bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–05–31
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.
  2. Mechanism of age-related accumulation of mtDNA mutations in human blood.
  3. Universal transcriptomic hallmarks of mammalian ageing and mortality.
  4. A transport-independent role for SLC25A12 in mitochondrial stress signalling.
  5. Mesenchymal drift: A convergent framework for the hallmarks of aging.
  6. Dietary sulfur amino acids enhance anti-tumor immunity in colon cancer via an NKT cell-XCL1-cDC1 circuit.
  7. The Influence of Diet on Cancer Progression and Treatment.
  8. Mitochondrial flagella-like extensions (MitoFLARE) dysfunction triggers STING-mediated immune dysregulation in sepsis.
  9. Lactylation landscape of mitochondrial proteins in myocardial infarction.
  10. Breaking the membrane heredity paradox through de novo protocell formation.
  11. Dynamical Systems-Constrained Metabolic Modeling Enables Forecasting of Host-Microbiome Dynamics.
  12. MechAInistic: An LLM-guided Multi-Agent System for Reasoning over Genome-Scale Constraint-Based Metabolic Models.
  13. Pan-cancer spatial atlas of tertiary lymphoid structures.
  14. Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
  15. Real-time cell viability monitoring for high-throughput drug screening using tumor xenograft-derived cells.
  16. Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
  17. Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma.
  18. Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.
  19. Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma.
  20. Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
  21. Mitochondrial drivers of stem cell aging and inflammaging.
  22. Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.
  23. Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.
  24. Disruption of ER-mitochondria contact sites by coronavirus replication organelles sustains viral replication via NSP3 stabilization.
  25. Pro-aging effects of chronic glucocorticoid signaling.
  26. Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.
  27. Metabolite Damage and Repair in Health and Disease.
  28. CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.
  29. Essential genetic mutations impair DNA damage repair and modulate tumor immune microenvironment in ccRCC.
  30. A multilayered stress-response circuit: The mammalian mitochondrial UPR.
  31. Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.
  32. A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.
  33. Heavy water labeling reveals metabolic flexibility of amino acid and polyamine pathways in mammalian cells.
  34. Obesity suppresses neutrophil-dependent itaconate signaling promoting ferroptosis in acute pancreatitis.
  35. A Hormone Cell Atlas maps the human endocrine system at cellular resolution.
  36. Neuronal glycogen powers anticipatory brain responses to food.
  37. Tissue-dependent enzymatic control of N-acetyl-β-alanine by PTER.
  38. Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
  39. A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells.
  40. The Interplay between Gut Microbiota and Diet-Induced Kidney Protection.
  41. L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.
  42. Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.
  43. Circulating Dipeptides in Cancer: Degradation Fragments or Functional Metabolites?
  44. Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
  45. Metabolic Reprogramming of B Cells in Cancer: Effects of Altered Energetics.
  46. Gut microbiota and metabolic control of immune checkpoint blockade in cancer.
  47. Time-restricted feeding enhances cross-tissue temporal coordination of mitochondrial-associated transcripts.
  48. Dehydration promotes intracellular lipid synthesis and accumulation.
  49. IL4i1 activity generates oncometabolites that rescue neuroblastoma cells from oxidative death.
  50. Epigenetic programming by H3K23ac defines lineage fate of Meg3+ haematopoietic stem cells and drives immune ageing.
  51. Genomics-Informed Approach Identifies Which Cell Types Regulate the Metabolome.
  52. Human haematopoietic stem cells remember inflammatory stress.
  53. Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
  54. Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
  55. MiTo: tracing the phenotypic evolution of somatic cell lineages via mitochondrial single-cell multi-omics.
  56. Reduction in Hepatic Phosphatidylcholine Biosynthesis Promotes MASH Through Copper Deficiency.
  57. A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
  58. Gene clock predicts time to death in humans - and assesses 'biological' age.
  59. Very low-carbohydrate ketogenic diet in treatment-naïve women with endometrial cancer and overweight: a randomized feasibility study.
  1. Nature. 2026 May 27.
    αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.
    Apoorva Uboveja, Baixue Yang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Julie A Disharoon, Richard S Fang, Evan Levasseur, Miho Naruse, Zhentai Huang, Emily Megill, Daniel S Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Sarah Graff, Ellen De Pieri, Andrea Andress Huacachino, Frank P Vendetti, Jeff Danielson, Erika S Dahl, Jennifer L Pennise, Esther Elishaev, Alison Jaccard, Lauren Borho, Miriam D Post, Kristine Cooper, Francesmary Modugno, Nadine Hempel, Wayne Stallaert, Christopher J Bakkenist, Simone Sidoli, Kathryn E Wellen, Benjamin G Bitler, David T Long, Nathaniel W Snyder, Katherine M Aird.
      Homologous recombination (HR) deficiency increases sensitivity to DNA-damaging agents that are commonly used to treat cancer1. In HR-proficient cancers, the metabolic mechanisms that drive response or resistance to DNA-damaging agents remain unclear. Here we have identified that depletion of α-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA-damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases2 (αKGDDs), and previous work has focused almost exclusively on the demethylase functions of αKGDD. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that trimethyllysine hydroxylase epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for the survival of HR-proficient cells in the presence of DNA-damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation and was non-redundant with other nucleo-cytosolic acetyl-CoA-generating pathways. The increase in histone acetylation by means of the αKG-carnitine axis promoted HR-mediated DNA repair through site-specific histone acetylation. Finally, we observed a positive correlation between TMLHE and histone acetylation in patient samples and found that high TMLHE or acetylcarnitine correlates with worse progression-free survival in patients treated with DNA-damaging agents. This study demonstrates for the first time, to our knowledge, that αKG affects site-specific histone acetylation and provides a mechanism of HR proficiency through carnitine synthesis. Moreover, these data provide a metabolic avenue for inducing HR deficiency and promoting sensitivity to DNA-damaging agents.
    DOI:  https://doi.org/10.1038/s41586-026-10584-7
  2. Nature. 2026 May 27.
    Mechanism of age-related accumulation of mtDNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Masahiro Kanai, Md Mesbah Uddin, Wenhan Lu, M Austin Argentieri, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
    DOI:  https://doi.org/10.1038/s41586-026-10569-6
  3. Nature. 2026 May 27.
    Universal transcriptomic hallmarks of mammalian ageing and mortality.
    Alexander Tyshkovskiy, Daria Kholdina, Maria Davitadze, Adrian Molière, Alibek Moldakozhayev, Yoshiyasu Tongu, Tomoko Kasahara, Dmitrii Glubokov, Alec Eames, Leonid M Kats, Anastasiya Vladimirova, Kejun Ying, Hanna Liu, Bohan Zhang, Uma Khasanova, Mahdi Moqri, Jeremy M Van Raamsdonk, David E Harrison, Randy Strong, Takaaki Abe, Sergey E Dmitriev, Vadim N Gladyshev.
      Ageing and interventions modulate health and mortality1, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank. Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification and extracellular matrix organization. To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho (also known as Kl) deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.
    DOI:  https://doi.org/10.1038/s41586-026-10542-3
  4. Nat Cell Biol. 2026 May 27.
    A transport-independent role for SLC25A12 in mitochondrial stress signalling.
    Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.
      Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-01973-1
  5. Cell. 2026 May 28. pii: S0092-8674(26)00455-1. [Epub ahead of print]189(11): 3184-3213
    Mesenchymal drift: A convergent framework for the hallmarks of aging.
    Jinlong Y Lu, William B Tu, Shuai Ma, Zaijun Ma, Ivan Imaz-Rosshandler, Mingxi Weng, Jing Qu, Concepcion Rodriguez Esteban, Pradeep Reddy, Guang-Hui Liu, Juan Carlos Izpisua Belmonte.
      Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.
    Keywords:  Yamanaka factors; aging; biomarkers; cellular identity and plasticity; endothelial-to-mesenchymal transition; epithelial-to-mesenchymal transition; fibrosis; geroscience; partial reprogramming; rejuvenation
    DOI:  https://doi.org/10.1016/j.cell.2026.04.020
  6. Immunity. 2026 May 26. pii: S1074-7613(26)00181-0. [Epub ahead of print]
    Dietary sulfur amino acids enhance anti-tumor immunity in colon cancer via an NKT cell-XCL1-cDC1 circuit.
    Lior Lobel, Diogo Fonseca-Pereira, Geicho Nakatsu, Monia Michaud, Y Grace Cao, Sena Bae, Cathleen Krabak, Yaara Oren, Slater L Clay, Geniver El Tekle, Eunyoung Chun, Shigeyuki Kon, Andrew T Chan, Jon Clardy, Jonathan N Glickman, Nadim J Ajami, Abderrahman Day, Ashish Damania, Erez N Baruch, Michael G White, Laurence P Diggs, Jennifer Wargo, Thomas Riffelmacher, Ann Balancio, Mitchell Kronenberg, Curtis Huttenhower, Wendy S Garrett.
      The efficacy of immune checkpoint inhibitors (ICIs) in colon cancer (CC) is limited by the tolerogenic immune landscape of both the tumor and the intestine. Here, we investigated the impact of microbial metabolic pathways associated with ICI responsiveness on anti-tumor immunity in CC. Sulfur amino acid (Saa) metabolic pathways were enriched in ICI responders and in individuals without CC. In murine models, high-Saa diets restricted CC progression, increased colonic mucus thickness, and promoted the expansion of mucus-dwelling Mucispirillum schaedleri (M. schaedleri). Dietary Saa supplementation increased the frequency of activated intratumoral cytotoxic CD8+ T cells. The protective effect of high-Saa diets required type 1 conventional dendritic cells (cDC1s) in tumor-draining lymph nodes, where M. schaedleri was sufficient to drive cDC1 expansion and activation. Mechanistically, M. schaedleri stimulated natural killer T (NKT) cell expansion and secretion of the chemokine XCL1, which was essential for cDC1 recruitment and anti-tumor immunity. Dietary modulation of this NKT-XCL1-cDC1 axis in combination with ICIs may open avenues for improved treatments of CC.
    Keywords:  Mucispirillum schaedleri; NKT; XCL1; anti-tumor immunity; cDC1; colon cancer; microbiome; mucus; sulfur amino acids
    DOI:  https://doi.org/10.1016/j.immuni.2026.05.001
  7. Annu Rev Nutr. 2026 May 26.
    The Influence of Diet on Cancer Progression and Treatment.
    Anna M Barbeau, John W R Kincaid, Alissandra L Hillis, Edrees H Rashan, Yichi Zhang, Gillian E Oaks, Matthew G Vander Heiden.
      Growing evidence suggests that dietary interventions can influence cancer progression and patient outcomes. Here, we discuss mechanistic links between diet and cancer biology including those related to systemic hormone signaling, modulation of nutrient availability within the tumor microenvironment, and interactions with the immune system and microbiome, while highlighting their interconnectedness. Further, we review preclinical and clinical data evaluating specific diets, including their use with cancer therapies. Given the interest in diet as an adjunct to cancer care, it is essential to establish evidence-based dietary strategies for optimizing patient outcomes and quality of life.
    DOI:  https://doi.org/10.1146/annurev-nutr-062122-021518
  8. Nat Commun. 2026 May 25.
    Mitochondrial flagella-like extensions (MitoFLARE) dysfunction triggers STING-mediated immune dysregulation in sepsis.
    Weilong Hong, Ruiyan Ma, Shiyun Long, Rui Song, Shuang Ren, Xiaoping Ran, Junfang Wan, Yifei Liu, Xiaofeng Li, Qian Chen, Daqing Ma, Zhaocai Zhang, He Huang, Milad Ashrafizadeh, João Conde, Liangming Liu, Chenyang Duan.
      Sepsis is an immune dysregulation syndrome triggered by infection, characterized by host self-damage due to immune imbalances. This study focuses on dynamic changes of mitochondrial symbiotic function in host cells during sepsis and systematically investigates dysregulation of mitochondrial communication modes and the intrinsic link between mitochondrial DNA (mtDNA) release and immune dysregulation. We demonstrate that during early-stage LPS treatment, mitochondria actively remodel by extruding flagella-like extensions (termed mitoFLARE). These structures, nanotubes mediating long-distance transport, form through glycosylated TRAK1 binding FHL2 to drive actin network formation, thereby shifting mitochondrial communication from direct fusion to nanotube-mediated transport. This helps maintain dynamic exchange within the inner mitochondrial membrane under LPS treatment. However, as inflammation progresses, deteriorated mitochondrial quality control disrupts the MICOS-SAM complex, abrogates inner-outer membrane anchoring, and suppresses mitoFLARE functions. All these ultimately enhance endoplasmic reticulum-mitochondrial contacts to promote outer membrane rupture and result in mtDNA release into the cytoplasm to activate cGAS-STING signaling, further triggering immune dysregulation and inflammatory storm, culminating in programmed cell death and organ dysfunction. This study elucidates the pivotal role of dysregulated mitochondrial-host symbiosis in sepsis progression and provides important insights into the underlying mechanisms of sepsis-associated immune imbalances, laying a theoretical foundation for targeted therapy development.
    DOI:  https://doi.org/10.1038/s41467-026-73523-0
  9. Redox Biol. 2026 May 18. pii: S2213-2317(26)00224-7. [Epub ahead of print]94 104226
    Lactylation landscape of mitochondrial proteins in myocardial infarction.
    Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.
      Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently discovered lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we mapped the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocyte-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
    Keywords:  AZD3965; Lactate; Lactylation; MCT1; Mitochondria; Myocardial infarction
    DOI:  https://doi.org/10.1016/j.redox.2026.104226
  10. Nat Commun. 2026 May 28.
    Breaking the membrane heredity paradox through de novo protocell formation.
    Satyam Khanal, Alessandro Fracassi, Alexander Harjung, Michael D Burkart, Neal K Devaraj.
      Lipid membranes define cell boundaries, acting as gatekeepers for transport and signaling. A central paradigm in biology is that all cellular membranes descend from a common ancestral membrane, as they cannot be generated in the absence of pre-existing lipid structures. It is thus unclear whether lipid membranes can arise from membrane-less precursors. Here we demonstrate the de novo generation of lipid bilayers in the absence of any pre-existing membranes, membrane-bound proteins, or lipid nanostructure templates. Using acetate and cysteine as simple metabolites, lipid tails are constructed by soluble enzymes and spontaneously form diacyl lipids that assemble into vesicles. Pore-forming peptides facilitate precursor transport into vesicles, allowing the continuous generation of new lipids. Formation of glycolipid membranes creates compartments that can maintain proton gradients. Our findings demonstrate that lipid compartments can form without pre-existing membranes, establishing a unique route linking lipid synthesis to compartment formation and function.
    DOI:  https://doi.org/10.1038/s41467-026-73667-z
  11. bioRxiv. 2026 May 12. pii: 2026.05.08.723020. [Epub ahead of print]
    Dynamical Systems-Constrained Metabolic Modeling Enables Forecasting of Host-Microbiome Dynamics.
    Hayden Gallo, Vanni Bucci.
      Forecasting how microbiome-host ecosystems evolve through time simultaneously at the compositional and functional level remains a central challenge in biology. While dynamical systems models (DSMs) can infer and predict community composition from longitudinal abundance data, and constraint-based metabolic models (CBMMs) can estimate metabolic fluxes from genome-scale reconstructions, no existing framework unifies these approaches to generate mechanistically grounded, time-resolved forecasts of both microbial abundances and metabolite dynamics from ecological data alone. Here, we introduce the Dynamical Systems Constrained Metabolic Modeling (DySCoMeMo) framework, a new hybrid computational pipeline that integrates ecological DSMs with CBMMs to predict temporal dynamics of biomass and metabolites across microbial communities and hosts. DySCoMeMo leverages parameters inferred from application of DSMs to microbiome time series data to constrain metabolic modeling over time, thereby bridging ecological interaction networks with genome-scale metabolic modeling. DySCoMeMo is able to predict future community and metabolite dynamics in vitro with accuracy that is superior or on-par compared to that achieved with established methods that require actual microbial abundances and/or metabolites data for metabolite network inference or for estimating the per-microbe contribution to the extracellular metabolic pool. DySCoMeMo also generalizes to in vivo data as it is capable of accurately forecasting microbial and metabolite dynamics in response to dietary perturbations even when host metabolism is included. Finally, DySCoMeMo uniquely enables the identification of keystone species by quantifying their contributions to sustaining metabolic environments. Together, our work establishes a generalizable, mechanistically grounded framework for time-resolved forecasting of microbiome-host microbial and metabolic dynamics, bridging ecological interaction inference with genome-scale metabolism of communities.
    DOI:  https://doi.org/10.64898/2026.05.08.723020
  12. bioRxiv. 2026 May 13. pii: 2026.05.11.723319. [Epub ahead of print]
    MechAInistic: An LLM-guided Multi-Agent System for Reasoning over Genome-Scale Constraint-Based Metabolic Models.
    Josh Loecker, Narayna Puraja, William Bryant, Bhanwar Lal Puniya, Prakash Packrisamy, Ahmed Abdeen Hamed, Tomáš Helikar.
      Constraint-based metabolic modeling is a powerful way to study the mechanistic basis of cellular states and disease, but effective use demands substantial computational expertise and careful coordination of multi-step analyses. We developed MechAInistic to lower this barrier enabling researchers to ask complex biological questions in natural language. MechAInistic is a multi-agent system harnessing large language models organized around an Architect-Reviewer pattern that that converts a natural-language question into an executable, model-grounded workflow and produces a structured report. It supports pathway comparison, perturbation analysis, drug-target exploration, and literature interpretation across healthy and disease paired states. We evaluated MechAInistic's therapeutic hypothesis generation using two immune-cell use-cases. For rheumatoid arthritis/healthy Naive B models, it identified mitochondrial metabolic rewiring and nominated Devimistat/CPI-613 as an investigational OGDH-centered hypothesis. In CD4+ Th17 multiple sclerosis/healthy models, the workflow identified NADP-dependent isocitrate dehydrogenase as the optimal target and proposed Ivosidenib as an FDA-approved repurposing candidate.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.05.11.723319
  13. Science. 2026 May 28. 392(6801): eadz2742
    Pan-cancer spatial atlas of tertiary lymphoid structures.
    Kyung Serk Cho, Yunhe Liu, Guangsheng Pei, Jianfeng Chen, Yibo Dai, Yang Liu, Tieling Zhou, Antoine Bougouin, Alejandra Serrano, Khalida Wani, Akshaya Jadhav, Jimin Min, Sharia Hernandez, Wei Lu, Daiwei Zhang, Jiahui Jiang, Diana Shamsutdinova, Enyu Dai, Fuduan Peng, Ansam Sinjab, Paola A Guerrero, Idania Carolina Lubo Julio, Kai Yu, Helen Clark, Dipen Maru, Mingyao Li, Andrew Futreal, Sanghoon Lee, Luisa Maren Solis Soto, Lulu Shang, Pavlos Msaouel, Jaffer A Ajani, Hannah Beird, Amir A Jazaeri, Alexander J Lazar, Catherine Sautes-Fridman, Wolf H Fridman, Anirban Maitra, Humam Kadara, Jianjun Gao, Padmanee Sharma, Linghua Wang.
      Tertiary lymphoid structures (TLSs) are critical regulators of antitumor immunity, yet their spatial organization, maturation, and clinical relevance remain incompletely defined across cancers. We analyzed spatial transcriptomics spanning 12 cancer types to construct a pan-cancer TLS atlas and characterized TLS spatial architecture and maturation states. TLS maturation was accompanied by coordinated remodeling of distinct niche cell populations and distance-dependent gradients in tumor programs, orthogonally supported by ultrahigh-plex single-cell spatial profiling. To enable scalable TLS profiling, we trained an artificial intelligence framework that predicts TLS maturation states directly from hematoxylin and eosin-stained images and evaluated it across TCGA and independent therapy cohorts. We further derived a maturation-aware composite score capturing intratumoral TLS state composition, which robustly stratifies patients across cancer and treatment contexts, outperforming conventional TLS metrics.
    DOI:  https://doi.org/10.1126/science.adz2742
  14. Nat Cancer. 2026 May 25.
    Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity.
    Alan Y L Wong, Jacob W Myers, Gyan Prakash, Alice Ma, Jeannette R Brook, Boryana Petrova, Baran Bulut, Ralph White, Catherine Merz, Maeve de Souza, Adam G Maynard, Peng Wang, Amy Yu, Nancy K Pohl, Michal Weitman, Lewis B Silverman, Kimberly Stegmaier, L Stirling Churchman, Peter D Cole, Donita C Brady, Naama Kanarek.
      The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.
    DOI:  https://doi.org/10.1038/s43018-026-01177-4
  15. Cell Rep Methods. 2026 May 27. pii: S2667-2375(26)00164-5. [Epub ahead of print] 101464
    Real-time cell viability monitoring for high-throughput drug screening using tumor xenograft-derived cells.
    Elham Esmaeilishirazifard, Daniel Guerrero-Romero, Allan J W Lui, Abigail Shea, Long V Nguyen, Maurizio Callari, Riccardo Masina, Kevin Tu, Richard Baird, Paul Edwards, Wendy Greenwood, Steve Fuller, Claire Crafter, Mandy Lawson, Alejandra Bruna, Oscar M Rueda, Carlos Caldas.
      Patient-derived tumor xenografts (PDTXs) recapitulate the molecular and phenotypic heterogeneity of human cancers, making them valuable pre-clinical models for cancer drug development. However, high-throughput drug screening (HTDS) using ex vivo short-term cultures of PDTX-derived tumor cells (PDTCs) is hindered by endpoint viability assays that provide only static measures of drug response. Here, we establish an optimized a screening platform by validating the RealTime-Glo (RTG) bioluminescent assay for dynamic, real-time measurements of PDTC viability. We further introduce an analytical metric to quantify drug responses independent of cell growth rate. Using this approach, we screened 67 compounds across 43 breast cancer PDTCs and revealed model-specific pharmacodynamic heterogeneity. Our PDTC-based HTDS pipeline improves assay robustness and offers an enhanced platform for leveraging patient-derived xenograft models in precision medicine.
    Keywords:  CP: cancer biology; PDTCs; PDTX-derived tumor cells; PDTXs; breast cancer; drug response kinetics; dynamic viability monitoring; ex vivo drug sensitivity; high-throughput drug screening; isotonic regression modeling; patient-derived tumor xenografts; pharmacodynamic profiling; real-time viability monitoring
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101464
  16. Cell Death Differ. 2026 May 27.
    Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
    Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.
      Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-026-01769-8
  17. Nat Commun. 2026 May 26.
    Small extracellular vesicle signaling and mitochondrial transfer reprogram T helper cell function in human asthma.
    Kenneth P Hough, Jennifer L Trevor, Shaheer Ahmad, Yong Wang, Balu K Chacko, Kayla F Goliwas, John G Strenkowski, Yuelong Liu, Joanna I Nowak, Eugene J Becker, Young-Il Kim, Renita Holmes, Nathaniel B Bone, Shia Vang, Alexandra Pritchard, Jay Chin, Sandeep Bodduluri, Veena B Antony, Sultan Tousif, Mohammad Athar, Diptiman Chanda, Kasturi Mitra, Jaroslaw W Zmijewski, Jianhua Zhang, Steven R Duncan, Victor J Thannickal, Susanne Gabrielsson, Victor M Darley-Usmar, Jessy S Deshane.
      Small extracellular vesicles (sEVs) orchestrate cell-cell communication, but the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. Myeloid-derived regulatory cells (MDRCs) control CD4+ T cell responses in asthma. We demonstrate that airway MDRC-derived sEVs from asthmatics mediate T cell receptor engagement and transfer of mitochondria that induce antigen-specific activation and polarization of Th17 and Th2 cells. sEV-dependent T cell activation and Th polarization were mediated by mitochondrial oxidant-dependent NF-κB signaling, which, when blocked, mitigated CD4+ T cell activation. Mitochondrial fission regulator, DRP-1, promoted mitochondrial packaging within MDRC-sEVs. Internalized sEVs co-localized with the polarized cytoskeleton and mitochondrial networks in recipient T cells. Intranasal transfer of mitochondria packaged sEVs enhanced allergic airway inflammation and Th polarization in a murine asthma model. Our studies indicate a previously unrecognized role for mitochondrial fission and sEV- mitochondria-mediated signaling in dysregulated T cell activation, Th polarization, and pathology in asthma.
    DOI:  https://doi.org/10.1038/s41467-026-73684-y
  18. Cell Death Differ. 2026 May 26.
    Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.
    Markus S Hess, Kamal M Al-Shami, Carolina Dehesa Caballero, Julie Haenlin, Adriano B Chaves-Filho, Lisa Schlicker, Philipp Poeller, Felix C E Vogel, Ioanna Koltsaki, Deniz Gedik, Marta Campos Alonso, Susanne Walz, Carsten P Ade, Martin Eilers, Beate K Straub, Jochen S Utikal, Svenja Meierjohann, Mathias T Rosenfeldt, Marteinn T Snaebjornsson, Almut Schulze.
      Oncogene-induced senescence (OIS), a cellular programme initiated by activation of oncogenic signalling, provides a barrier to transformation and is accompanied by major reprogramming of cellular metabolism. We show here that induction of OIS by BRAFV600E expression in human diploid fibroblasts led to global changes in the cellular lipidome, characterised by a strong increase in triglycerides (TG) and a marked reduction in membrane phosphoglycerides carrying polyunsaturated fatty acids (PUFA) in their acyl-chains. Induction of BRAFV600E OIS resulted in a marked resistance towards lipid peroxidation and ferroptosis. Inhibition of TG synthesis by blocking diacylglycerol O-acyltransferase 1 (DGAT1) resulted in PUFA re-distribution to membrane lipids and increased ferroptosis sensitivity of senescent cells. Inhibition of DGAT also altered the senescence-associated secretory phenotype (SASP) and enhanced the secretion of oxylipins by BRAFV600E OIS cells. Combined blockade of DGAT1-dependent TG and COX2-dependent oxylipin synthesis fully restored ferroptosis sensitivity in BRAFV600E OIS cells. Together, these findings indicate that channelling of PUFA towards TG synthesis confers protection from oxidative stress and ferroptosis during BRAFV600E OIS but also limits the production of pro-inflammatory lipid mediators, a key feature of the senescent phenotype.
    DOI:  https://doi.org/10.1038/s41418-026-01766-x
  19. Cell Rep. 2026 May 28. pii: S2211-1247(26)00468-7. [Epub ahead of print]45(6): 117390
    Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma.
    Khushbu Patel, Begoña Zapateria, Alexander J Ledet, Saba S Hazaveh, Floralba Gjergjova, Antonio Diaz, Simone Sidoli, Amaia Lujambio, Ana María Cuervo, Fernando Macian, Esperanza Arias.
      Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway essential for proteostasis and stress adaptation that declines with aging and metabolic disease, conditions closely linked to hepatocellular carcinoma (HCC). Using genetically engineered mouse models with systemic, hepatocyte-specific, or T cell-specific deletion of the CMA regulator LAMP2A in an MYC-driven, TP53-deficient HCC context, we demonstrate that CMA exerts cell-type-dependent tumor-suppressive functions. Hepatocyte-intrinsic CMA loss promotes early malignant transformation, whereas T cell-specific CMA deficiency impairs early immune-mediated tumor control but is also required to sustain tumor growth. Proteomic profiling identifies the cohesin complex component STAG2 as a putative CMA substrate that accumulates in CMA-dysregulated hepatocytes, a finding validated in human HCC tissues, shown to drive cell cycle dysregulation and proliferation, contributing to hepatocarcinogenesis. These results establish CMA as a dual hepatocyte- and immune-dependent mechanism that suppresses liver tumorigenesis and positions STAG2 as a CMA-controlled node with therapeutic relevance in HCC.
    Keywords:  CP: cancer; CP: immunology; cancer; cell-type specificity; liver disease; lysosomal degradation; malignant transformation; proteostasis; stromal antigen 2; tumor suppression
    DOI:  https://doi.org/10.1016/j.celrep.2026.117390
  20. Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]
    Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
    Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.
      Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.
    Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
  21. NPJ Aging. 2026 May 28.
    Mitochondrial drivers of stem cell aging and inflammaging.
    Jhommara Bautista, Andrés López-Cortés.
      Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.
    DOI:  https://doi.org/10.1038/s41514-026-00422-5
  22. Sci Adv. 2026 May 29. 12(22): eaeb2368
    Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.
    Marian Brenner, Sina Höhlein, Paul Wirth, Leon Neidt, Melina Lappe, Elisa Hopke, Eirini Sfakianaki, Martina Fischer, Kerstin Hadamek, Angelika Keller, Sebastian Bothe, José Pedro Friedmann Angeli, Anna M Schmoker, Arminja N Kettenbach, Agnes Fekete, Werner Schmitz, Ingrid Tessmer, Elisabeth Jeanclos, Antje Gohla.
      Modulating ferroptosis, a form of cell death driven by uncontrolled lipid peroxidation, is of interest in numerous diseases. Here, we found that the deletion of phosphoglycolate phosphatase (PGP), an essential enzyme that safeguards high glycolytic flux, suppresses ferroptosis. Using metabolomic and isotopic labeling experiments together with lipid and proteomic profiling, we find that PGP loss drives a rewiring of the pentose phosphate pathway and of cellular energy and lipid metabolism that triggers a multifactorial antioxidant response. Paradoxically, our attempts to block PGP pharmacologically led to the realization that the recently described PGP inhibitor compound 1 (CP1) exerts a strong ferroptosis-sensitizing effect. Using genetic, biochemical, and biophysical approaches, we characterize CP1 as a direct, species-independent, dual inhibitor of PGP and ferroptosis suppressor protein 1 (FSP1), and further find that CP1 triggers FSP1 self-assembly. In sum, we identify PGP as a target protein for ferroptosis control and introduce a small-molecule FSP1 inhibitor with unique features to the armamentarium of pharmacological ferroptosis modulators.
    DOI:  https://doi.org/10.1126/sciadv.aeb2368
  23. Nat Cell Biol. 2026 May 26.
    Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.
    Arda Mizrak, Jacob Kæstel-Hansen, Jessica Matthias, J Wade Harper, Nikos S Hatzakis, Robert V Farese, Tobias C Walther.
      Numerous metabolic enzymes translocate from the endoplasmic reticulum (ER) membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease. However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here using minimal fluorescence photon fluxes nanoscopy and highly inclined and laminated optical single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4 and the model cargo 'LiveDrop' diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently alter local motion and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.
    DOI:  https://doi.org/10.1038/s41556-026-01963-3
  24. EMBO J. 2026 May 28.
    Disruption of ER-mitochondria contact sites by coronavirus replication organelles sustains viral replication via NSP3 stabilization.
    Xinyue Zheng, Liqiao Hu, Xubing Long, Zhilei Zhao, Rongrong Chen, Rong Bai, Buyun Tian, Maoge Zhou, Binbin Ding, Tao Xu, Zonghong Li.
      Coronaviruses establish infection by reorganizing the host endoplasmic reticulum (ER) to form double-membrane vesicles (DMVs), which function as viral replication platforms. However, the role of other cellular organelles in this process remains incompletely understood. Here, we uncover a self-reinforcing cycle between viral replication organelles and mitochondrial damage that sustains coronavirus replication. We show that DMV formation disrupts ER-mitochondria contact sites (ERMCs), causing mitochondrial damage. This injury initiates a feed-forward mechanism wherein mitochondria release the matrix enzyme ECHS1 into the cytosol. Cytosolic ECHS1 then binds and stabilizes the DMV inducer protein NSP3 by blocking its K963 ubiquitination via the host E3 ligase RBBP6, thereby promoting further DMV formation. Disrupting this cycle, either through enhanced ER-mitochondria tethering or targeted interference with ECHS1-NSP3 binding, effectively suppresses viral replication. Our findings reveal that coronaviruses exploit an inter-organellar feedback loop linking mitochondrial damage to DMV formation, identifying new potential therapeutic targets for inhibition of coronaviral replication.
    DOI:  https://doi.org/10.1038/s44318-026-00816-x
  25. Cell Metab. 2026 May 28. pii: S1550-4131(26)00187-7. [Epub ahead of print]
    Pro-aging effects of chronic glucocorticoid signaling.
    Flavia Lambertucci, Frederic Castinetti, Isabelle Martins, Carlos López-Otín, Guido Kroemer.
      Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.
    Keywords:  Cushing syndrome; corticosteroid; hallmarks of aging; hypercortisolism; multimorbidity; neuroendocrine system
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.002
  26. Nat Chem Biol. 2026 May 27.
    Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription.
    Zhiqiang Hu, Wei Lv, Ting Wen, Junyi Sun, Guimei Ji, Shuo Ru, Xue Sun, Zheng Wang, He Ren, Yudi Zhang, Pengkun Chen, Linlin Zhou, Shiqi Wu, Xiaoqian Jia, Shanshuo Liu, Zheng Zhu, Jiawei Xu, Tong Liu, Yuxiong Feng, Gaopeng Li, Yuan Ding, Yuhao Wang, Yang Luo, Chang Liu, Zhimin Lu, Zhigang Ren, Sheng-Zhong Duan, Daqian Xu.
      Understanding of the metabolic determinants influencing immunotherapy responsiveness remains limited. Here we performed a multiomics analysis of tumor biopsies from patients with hepatocellular carcinoma (HCC) treated with immune checkpoint blockade (ICB) and revealed that heightened expression of OXCT1, a rate-limiting enzyme in ketone body metabolism, was negatively correlated with ICB efficacy, whereas its metabolic substrate, β-hydroxybutyrate (BHB), displayed an opposite effect. Mechanistically, glucose deprivation in HCC cells promotes AMPK-mediated OXCT1 S113 phosphorylation, which exposes the nuclear localization sequence of OXCT1 to trigger its nuclear translocation. Nucleus-translocated OXCT1 associates with IRF1 to locally consume BHB and suppress histone H3K9 BHB at the major histocompatibility complex class I (MHC-I) and chemokine gene loci, leading to repressed transcription of these immune genes. Targeting the AMPK-OXCT1-IRF1 axis sensitizes tumor cells to ICB upon ketogenic diet. These findings reveal a mechanism by which a non-canonical function of nuclear OXCT1 coordinates the interplay between ketone body metabolic reprogramming and immunotherapy responsiveness.
    DOI:  https://doi.org/10.1038/s41589-026-02229-7
  27. Annu Rev Nutr. 2026 May 28.
    Metabolite Damage and Repair in Health and Disease.
    Carole L Linster, Maria Veiga-da-Cunha, Thomas D Niehaus, Guido T Bommer, Emile Van Schaftingen.
      Metabolite repair, or metabolite damage control, has emerged as a fundamental pillar of intermediary metabolism alongside catalysis and regulation. Enzyme promiscuity and spontaneous chemical reactions inevitably generate abnormal metabolites that can interfere with classical metabolic processes. Dedicated metabolite repair enzymes prevent or reverse such damage, thereby preserving metabolic integrity. Defects in these systems define a growing class of inborn errors of metabolism, several of which are now clinically recognized and, in some cases, treatable. We summarize recent advances in the discovery and characterization of metabolite damage and repair systems in the tricarboxylic acid cycle, glycolysis, and other pathways, highlighting examples with established or potential links to human disease. We outline strategies for identifying additional metabolite repair defects and discuss diagnostic challenges, therapeutic perspectives, and connections between metabolite repair and aging. Understanding metabolite repair exposes the mechanisms that safeguard metabolism and opens new paths toward molecular diagnosis and targeted therapy.
    DOI:  https://doi.org/10.1146/annurev-nutr-062024-123639
  28. Cell Death Dis. 2026 May 28.
    CPT1A drives cisplatin resistance via acetylation‑dependent activation of DRP1 and mitochondrial fission in small cell lung cancer.
    Kuanbing Chen, Shi Zong, Kefeng Li, Li Yu.
      Cisplatin resistance represents a major clinical challenge in small-cell lung cancer (SCLC), yet the underlying metabolic adaptations remain poorly understood. Here, we identify a novel regulatory axis centered on the fatty acid oxidation (FAO) enzyme carnitine palmitoyltransferase 1 A (CPT1A) that governs mitochondrial dynamics to drive chemoresistance. In cisplatin-resistant SCLC, CPT1A is markedly upregulated and undergoes functional acetylation. This modified CPT1A not only sustains cellular bioenergetics and redox balance through enhanced FAO but also directly recruits dynamin-related protein 1 (DRP1) to mitochondria. By facilitating DRP1-dependent mitochondrial fission, CPT1A orchestrates a metabolic adaptation that confers a survival advantage. Genetic or pharmacological inhibition of CPT1A reversed this phenotype, impairing mitochondrial fission, depleting energy stores, and resensitizing resistant cells to cisplatin. In vivo, targeting CPT1A markedly suppressed tumor growth and restored cisplatin sensitivity. Our results uncover an acetylated CPT1A-DRP1 axis as a critical metabolic vulnerability in cisplatin-resistant SCLC, providing a compelling therapeutic strategy to overcome treatment failure.
    DOI:  https://doi.org/10.1038/s41419-026-08868-x
  29. MedScience. 2026 May 26.
    Essential genetic mutations impair DNA damage repair and modulate tumor immune microenvironment in ccRCC.
    Hongchao He, Xian-De Liu, Eric Jonasch.
      Targeting DNA repair defects has shown therapeutic benefits in solid tumors with genetic mutations that disrupt DNA damage repair (DDR) pathways. Clear cell renal cell carcinoma (ccRCC) demonstrates an intermediate level of genomic instability, while it rarely carries mutations in these genes. Instead, it is characterized by the loss of chromosome 3p, the von Hippel-Lindau (VHL) tumor suppressor gene inactivation, and secondary mutations in Polybromo-1 (PBRM1), SET domain-containing 2 (SETD2), and BRCA-associated protein 1 (BAP1). Here, we summarize and discuss how these essential mutations impair the DDR, activate the cytosolic DNA sensing pathway, alter the tumor immune microenvironment, and offer promising therapeutic targets.
    Keywords:  DNA damage repair defect; clear cell renal cell carcinoma; tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s11684-025-1136-4
  30. FEBS J. 2026 May 29.
    A multilayered stress-response circuit: The mammalian mitochondrial UPR.
    Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.
      Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.
    Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.1111/febs.70607
  31. bioRxiv. 2026 May 11. pii: 2026.05.06.723011. [Epub ahead of print]
    Compartmentalized glycolysis powers ATP production in primary cilia and engages mitochondria via the phosphoenolpyruvate cycle.
    Shih Ming Huang, Hannah R Foster, Eun Young Lee, Jeong Hun Jo, Xinhang Dong, Byoung-Kyu Cho, Young Ah Goo, Jing W Hughes, Matthew J Merrins.
      Primary cilia are antenna-like sensory and signaling organelles present on most mammalian cells, including glucose-sensing pancreatic β-cells. Here, we show that the local energetic demands of primary cilia require the ATP-producing enzyme pyruvate kinase, with loss of PKm1, but not PKm2, impairing ciliary glycolytic flux. While the entire glycolytic machinery localizes to cilia, our data indicate that mitochondria are a critical source of phosphoenolpyruvate (PEP), the high-energy glycolytic intermediate that drives the pyruvate kinase reaction. Abolishing PCK2, the mitochondrial enzyme that generates PEP, prevents cilia from sensing not only glucose but also the amino acids glutamine and leucine. Finally, by mislocalizing glycolysis, we demonstrate that primary cilia can utilize ATP generated within the cell body when glucose is limiting. These findings indicate that primary cilia, while possessing the capacity for local ATP generation, leverage a ciliary-mitochondrial signaling axis to meet their bioenergetic needs.
    DOI:  https://doi.org/10.64898/2026.05.06.723011
  32. Mol Cell. 2026 May 29. pii: S1097-2765(26)00311-4. [Epub ahead of print]
    A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.
    Marine Berquez, Alexander L Li, Matthew A Luy, Anthony C Venida, Simon McDowall, Thomas O'Loughlin, Gilles Rademaker, Abhilash Barpanda, Jingjie Hu, Julian Yano, Arun P Wiita, Luke A Gilbert, Peter M Bruno, Rushika M Perera.
      Pancreatic ductal adenocarcinoma (PDAC) evades immune surveillance in part through autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I), though the basis for this vulnerability is unclear. Using synchronized endoplasmic reticulum (ER) exit assays, we show that PDAC cells retain MHC-I in the ER and inefficiently traffic it to the plasma membrane. We identify an autophagic capture complex composed of the ER-phagy receptor TEX264 and the cargo receptor NBR1 that targets MHC-I for degradation. Suppression of either receptor restores total and surface MHC-I levels. Capture is linked to antigen loading, as impaired peptide loading increases MHC-I binding to the TEX264-NBR1 complex, while high-affinity peptides reduce binding and promote increased surface localization. A genome-wide CRISPRi screen identified the ER-localized E3 ligase NFXL1 as a mediator of MHC-I ubiquitylation and capture. Elevated NFXL1 correlates with reduced MHC-I expression and poor prognosis, highlighting a targetable pathway regulating PDAC immunogenicity.
    Keywords:  ER-phagy; MHC-I; autophagy; lysosome; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.005
  33. 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
  34. Redox Biol. 2026 May 21. pii: S2213-2317(26)00228-4. [Epub ahead of print]94 104230
    Obesity suppresses neutrophil-dependent itaconate signaling promoting ferroptosis in acute pancreatitis.
    Néstor Jiménez-Cañete, Alicia Aliena-Valero, Caroline A Bressan, Salvador Pérez, Isabel Torres-Cuevas, Laura Benkenstein, Sandra Pinto, Antonio Cuadrado, Juan Sastre, Sergio Rius-Pérez.
      Obesity is a well-established risk factor for increased severity and mortality in acute pancreatitis. However, the mechanisms by which obesity alters pancreatic immune regulation and favors the progression of acute pancreatitis are not elucidated yet. Here, we identify a neutrophil-driven immune-metabolic pathway that controls ferroptosis during pancreatic inflammation. We show that infiltrating myeloid cells represent the principal source of the immunometabolite itaconate during acute pancreatitis. Through paracrine transfer via the SLC13A3 transporter, myeloid-derived itaconate protects pancreatic acinar cells from ferroptosis by sustaining NRF2-dependent antioxidant responses. Obesity disrupts this protective axis by suppressing ACOD1 expression in infiltrating neutrophils. Proteomic profiling of pancreatic neutrophils from obese mice confirmed reduced ACOD1 abundance and decreased expression of enzymes linked to the tricarboxylic acid cycle and pyruvate metabolism. This metabolic reprogramming limits itaconate production and weakens NRF2-driven redox defenses, leading to downregulation of the xCT-GPX4 ferroptosis-protective pathway and increased lipid peroxidation in the pancreas of obese mice with pancreatitis. Pharmacological restoration of itaconate signaling with the cell-permeable derivative 4-octyl itaconate reactivates NRF2 signaling, the xCT-GPX4 antioxidant axis, and the trans-sulfuration pathway, mitigating pancreatic injury. Together, these findings identify neutrophil-derived itaconate as a key modulator of ferroptosis susceptibility and reveal immune cell metabolism as a critical determinant of obesity-associated severity in acute pancreatitis.
    DOI:  https://doi.org/10.1016/j.redox.2026.104230
  35. Science. 2026 May 28. eaeb2672
    A Hormone Cell Atlas maps the human endocrine system at cellular resolution.
    Lijiang Fei, Isabel Huang-Doran, Katherine Lawler, Yizhou Yu, Jan Patrick Pett, Kevin M Méndez-Acevedo, Dinesh Shah, Jaume Margalef-Rieres, Joseph S Pohlman, Batuhan Cakir, Madelyn R Moy, Robert G Legg, Chuan Xu, Ken To, Duy Pham, Alexander V Predeus, Ruth Hanssen, Tessa M Cacciottolo, Rakesh K Kapuge, Krzysztof Polanski, Amanda J Oliver, Sarah A Teichmann, I Sadaf Farooqi.
      Hormones act across tissues and organs to coordinate physiological functions. Drawing inspiration from the Human Cell Atlas, we analyzed expression of 379 hormone and receptor genes in a transcriptomic dataset comprising 14 million single cells and nuclei across 47 human tissues. Using hormone2cell, we mapped putative hormone-producing and hormone-receiving cell types, defining tissue-specific and cross-tissue endocrine signatures. We predicted non-classical sites of hormone expression, including secretin in plasmacytoid dendritic cells, inferred convergent hormone action and endocrine feedback loops, and implicated cell populations in monogenic endocrine disorders. In a cross-tissue integration of adipocyte datasets, we uncovered dynamic endocrine programs across depots, within adipocyte subtypes and through adipogenic differentiation. Cumulatively, the Hormone Cell Atlas (hormonecellatlas.org.uk) provides a comprehensive framework for dissecting hormonal impact on health and disease.
    DOI:  https://doi.org/10.1126/science.aeb2672
  36. Nat Metab. 2026 May 27.
    Neuronal glycogen powers anticipatory brain responses to food.
      
    DOI:  https://doi.org/10.1038/s42255-026-01536-6
  37. J Biol Chem. 2026 May 24. pii: S0021-9258(26)02063-6. [Epub ahead of print] 113191
    Tissue-dependent enzymatic control of N-acetyl-β-alanine by PTER.
    Ruida Li, Sipei Fu, Zhenyu Lyu, Boyuan Wang, Rowan Hassman, John Shuster, Thomas Kizzar, Judith A Simcox, Wei Wei.
      β-alanine is one of the most abundant β-amino acids in mammals and occupies a central position at the intersection of vitamin, dipeptide, and energy metabolism. In addition to dietary intake, β-alanine availability in mammalian tissues is shaped by endogenous biochemical pathways, including pyrimidine catabolism, transamination reactions, and dipeptide turnover, and contributes to the synthesis of carnosine-related dipeptides that support cellular buffering and stress responses. Beyond these established biochemical fates, β-alanine also gives rise to secondary metabolites, including N-acetyl-β-alanine. Although N-acetyl-β-alanine has been associated with metabolic disorders such as obesity and type II diabetes, its enzymatic regulation and physiological relevance have remained unknown. Here we show that the N-acetyltaurine hydrolase PTER (phosphotriesterase-related) also catalyzes the hydrolysis of N-acetyl-β-alanine. In vitro, recombinant PTER converts N-acetyl-β-alanine to free β-alanine at a substantially faster rate than N-acetyltaurine hydrolysis, whereas structurally similar metabolites, including N-acetyl-α-alanine and N-acetyl-γ-aminobutyric acid (N-acetyl-GABA), are not substrates. Genetic ablation of Pter in mice results in a tissue-dependent reduction in N-acetyl-β-alanine hydrolase activity and leads to unexpected tissue-dependent bidirectional dysregulation of N-acetyl-β-alanine levels. Levels of carnosine and other β-alanine pathway metabolites remain unaffected. In contrast, N-acetyltaurine exhibits uniform accumulation across tissues in Pter-deficient mice. Circulating levels of N-acetyl-β-alanine and N-acetyltaurine are regulated in a substrate availability-dependent manner, and pharmacological elevation of N-acetyl-β-alanine suppresses feeding and obesity, although less effectively than N-acetyltaurine in a diet-induced obesity mouse model. Together, these findings demonstrate that PTER exerts tissue-dependent control of N-acetyl-β-alanine abundance, thereby defining a previously unrecognized regulatory node in β-amino acid metabolism.
    Keywords:  acetylation; amino acid; energy metabolism; enzyme; hydrolase; metabolomics; β-alanine
    DOI:  https://doi.org/10.1016/j.jbc.2026.113191
  38. EMBO J. 2026 May 27.
    Mitochondrial NADH-redox inflexibility constrains genomic and epigenetic stability in pluripotent stem cells.
    Tanveer Ahmed, Hui Zhang, Ghulam M Mushraf, Yongzhang Pan, Zeyu Zhang, Zhenzhu Sun, Mengran Yin, Xueting Xu, Xinyu Wu, Yin Gao, Yan Li, Peizhi Li, Liang Ding, Qiang Zhang, Runxia Lin, Khair Ullah, Yinghua Huang, Bushra Mirza, Yifeng Huang, Abdul Sammad, Xiangqian Kong, Dajiang Qin, Miguel A Esteban, Lulu Wang, Baoming Qin.
      The electron transport chain (ETC) is essential for NAD+ regeneration and proliferation. While many cell types tolerate ETC inhibition when pyruvate or aspartate is supplied, pluripotent stem cells (PSCs) enter a reversible paused state even at abundant pyruvate levels. Here, we show that ETC inhibition triggers severe NADH reductive stress in mouse embryonic stem cells (mESCs), driven mainly by threonine dehydrogenase (TDH). TDH-derived NADH establishes a metabolic environment that disfavors cells with compromised mitochondrial function, maintains inhibition of pyruvate dehydrogenase (PDH), and is associated with increased genomic and epigenetic stability at the cellular population level. ETC inhibition similarly induces pausing in early mouse embryos and in human pluripotent stem cells (hPSCs). In hPSCs, combined inhibition of the one-carbon metabolism enzymes serine hydroxymethyltransferase (SHMT1/2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) effectively reduced reductive stress and rescued the paused phenotype. Together, these findings support a model in which limited mitochondrial redox adaptability represents a conserved metabolic feature of pluripotent stem cells and in which NADH reductive stress is associated with genomic and epigenetic stability.
    DOI:  https://doi.org/10.1038/s44318-026-00784-2
  39. Nat Cell Biol. 2026 May 25.
    A kinetics-based model of haematopoiesis reveals extrinsic regulation of skewed lineage output from stem cells.
    Esther Rodríguez-Correa, Florian Grünschläger, Tamar Nizharadze, Natasha Anstee, Jude Al-Sabah, Vojtech Kumpost, Anastasia Sedlmeier, Congxin Li, Melanie Ball, Foteini Fotopoulou, Jeyan Jayarajan, Ian Ghezzi, Julia Knoch, Megan Druce, Kleo Aurich, Marleen Büchler-Schäff, Susanne Lux, Pablo Hernández-Malmierca, Julius Gräsel, Dominik Vonficht, Marta López-Osias, Elvira González-Saiz, Daniel Fernández-Pérez, Anna Mathioudaki, Judith Zaugg, Alejo Rodríguez-Fraticelli, Ralf Mikut, Andreas Trumpp, Thomas Höfer, Daniel Hübschmann, Simon Haas, Michael D Milsom.
      Haematopoietic stem cells (HSCs) display extensive molecular and functional heterogeneity. However, a cohesive model that explains the relationship and biological relevance of these diverse HSC states remains elusive. Here, by performing single-cell transplantations of over 1,000 highly purified murine long-term HSCs combined with in-depth phenotyping of their clonal progeny, we define kinetics-based reconstitution parameters which aligned HSCs into a single hierarchical trajectory reflective of functional potency. This approach revealed that previously identified lineage biases are actually transitory states along this linear trajectory, not a discrete stable condition. Single-cell secondary transplantations validated hierarchical ordering based on reconstitution kinetics, whereas mathematical modelling combined with experimental modulation of lineage-biased blood production revealed that apparent lineage-biased outputs actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to fill mature lineages to their compartment size limit. This study reconciles multiple layers of HSC heterogeneity into a unifying framework.
    DOI:  https://doi.org/10.1038/s41556-026-01958-0
  40. Kidney360. 2026 May 26.
    The Interplay between Gut Microbiota and Diet-Induced Kidney Protection.
    Francisco Lopes, Daniel Martinez-Martinez, Martin R Späth, K Johanna R Hoyer-Allo, Sebastian Strubl, Sadrija Cukoski, Luisa Knieps, Susanne Brodesser, Heike Göbel, Günter Schwarz, Bernard M van den Berg, Ton J Rabelink, Bernhard Schermer, Thomas Benzing, Roman-Ulrich Müller, Andreas Beyer, Filipe Cabreiro, Felix C Koehler.
       BACKGROUND: On the one hand, dietary interventions are known for their pivotal role in regulating diversity, composition as well as function of the gut microbiome. On the other hand, specific diets show an immense potential in preventing kidney injury from various damaging stimuli in rodents and recent findings, in turn, highlight a central role of gut microbiota in kidney health and disease.
    METHODS: Three protective dietary regimens - a fasting mimicking diet, a diet depleted in sulfur containing amino acids and caloric restriction - were examined in parallel in a rodent model of ischemia-reperfusion injury. To delineate the diet-induced effect on gut microbiota in response to ischemic kidney damage we used comparative shotgun metagenomics for taxonomic as well as functional profiling. We further examined the renal metabolic response using comparative transcriptomics to unravel the interplay between gut microbiota and kidney protection.
    RESULTS: Beneficial dietary preconditioning strategies changed the composition of gut microbiota in an IRI-dependent manner. Using ternary plots to investigate the role of dietary interventions over time before and after ischemic insult, we detected a central role of Lachnospiraceae that commonly expanded in response to renal IRI in dietary-preconditioned mice. Further functional profiling of gut microbiota in our model revealed an increase in plasma levels of bacterial derived short chained fatty acids in diet-induced kidney protection. Comparative bulk transcriptomics in our model, in turn, pointed towards the metabolic use of these bacterial derived short-chained fatty acids in kidneys of protected mice.
    CONCLUSIONS: As proximal tubules lack sufficient glycolytic capacity, products of microbial metabolism may serve as an additional energy source to fulfill their high demands when withstanding ischemic damage. Our data shed light on a close interplay between gut microbiota and diet-induced kidney protection calling for further research at the crossroads of microbiology, metabolism and molecular nephrology.
    DOI:  https://doi.org/10.34067/KID.0000001219
  41. Blood. 2026 May 26. pii: blood.2025032136. [Epub ahead of print]
    L-Carnitine Regulates Regeneration of Human Hematopoietic Stem and Progenitor Cells.
    Honglin Duan, Bohong Wang, Yawei Zheng, Yanling Lv, Ting Lu, Haoyuan Li, Pujiao Li, Ruonan Li, Xiaowei Xie, Zining Yang, Guohuan Sun, Xiangnan Zhao, Meng Yang, Yicheng He, Chang Xu, Shuangshuang Pu, Linmin Zhang, Jun Shi, ErLie Jiang, Tao Cheng, Zeping Hu, Hui Cheng.
      Understanding how metabolism governs human hematopoietic stem cells (HSCs) function is essential for advancing regenerative therapies, yet direct metabolic profiling of human HSCs has been limited by their extreme scarcity and the technical limitations of conventional methods. Here, we apply a low-input mass spectrometry-based metabolomics platform, optimized for rare cell populations, to generate metabolic profiles of 13 immunophenotypically defined hematopoietic cell types from adult human bone marrow. Using as few as ~10,000 cells per sample, we detect over 80 metabolites and uncover both conserved metabolic programs in primitive hematopoietic stem and progenitor cells (HSPCs) and lineage-specific metabolic specializations. Notably, we identify L-carnitine-driven fatty acid oxidation (FAO) as a key metabolic feature supporting HSPC function. Mechanistically, L-carnitine activates the PPARA-TFEB signalling axis, promoting mitochondrial metabolism and autophagy to preserve regenerative capacity. Functional assays in primary CD34+ HSPCs derived from healthy donors or patients with aplastic anemia confirm that L-carnitine supplementation improves stem cell function ex vivo and in vivo. Together, this work provides a foundation for human hematopoietic metabolism and reveals a targetable metabolic circuit governing HSPC regenerative fitness with therapeutic potential for improving stem cell-based interventions.
    DOI:  https://doi.org/10.1182/blood.2025032136
  42. Cell Metab. 2026 May 27. pii: S1550-4131(26)00185-3. [Epub ahead of print]
    Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.
    Chesta Jain, Muqit Essani, Roshan Kumar, Nupur K Das, Rashi Singhal, Nicholas J Rossiter, Brandon Chen, Wesley Huang, Zheng Hong Lee, Sumeet Solanki, Yuezhong Zhang, Peter Sajjakulnukit, Li Zhang, Prarthana J Dalal, David A Hanna, Cristina Castillo, Harrison S Greenbaum, Shannon E McCollum, Elena M Stoffel, Joel K Greenson, L James Maher, Costas A Lyssiotis, Ruma Banerjee, Yatrik M Shah.
      Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. Ferroptosis, an iron-dependent form of cell death, is thought to mediate iron toxicity. However, whether most ferroptosis regulators, identified through synthetic chemical screens or small molecule activators, play a role in modulating iron toxicity, particularly in vivo, remains unclear. Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid reactive oxygen species (ROS) as a radical-trapping antioxidant. These findings reveal that CRCs co-opt metabolic cofactors both for growth and for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.
    Keywords:  colorectal cancer; iron toxicity; mitochondrial antioxidant; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.020
  43. Int J Mol Sci. 2026 May 15. pii: 4438. [Epub ahead of print]27(10):
    Circulating Dipeptides in Cancer: Degradation Fragments or Functional Metabolites?
    Kyung-Hee Kim, Byong Chul Yoo.
      Advances in mass spectrometry-based metabolomics have enabled the detection of numerous small molecules in biological systems, revealing complex metabolic alterations associated with cancer. Among these, dipeptides are consistently detected in plasma, serum, and tumor tissue metabolomic profiles, yet their biological significance is not fully understood. In most studies, circulating dipeptides are interpreted as nonspecific byproducts of protein degradation generated during increased proteolysis. However, accumulating evidence suggests that at least some endogenous dipeptides may have biological activities, including antioxidant effects, metabolic modulation, and potential signaling functions. In this review, we examine the possible origins, transport mechanisms, and biological implications of circulating dipeptides in cancer metabolomics. We discuss multiple sources of dipeptide generation, including intracellular proteolysis, autophagy, extracellular matrix remodeling, tumor cell death, host tissue catabolism, and microbiome metabolism. We also summarize current knowledge regarding peptide transport systems and intracellular dipeptide metabolism that may regulate the fate of these molecules within mammalian systems. In addition, evidence supporting the biological activities of certain endogenous dipeptides is reviewed to evaluate the possibility that some circulating dipeptides may function as bioactive metabolites. Finally, we propose conceptual frameworks for interpreting circulating dipeptides in cancer, including their potential roles as indicators of protein turnover, intermediates in amino acid recycling, stress-buffering molecules, metabolic signals, or components of tumor-host metabolic communication. A better understanding of circulating dipeptides may provide new insights into cancer metabolism and reveal previously overlooked metabolite classes with potential biomarker or functional significance.
    Keywords:  bioactive peptides; cancer metabolomics; circulating dipeptides; metabolic communication; peptide metabolism; proteolysis; tumor metabolism
    DOI:  https://doi.org/10.3390/ijms27104438
  44. Commun Biol. 2026 May 27.
    Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
    Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.
    DOI:  https://doi.org/10.1038/s42003-026-10312-x
  45. Biology (Basel). 2026 May 08. pii: 744. [Epub ahead of print]15(10):
    Metabolic Reprogramming of B Cells in Cancer: Effects of Altered Energetics.
    Uday Aditya Sarkar, Naqiya Ambareen, Parash Prasad, Mohd Kamran, Sampurna Ghosh.
      B cells, an important component of adaptive immunity, play a key role in defense against a variety of infections and diseases including cancer. B cells play a dual role in cancer, contributing to both anti-tumor immunity and tumor progression. Metabolic reprogramming in the TME has a profound impact on B cell dynamics, reshaping their energetic landscape, influencing their differentiation and effector cell functions. These alterations arise from the complex interplay between intrinsic metabolic pathways and extrinsic factors, such as nutrient availability, hypoxic conditions, and tumor-derived signals. In the TME, B cells promote glycolysis over oxidative phosphorylation (OXPHOS) to meet the high energy demands of activation and proliferation. However, this metabolic plasticity is also mimicked by tumors, leading to dysfunctional B cell phenotypes, such as regulatory B cells (Bregs), which suppress anti-tumor immunity. Nutrient deprivation and accumulation of metabolic byproducts, including lactate, further impair B cell-mediated immune responses. This review highlights the complex interaction between B cell metabolism and cancer, emphasizing the effects of altered energetics on B cell function and implications on tumor progression and therapy. Decoding the metabolic vulnerabilities of B cells in the tumor niche can uncover novel therapeutic strategies against cancer.
    Keywords:  B cells; TME; metabolic reprogramming
    DOI:  https://doi.org/10.3390/biology15100744
  46. Cell Metab. 2026 May 25. pii: S1550-4131(26)00156-7. [Epub ahead of print]
    Gut microbiota and metabolic control of immune checkpoint blockade in cancer.
    Joseph L Gladstone, Gregory F Sonnenberg.
      The human gastrointestinal tract is colonized by trillions of microbes, collectively termed the gut microbiota, which dynamically shape states of health and disease. This occurs through the modulation of host immunity and through metabolites produced by these microbes, which act both locally and at distal organs. Seminal research has defined that the gut microbiota are essential for successful cancer immunotherapy, with specific microbes and associated metabolites linked to therapeutic outcomes. The mechanisms accounting for this remain preliminary, with additional research implicating diet in shaping the composition and functional potential of the gut microbiota to steer host immunity toward fighting or supporting malignant tumors. The goal of this review is to summarize recent advances in a key communication loop between diet, the gut microbiota, and host immunity as it relates to immune checkpoint blockade in cancer. Further, we discuss gaps in knowledge and future opportunities to harness this knowledge to improve therapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.018
  47. iScience. 2026 Jun 19. 29(6): 115957
    Time-restricted feeding enhances cross-tissue temporal coordination of mitochondrial-associated transcripts.
    Dylan C Sarver, Yaniv Maddahi, Christopher S Colwell, Aldons Jake Lusis.
      Coordinating metabolism with the day-night cycle is essential for health. Circadian rhythms synchronize cellular and tissue functions with the external environment. Nutrient timing is a potent circadian cue that entrains peripheral clocks across organs. Mitochondria exhibit daily rhythms in energy metabolism and redox regulation; however, the temporal organization of mitochondrial-associated transcriptional programs across tissues remains unknown. We hypothesized that time-restricted feeding (TRF) enhances the cross-tissue coordination of mitochondrial-associated transcripts (MATs). Using a 22-tissue, 24-h transcriptomic dataset from mice under ad libitum or TRF conditions, we applied correlation- and phase-based analyses to quantify the intra- and inter-tissue alignment of MAT expression. TRF markedly increased cross-tissue coordination, nearly quadrupling the number of globally aligned MATs. Among these, Coq10b emerged as the most rhythmically aligned gene across organs, highlighting it as a representative marker of coordinated MAT expression. Together, these findings reveal a previously unrecognized temporal organization of mitochondrial-associated gene networks shaped by nutrient timing.
    Keywords:  biological sciences; systems biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115957
  48. Nat Commun. 2026 May 25.
    Dehydration promotes intracellular lipid synthesis and accumulation.
    Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don A Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter K Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.
      Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.
    DOI:  https://doi.org/10.1038/s41467-026-73534-x
  49. Cell Rep. 2026 May 22. pii: S2211-1247(26)00519-X. [Epub ahead of print]45(6): 117441
    IL4i1 activity generates oncometabolites that rescue neuroblastoma cells from oxidative death.
    Camille Guyot, Lee-Ann Van de Velde, Lisa Kainacher, Johanna Ruoff, Ana Bici, Nicolas Bernard Peterson, Patricia P Ogger, E Kaitlynn Allen, Barbara Steigenberger, Assa Yeroslaviz, Jun Yang, Leonie Zeitler, Paul G Thomas, Peter J Murray.
      High-risk neuroblastoma (NB) is driven by the amplification of MYCN in conjunction with additional oncogenic mutations in genes encoding kinases such as ALK. NB cells require antioxidant responses to maintain redox balance and are highly sensitive to ferroptosis. Here, we show that metabolites derived from infiltrating immune cells expressing IL4i1, a secreted oxidoreductase, are potent suppressors of NB ferroptosis. IL4i1 metabolites (indole-3-pyruvate and 4-hydroxyphenylpyruvate) blocked ferroptosis in all human NB cell lines via a mechanism that depended on free radical scavenging and NRF2 activation but did not require the aryl hydrocarbon receptor. Supernatant transfer experiments confirmed that IL4i1 creates a milieu that protects NB cells from oxidative cell death. Importantly, mice lacking IL4i1 were protected from NB in a high-penetrance MYCN and mutant ALK-driven autochthonous cancer model. Therefore, we propose that immune IL4i1 is permissive for NB growth and survival. IL4i1 produces context-dependent oncometabolites and, as a secreted enzyme, represents a target for cell death manipulation in cancers sensitive to oxidative stress-driven cell death.
    Keywords:  AHR; CP: cancer; CP: metabolism; IL4i1; NRF2; amino acids; aromatic keto acids; cell death; ferroptosis; neuroblastoma
    DOI:  https://doi.org/10.1016/j.celrep.2026.117441
  50. Nat Cell Biol. 2026 May 26.
    Epigenetic programming by H3K23ac defines lineage fate of Meg3+ haematopoietic stem cells and drives immune ageing.
    Ni Wei, Huiwen Zhan, Yujun Deng, Min Liu, Yao Xiao, Yanqiu Gong, Xiaodong Wang, Pengbo Guan, Xiaoxian Lou, Yusi Xie, Yuemeng Wang, Zhonghan Li, Lunzhi Dai, Hongbo Hu, Huiyuan Zhang.
      Haematopoietic stem cells (HSCs) produce all blood and immune cells throughout life, but ageing progressively impairs their function, generating excessive myeloid and megakaryocyte cells at the expense of lymphocytes. This lineage imbalance contributes to immune decline, chronic inflammation and increased disease susceptibility in the elderly, yet the underlying mechanisms remain poorly understood. Here we show that a specific Meg3+ HSC subset (CD150hiSca1hiCD24hiCD201+CD9+CD63+ long-term HSCs) expands dramatically during ageing and drives this lineage skewing. Using multi-omics profiling, we found that inflammatory signals increase H3K23ac levels in aged Meg3+ HSCs, enhancing PU.1 activity through recruitment of the reader protein TRIM24. This epigenetic mechanism promotes excessive megakaryocyte and myeloid production. Of note, disrupting H3K23ac-TRIM24 interaction in aged HSCs restored balanced lineage output and reduced inflammatory signals. Our findings reveal a key mechanism linking inflammation to HSC ageing and identify potential therapeutic targets for reversing ageing-related immune decline.
    DOI:  https://doi.org/10.1038/s41556-026-01960-6
  51. Bioinformatics. 2026 May 29. pii: btag330. [Epub ahead of print]
    Genomics-Informed Approach Identifies Which Cell Types Regulate the Metabolome.
    Haim Krupkin, Evin M Padhi, Daniel Nachun, Jessica Kain, Jonathan Z Long, Stephen B Montgomery.
      Metabolism occurs in a cell type-specific manner, but which cells regulate metabolite levels remains unclear. Here, we integrate some of the largest metabolite quantitative trait loci datasets, TOPMed and UK Biobank, with one of the most extensive single-cell RNA sequencing resources, Tabula Sapiens. This integration allows us to identify cell types that regulate metabolites body-wide. We find hepatocytes are the primary regulatory cell type for most metabolites, associating with 385/410 (94%) metabolites for whom an association is found. Additionally, our multi-gene approach reveals more metabolite associations with beta cells compared to those identified using a single-gene approach. For example, we identify novel metabolite-cell type associations, such as the association between phenylpropanoic acid and beta cells, this metabolite that was previously thought to be regulated by the microbiome.
    DOI:  https://doi.org/10.1093/bioinformatics/btag330
  52. Nature. 2026 May 27.
    Human haematopoietic stem cells remember inflammatory stress.
    Andy G X Zeng, Murtaza S Nagree, Niels Asger Jakobsen, Sayyam Shah, Angelica Varesi, Jasmine Ryu Won Kang, Alex Murison, Jin-Gyu Cheong, Sven Turkalj, Xuan Zhang, Felix A Radtke, Tsega-Ab Abera, Isabel N X Lim, Liqing Jin, Joana Araújo, Alicia G Aguilar-Navarro, Darrien Parris, Jessica McLeod, Hyerin Kim, Ho Seok Lee, Lin Zhang, Mason Boulanger, Elyssa Bader, Elias Gbeha, Christopher N Parkhurst, Elvin Wagenblast, Eugenia Flores-Figueroa, Bo Wang, Gregory W Schwartz, Leonard D Shultz, Anna S Nam, H Leighton Grimes, Steven Z Josefowicz, Philip Awadalla, Paresh Vyas, John E Dick, Stephanie Z Xie.
      Inflammation activates blood cells, contributing to ageing and malignancy1-3. Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis1-9, but how human HSCs respond and adapt to inflammatory stress is largely unknown. Here, to empirically understand this adaptation, we developed xenograft inflammation-recovery models and performed single-cell multiomics on xenografted human HSCs. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining a molecular memory of previous inflammatory treatments. The HSC-iM subset exhibited quiescence and restrained haematopoietic output. Molecularly, the HSC-iM program was enriched in HSCs from adult and paediatric samples across conditions ranging from COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. Clonal haematopoiesis mutations in HSC-iM attenuated the effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, transmission of the pro-inflammatory HSC-iM transcriptional program to differentiated immune progeny was demonstrated in xenograft and physiological settings. Finally, HSC-iM program enrichment in circulating blood cells was associated with a heightened risk score for all-cause mortality in population cohort analyses, underscoring the clinical relevance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.
    DOI:  https://doi.org/10.1038/s41586-026-10522-7
  53. Mol Cell. 2026 May 26. pii: S1097-2765(26)00308-4. [Epub ahead of print]
    Uncovering the initial response: Intra-mitochondrial surveillance activates the UPRmt.
    Asli Aras Taskin, Sahana Shankar, Carlotta Peselj, Annette Flotho, Maria Gomez-Fabra Gala, Daniel Poveda-Huertes, Lisa Myketin, Duygu Mutlu, Adinayarana Marada, Sebastian Schuck, Mandy Jeske, Sabrina Büttner, Marcin Luzarowski, Chris Meisinger, F-Nora Vögtle.
      The mitochondrial unfolded protein response (UPRmt) protects mitochondria from proteotoxic stress. Current models induce acute and severe mitochondrial disruption and propose cytosolic detection following the release of mitochondrial damage signals into the cytosol. However, this mode of toxicity contrasts sharply with physiological stress, such as the gradual accumulation of reactive oxygen species (ROS) during aging or chronic respiratory chain defects. Here, we employ a chemogenetic strategy in yeast to induce low levels of hydrogen peroxide (H2O2) in the mitochondrial matrix and show that mild oxidative stress activates the UPRmt independently of cytosolic damage. We identify the presequence proteases MPP and Oct1 as early ROS targets, thereby linking redox imbalance to UPRmt activation: oxidative stress induces glutathionylation of critical cysteines, impairing protease activity and causing the accumulation of unprocessed precursors in proteotoxic matrix aggregates. These aggregates are detected by intra-mitochondrial surveillance, activating UPRmt signaling. Thus, mitochondrial self-surveillance initiates rapid protective signaling as a primary response to mitochondrial dysfunction.
    Keywords:  mitochondria-nucleus communication; mitochondrial protein biogenesis; mitochondrial unfolded protein response; oxidative stress; presequence processing; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.002
  54. bioRxiv. 2026 May 17. pii: 2026.05.15.725497. [Epub ahead of print]
    Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
    Yaw Akosah, Ioannis Azoidis, Dane Jensen, Paolo Bernardi, Evgeny Pavlov.
      Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and cristae dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the sub-organellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K + ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K + influx leads to increase of mitochondrial matrix volume while stimulation of K + efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.
    DOI:  https://doi.org/10.64898/2026.05.15.725497
  55. Nat Commun. 2026 May 25.
    MiTo: tracing the phenotypic evolution of somatic cell lineages via mitochondrial single-cell multi-omics.
    Andrea Cossa, Alberto Dalmasso, Guido Campani, Elisa Bugani, Chiara Caprioli, Noemi Bulla, Andrea Tirelli, Yinxiu Zhan, Pier Giuseppe Pelicci.
      Mitochondrial single-cell lineage tracing has recently emerged as a scalable and non-invasive tool to trace somatic cell lineages. However, the reliability and resolution of this technology remains highly debated. Here, we present MiTo, a novel end-to-end framework for robust mitochondrial single-cell lineage tracing data analysis. Benchmarked against real-world datasets, MiTo outperforms state-of-the-art methods and baselines in data pre-processing and clonal inference. Applied to a time-resolved dataset of breast cancer evolution (>2,500 cells), MiTo accurately infers ground-truth cell lineages (ARI = 0.94) and cell state transitions, detects clonal fitness markers, and quantifies heritability of gene regulatory networks. Comparing alternative lineage markers, MiTo quantifies the resolution limit of existing mitochondrial single-cell lineage tracing systems, which currently enable reliable inference of coarse-grained cellular ancestries, but not high-resolution phylogenetic inference. In conclusion, this work provides robust tools and practical guidelines to dissect somatic evolution with single-cell multi-omics.
    DOI:  https://doi.org/10.1038/s41467-026-71607-5
  56. bioRxiv. 2026 May 14. pii: 2026.05.13.723926. [Epub ahead of print]
    Reduction in Hepatic Phosphatidylcholine Biosynthesis Promotes MASH Through Copper Deficiency.
    Jaclyn E Welles, James P Garifallou, Michael V Gonzalez, Dominic Santoleri, Feroza K Choudhury, Gina M DeNicola, Ryan W Martin, Chang Jiang, Jaehee Kim, Gen Li, Yuichi Aki, Christopher J Chang, David Li, Rebecca G Wells, Yang Xiao, Jiayu Zhang, Mitchell A Lazar, Donita C Brady, Paul M Titchenell.
      Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease for which the mechanisms linking lipid dysregulation to fibrosis remain poorly defined. Hepatic phosphatidylcholine (PC) content is reduced in MASH, but how this alteration drives disease progression is unclear. Here, we identify a role for copper (Cu) homeostasis as a downstream effector of impaired PC biosynthesis. Using single-nucleus RNA sequencing in complementary genetic and dietary mouse models, we found that reduced hepatic PC is associated with marked depletion of hepatic Cu and a concomitant increase in circulating Cu, indicating disrupted Cu distribution. Mechanistically, PC depletion impaired plasma membrane localization of the high-affinity Cu transporter CTR1 ( SLC31A1 ) in hepatocytes, limiting Cu uptake. In human hepatic stellate cells, Cu promoted fibrogenic activation, whereas suppression of Cu import or pharmacologic inhibition of MAPK signaling attenuated fibronectin deposition. In vivo , liver-directed Cu supplementation restored hepatic Cu levels and reduced steatosis but failed to improve fibrosis. In contrast, pharmacologic Cu chelation with bathocuproinedisulfonic acid (BCS) reduced fibrosis without affecting inflammation. Together, these findings identify Cu redistribution as a consequence of impaired PC biosynthesis and implicate Cu-dependent signaling in stellate cell activation, fibrogenesis and MASH pathogenesis.
    DOI:  https://doi.org/10.64898/2026.05.13.723926
  57. Int J Mol Sci. 2026 May 14. pii: 4387. [Epub ahead of print]27(10):
    A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
    Yung Wu, Hongyun Tang.
      Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPRmt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPRmt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPRmt.
    Keywords:  Caenorhabditis elegans; GLDI-8; electron transport chain dysfunction; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27104387
  58. Nature. 2026 May 27.
    Gene clock predicts time to death in humans - and assesses 'biological' age.
    Heidi Ledford.
      
    Keywords:  Ageing; Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01661-y
  59. Nat Commun. 2026 May 27.
    Very low-carbohydrate ketogenic diet in treatment-naïve women with endometrial cancer and overweight: a randomized feasibility study.
    Ezequiel Dantas, Katie C Hootman, Jenna Moyer, Morgan Tomberlin, Katherine Curran, Bhavani Ramesh, Hannah Price, Jeshua Kim, Alex C McPherson, Maurice A Hurd, Yuan-Shan Zhu, Andrew J Plodkowski, Erica Nagase, Anastasia Tsomides, Brandon M Cuevas, M Laura Martin, John Nguyen, Gabrielle Bennetti, Gissell Botero Rodriguez, Kaity Chang, Marissa Mezzancello, Ginger J Gardner, Vance Broach, Jennifer J Mueller, Yukio Sonoda, Oliver Zivanovic, Mario M Leitao, Alexia Iasonos, Krysten Soldan, Karen Carthew, Vania Hom, Francis N Villamater, Rema Rao Chaari, Kathryn Gorski, Michael Sigouros, Carol Aghajanian, Olivier Elemento, Lewis C Cantley, Benjamin D Hopkins, Britta Weigelt, Lora H Ellenson, Kari Hacker, Nadeem R Abu-Rustum, Vicky Makker, Marcus D Goncalves.
      This multicenter, prospective, randomized controlled trial (NCT03285152) evaluates the primary endpoint of feasibility of a very-low carbohydrate diet (VLCD) in 19 women with obesity/overweight and endometrial cancer, who are randomized 2:1 to either a VLCD or a standard diet for 21-28 days. Fifteen participants complete the study, with 91 ± 4% of VLCD meals consumed, 5.5 ± 0.8% weight lost, and no grade 3/4 adverse events. Secondary endpoints include assessments of tumor biology and circulating metabolic biomarkers. Fasting glucose and insulin fall 22 ± 5.9% and 60 ± 3.8%, while total cholesterol and low-density lipoprotein (LDL) rise 6 ± 2.7% and 17.8 ± 8.9%. In a pre-specified exploratory outcome, RNA-Seq shows enrichment of CD8 + T-cells (q < 0.034; NES > 1.75), confirmed by immunohistochemistry (IHC) showing CD8 + T-cells infiltration of the tumor margins (q = 0.034; NES = 1.75). We conclude that VLCD is feasible and well-tolerated.
    DOI:  https://doi.org/10.1038/s41467-026-73519-w
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