.org/10.1038/s41598-026-44451-2
  19. Cell Rep Methods. 2026 Mar 16. pii: S2667-2375(26)00030-5. [Epub ahead of print] 101330
    Application of spectral flow cytometry for comprehensive detection of immune metabolism in patient-derived microsamples.
    Yang Bai, Yuqing Wang, Yicheng Fu, Zhengyang Guo, Zhaoyuan Liang, Liu Yang, Jiawei Ribaudo, Dan Liu, Yanfang Li, Ting Zhang, Lixiang Xue, Jianling Yang, Huilin Liu, Xianlong Li, Jie Zhang.
      Single-cell metabolic characteristics are powerful indicators of cellular physiological and pathological states. Flow cytometry enables high-throughput single-cell metabolic profiling and immunophenotyping; however, spectral overlap impedes simultaneous detection of multi-parametric features. This limitation imposes larger sample requirements and increased variabilities due to metabolic dynamics-constraints acutely magnified in studies utilizing clinical microsamples. To overcome these shortcomings, we developed a spectral flow cytometry platform for immunometabolic features, using 13 dual-probe combinations and 11 fluorophore probes. Requiring only 100 μL of whole blood per assay, this platform enables concurrent detection of 4 metabolic biomarkers and 16 immune markers. Application to patients with heart failure revealed heterogeneous metabolic landscapes across 20 immune subpopulations, showing reduced frequencies of naive T cells and NK-like T cells, with a metabolic shift from fatty acid dependence to glucose avidity. Our framework captures metabolic interactions previously inaccessible by sequential detection and will help to enable precision immunometabolism research.
    Keywords:  CP: immunology; CP: metabolism; immunometabolic analysis in samples from patients; metabolic function by flow cytometry; metabolic probes; spectrum flow cytometry
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101330
  20. J Biol Chem. 2026 Mar 12. pii: S0021-9258(26)00237-1. [Epub ahead of print] 111367
    Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
    Karen Slattery, Gearóid Conlon, Ethan Collins, Derek P Nolan, Clair M Gardiner, Geraldine M O'Connor.
      Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111367
  21. Sci Rep. 2026 Mar 19.
    TREM1-NLRP3-driven pyroptosis in sepsis-associated acute kidney injury (AKI) with parallel autophagy changes.
    Xudong Liu, Qian Chen, Xiangyu Chen, Yaqi Wang, Junping Fan, Xinlun Tian, Xinjie Xu, Longxiang Su.
      
    Keywords:  NLRP3 inflammasome; Triggering receptor expressed on myeloid cells-1 (TREM-1); autophagy; pyroptosis; sepsis-associated acute kidney injury
    DOI:  https://doi.org/10.1038/s41598-026-40893-w
  22. Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]
    Do metabolic fluxes change with age?
    Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.
      Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.
    Keywords:  age-associated diseases; aging; autophagy; geroscience; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2026.01.013
  23. Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00185-3. [Epub ahead of print]45(4): 117107
    Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
    Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.
      Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.
    Keywords:  CP: cancer; CP: metabolism; GPT2; MYC; alanine metabolism; liver cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117107
  24. J Biol Chem. 2026 Mar 17. pii: S0021-9258(26)00250-4. [Epub ahead of print] 111380
    Siah2 Regulates Lipid Uptake in Adipose Tissue Macrophages.
    Bhaswati Ghosh, Pradip R Panta, Matthew C Scott, Jessica Taylor, Robbie Beyl, Krisztian Stadler, Z Elizabeth Floyd.
      In obesity, adipose tissue macrophages (ATMs) reprogram their metabolism to influence adipose tissue remodeling and function. Ubiquitin ligases are critical in modulating degradation of key proteins implicated in macrophage lipid metabolism. Yet, the role of ubiquitin ligases in ATM lipid metabolism is largely unexplored. Previously, we reported that the ubiquitin ligase Siah2 is crucial in mediating adipogenic pathways and adipose tissue inflammation. Here, we co-cultured bone marrow-derived macrophages with adipose tissue as an ex vivo model of bone marrow-derived ATMs to investigate Siah2's role in ATM lipid metabolism. We found that adipose tissue- induced lipid accumulation in ATMs was exacerbated by Siah2 deficiency via increased CD36-mediated lipid uptake and reduced lipid delivery to lysosomes. Together, these changes contributed to excessive lipid accumulation, lipid peroxidation and an inflammatory phenotype. Our data reveals a central role for Siah2 as a lipid uptake sensor in maintaining the balance between lipid influx and degradation in ATMs.
    Keywords:  Adipose tissue macrophages; CD36; Inflammation; Lipid metabolism; Lipolysis; Lysosome; PPARγ; Siah2; Ubiquitin ligase
    DOI:  https://doi.org/10.1016/j.jbc.2026.111380
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