bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–09–14
fifty-two papers selected by
Christian Frezza, Universität zu Köln
  1. An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
  2. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  3. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  4. Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
  5. Functional synapses between neurons and small cell lung cancer.
  6. DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.
  7. CD160+CD8+ T cells for improved immunotherapy.
  8. Chemotherapy modulation by a cancer-associated microbiota metabolite.
  9. Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.
  10. Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.
  11. SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
  12. Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.
  13. Nutritional advice on social media: clicks over credibility.
  14. Lipid droplets: Open questions and conceptual advances around a unique organelle.
  15. Next-gen tools in cancer neuroscience.
  16. Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
  17. HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
  18. The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level.
  19. Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.
  20. TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
  21. Fluctuating DNA methylation tracks cancer evolution at clinical scale.
  22. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  23. Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma.
  24. Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
  25. Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
  26. ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
  27. Brief but not bland.
  28. Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins.
  29. CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
  30. Are we getting closer to understanding why we age?
  31. Metabolic control of innate-like T cells.
  32. Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
  33. Mending a mother's mitochondrial DNA.
  34. Defining breast epithelial cell types in the single-cell era.
  35. Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.
  36. Imaging mass cytometry dataset of small-cell lung cancer tumors and tumor microenvironments.
  37. Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
  38. Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
  39. Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.
  40. The citrullinating enzyme PADI4 governs progenitor cell proliferation and translation in developing hair follicles.
  41. BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.
  42. Redox-dependent pathways in the pro-thermogenic effects of cysteine restriction.
  43. Glucose restriction: double edged sword in cancer treatment.
  44. Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1.
  45. Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
  46. Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis.
  47. Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
  48. Single-cell analysis of Barrett's esophagus and carcinoma reveals cell types conferring risk via genetic predisposition.
  49. Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  50. Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion.
  51. Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
  52. Comparative analysis of the effects of PSPH and PHGDH inhibitors on tumor cell proliferation.
  1. Nat Metab. 2025 Sep 08.
    An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Rachel 'Rae' J House, Althea Waldhart, Kelly H Sokol, Samuel R Daniels, Cameron J Lee, Joseph Longo, Amy Johnson, Vincent J Sartori, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53-/- pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1038/s42255-025-01366-y
  2. Nat Metab. 2025 Sep 10.
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Mack B Reynolds, Emeline Joulia, Maureen L Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1038/s42255-025-01363-1
  3. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  4. Sci Adv. 2025 Sep 12. 11(37): eadt3873
    Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.
    Kelly McCastlain, Catherine Welsh, Yonghui Ni, Liang Ding, Ti-Cheng Chang, Robert J Autry, Besian I Sejdiu, Qingfei Pan, Melissa Franco, Wenan Chen, Huiyun Wu, Veronica Gonzalez-Pena, Patrick Schreiner, Sasi Arunachalam, Joung Hyuck Joo, Samuel Brady, Jinghui Zhang, Charles Gawad, William E Evans, M Madan Babu, Konstantin Khrapko, Jiyang Yu, Gang Wu, Stanley Pounds, Mondira Kundu.
      Somatic mitochondrial DNA (mtDNA) mutations are frequently observed in tumors, yet their role in pediatric cancers remains poorly understood. The heteroplasmic nature of mtDNA-where mutant and wild-type mtDNA coexist-complicates efforts to define its contribution to disease progression. In this study, bulk whole-genome sequencing of 637 matched tumor-normal samples from the Pediatric Cancer Genome Project revealed an enrichment of functionally impactful mtDNA variants in specific pediatric leukemia subtypes. Collectively, the results from single-cell sequencing of five diagnostic leukemia samples demonstrated that somatic mtDNA mutations can arise early in leukemogenesis and undergo positive selection during disease progression, achieving intermediate heteroplasmy-a "sweet spot" that balances mitochondrial dysfunction with cellular fitness. Network-based systems biology analyses link specific heteroplasmic mtDNA mutations to metabolic reprogramming and therapy resistance. We reveal somatic mtDNA mutations as a potential source of functional heterogeneity and cellular diversity among leukemic cells, influencing their fitness and shaping disease progression.
    DOI:  https://doi.org/10.1126/sciadv.adt3873
  5. Nature. 2025 Sep 10.
    Functional synapses between neurons and small cell lung cancer.
    Vignesh Sakthivelu, Anna Schmitt, Franka Odenthal, Kristiano Ndoci, Marian Touet, Ali H Shaib, Abdulla Chihab, Gulzar A Wani, Pascal Nieper, Griffin G Hartmann, Isabel Pintelon, Ilmars Kisis, Maike Boecker, Naja M Eckert, Manoela Ianicelli Caiaffa, Olta Ibruli, Julia Weber, Roman Maresch, Christina M Bebber, Ali Chitsaz, Anna Lütz, Mira Kim Alves Carpinteiro, Kaylee M Morris, Camilla A Franchino, Jonas Benz, Laura Pérez-Revuelta, Jorge A Soriano-Campos, Maxim A Huetzen, Jonas Goergens, Milica Jevtic, Hannah M Jahn-Kelleter, Hans Zempel, Aleksandra Placzek, Alexandru A Hennrich, Karl-Klaus Conzelmann, Hannah L Tumbrink, Pascal Hunold, Joerg Isensee, Lisa Werr, Felix Gaedke, Astrid Schauss, Marielle Minère, Marie Müller, Henning Fenselau, Yin Liu, Alena Heimsoeth, Gülce S Gülcüler Balta, Henning Walczak, Christian Frezza, Ron D Jachimowicz, Julie George, Marcel Schmiel, Johannes Brägelmann, Tim Hucho, Silvia von Karstedt, Martin Peifer, Alessandro Annibaldi, Robert Hänsel-Hertsch, Thorsten Persigehl, Holger Grüll, Martin L Sos, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Julien Sage, Inge Brouns, Roland Rad, Roman K Thomas, Max Anstötz, Silvio O Rizzoli, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia.
      Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1-3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41586-025-09434-9
  6. Nat Genet. 2025 Sep;57(9): 2226-2237
    DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.
    TRACERx Consortium
      Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.
    DOI:  https://doi.org/10.1038/s41588-025-02307-x
  7. Nat Cell Biol. 2025 Sep;27(9): 1389-1390
    CD160+CD8+ T cells for improved immunotherapy.
    Yi-Hao Wang, Stanislav Dergun, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41556-025-01756-0
  8. Cell Syst. 2025 Sep 03. pii: S2405-4712(25)00230-3. [Epub ahead of print] 101397
    Chemotherapy modulation by a cancer-associated microbiota metabolite.
    Daniel Martinez-Martinez, Tanara V Peres, Kristin Gehling, Leonor Quintaneiro, Cecilia Cabrera, Maksym Cherevatenko, Stephen J Cutty, Lena Best, Georgios Marinos, Johannes Zimmerman, Ayesha Safoor, Despoina Chrysostomou, Joao B Mokochinski, Alex Montoya, Susanne Brodesser, Michalina Zatorska, Timothy Scott, Ivan Andrew, Holger Kramer, Masuma Begum, Bian Zhang, Bernard T Golding, Julian R Marchesi, Susumu Hirabayashi, Christoph Kaleta, Alexis R Barr, Christian Frezza, Helena M Cochemé, Filipe Cabreiro.
      Understanding how the microbiota produces regulatory metabolites is of significance for cancer and cancer therapy. Using a host-microbe-drug-nutrient 4-way screening approach, we evaluated the role of nutrition at the molecular level in the context of 5-fluorouracil toxicity. Notably, our screens identified the metabolite 2-methylisocitrate, which was found to be produced and enriched in human tumor-associated microbiota. 2-methylisocitrate exhibits anti-proliferative properties across genetically and tissue-diverse cancer cell lines, three-dimensional (3D) spheroids, and an in vivo Drosophila gut tumor model, where it reduced tumor dissemination and increased survival. Chemical landscape interaction screens identified drug-metabolite signatures and highlighted the synergy between 5-fluorouracil and 2-methylisocitrate. Multi-omic analyses revealed that 2-methylisocitrate acts via multiple cellular pathways linking metabolism and DNA damage to regulate chemotherapy. Finally, we converted 2-methylisocitrate into its trimethyl ester, thereby enhancing its potency. This work highlights the great impact of microbiome-derived metabolites on tumor proliferation and their potential as promising co-adjuvants for cancer treatment.
    Keywords:  cancer metabolism; cancer-associated microbiota; chemotherapy; host-microbe interactions; methylcitrate cycle; microbial metabolism
    DOI:  https://doi.org/10.1016/j.cels.2025.101397
  9. Cancer Discov. 2025 Sep 08. OF1-OF18
    Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.
    Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E Weeden, Donald M Bell, Eric Joo, Vittorio Barbè, Matthew G Jones, King L Hung, Emma L Nye, Mary Green, Lucy Meader, Emma J Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal-Hanjani, Thomas Santarius, Andrea Ventura, James A R Nicoll, Delphine Boche, Howard Y Chang, Vineet Bafna, Weini Huang, Paul S Mischel, Charles Swanton, Benjamin Werner.
      Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.
    SIGNIFICANCE: We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1555
  10. J Clin Invest. 2025 Sep 09. pii: e186258. [Epub ahead of print]
    Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9.
    Rui Guo, Yizhe Sun, Matthew Y Lim, Hardik Shah, Joao A Paulo, Rahaman A Ahmed, Weixing Li, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicholas A Smith, Meng Li, Merrin Man Long Leong, Michael Lutchenkov, Jin-Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael R Green, John M Asara, Adonia E Papathanassiu, Duane R Wesemann, Steven P Gygi, Vamsi K Mootha, Benjamin E Gewurz.
      B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states highly induced the transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mechanistic target of rapamycin complex 1 (mTORC1) activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes and identify BCAT1 as an activated B-cell therapeutic target.
    Keywords:  Adaptive immunity; Amino acid metabolism; Cell biology; Lymphomas; Metabolism
    DOI:  https://doi.org/10.1172/JCI186258
  11. Aging Cell. 2025 Sep;24(9): e70162
    SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
    Marine Barthez, Zehan Song, Yufan Feng, Yifei Wang, Chih-Ling Wang, Danica Chen.
      Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD+-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD+ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD+ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.
    DOI:  https://doi.org/10.1111/acel.70162
  12. Mol Metab. 2025 Sep 10. pii: S2212-8778(25)00155-3. [Epub ahead of print] 102248
    Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.
    Michaela E Trautman, Cara L Green, Michael R MacArthur, Krittisak Chaiyakul, Yasmine H Alam, Chung-Yang Yeh, Reji Babygirija, Isabella James, Michael Gilpin, Esther Zelenovskiy, Madelyn Green, Ryan N Marshall, Alexander Raskin, Michelle M Sonsalla, Victoria Flores, Judith A Simcox, Irene M Ong, Kristen C Malecki, Cholsoon Jang, Dudley W Lamming.
      The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.
    Keywords:  Branched-chain amino acids; Isoleucine; adiposity; insulin resistance; metabolic health; western diet
    DOI:  https://doi.org/10.1016/j.molmet.2025.102248
  13. Nat Metab. 2025 Sep 12.
    Nutritional advice on social media: clicks over credibility.
      
    DOI:  https://doi.org/10.1038/s42255-025-01385-9
  14. J Cell Biol. 2025 Oct 06. pii: e202406019. [Epub ahead of print]224(10):
    Lipid droplets: Open questions and conceptual advances around a unique organelle.
    W Mike Henne, Emma Reynolds, William A Prinz.
      Once viewed as mere lipid inclusions, the past four decades have witnessed an explosion of research into lipid droplet (LD) biogenesis and function. Pioneering cell biology, biochemical, genetics, and lipidomic studies now reveal LDs as active players in lipid metabolism and cellular homeostasis. Here, we discuss some of the major findings that defined LDs as bona fide organelles. However, despite what is known, much needs to be discovered. We highlight five enduring questions that continue to challenge the LD field and discuss a few misconceptions about this remarkable organelle.
    DOI:  https://doi.org/10.1083/jcb.202406019
  15. Cell Rep. 2025 Sep 10. pii: S2211-1247(25)01029-0. [Epub ahead of print]44(9): 116258
    Next-gen tools in cancer neuroscience.
    Vera Thiel, Debpali Sur, Caroline C Picoli, Tamara McErlain, Katalina Couto, David J Simon, Yuan Pan, Karen Olivia Dixon, Rajan P Kulkarni, Sebastien Talbot, Alexander Birbrair.
      The emerging field of cancer neuroscience is rapidly evolving, driven by novel technologies and tools. These include advances in single-cell and spatial transcriptomics; genetic mouse models paired with automated high-throughput; and innovative optical electrophysiological approaches, optogenetics, chemogenetics, engineered viruses, and new methods for visualizing neuronal activity. Collectively, these technologies are revolutionizing how we investigate, manipulate, and characterize distinct components that contribute to the nervous system-cancer interface. In the present review, we discuss the key technologies that are closing the gap between oncology and neuroscience, highlighting the innovations that are propelling the cancer neuroscience field forward.
    Keywords:  CP: Cancer; CP: Neuroscience; cancer neuroscience; chemogenetics; imaging; optogenetics; transcriptomics; viral vectors
    DOI:  https://doi.org/10.1016/j.celrep.2025.116258
  16. J Biol Chem. 2025 Sep 08. pii: S0021-9258(25)02545-1. [Epub ahead of print] 110693
    Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
    Oliver J Newsom, Eric Zheng, Lucas B Sullivan.
      Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110693
  17. Cell. 2025 Sep 02. pii: S0092-8674(25)00929-8. [Epub ahead of print]
    HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
    Jeany Delafiori, Mohammed Shahraz, Andreas Eisenbarth, Volker Hilsenstein, Bernhard Drotleff, Alberto Bailoni, Bishoy Wadie, Måns Ekelöf, Alexander Mattausch, Theodore Alexandrov.
      Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses. Profiling HeLa and NIH3T3 cells, we detected 73 small-molecule metabolites validated by bulk liquid chromatography tandem MS (LC-MS/MS), achieving high reproducibility and single-cell resolution. Interrogating nine NCI-60 cancer cell lines and HeLa, we identified cell-type markers in subpopulations and metabolic hubs. Upon inhibiting glycolysis in HeLa cells, we observed emerging glucose-centered metabolic coordination and intra-condition heterogeneity. Overall, we demonstrate how HT SpaceM enables robust, large-scale SCM across over 140,000 cells from 132 samples and provide guidance on how to interpret metabolic insights beyond population averages.
    Keywords:  LC-MS/MS; MALDI-imaging mass spectrometry; NCI-60; SpaceM; co-abundance; heterogeneity; high-throughput; reproducibility; single-cell metabolomics; small-molecule metabolites
    DOI:  https://doi.org/10.1016/j.cell.2025.08.015
  18. Cell Rep. 2025 Sep 10. pii: S2211-1247(25)01020-4. [Epub ahead of print]44(9): 116249
    The hexosamine biosynthetic pathway drives tumor immune evasion via translational control of PD-L1 at the elongation level.
    Bo Liu, Yingying Wu, Anyi Xiang, Yiyi Yu, Shushu Song, Ying Zhang, Jianxin Gu, Haojie Lu, Ping Xu, Fenglin Liu, Yuanyuan Ruan.
      Cancer cells reprogram cellular energetics to drive tumorigenesis and escape immunosurveillance. Nevertheless, how this is molecularly connected remains largely undefined. The hexosamine biosynthetic pathway (HBP) serves as a critical metabolic node in cancer cells that provides the basis for protein glycosylation. Herein, we show that HBP flux inhibition by knocking out its rate-limiting enzyme GFAT1 suppressed tumor growth and stimulated cytotoxic CD8+ T lymphocyte infiltration in a colorectal cancer model. GFAT1 induced the expression of the immune checkpoint PD-L1 at the translational level by bypassing signal peptide-mediated translation elongation arrest. Proteomic and glycoproteomic screening indicated that GFAT1 facilitated the N-linked glycosylation and protein expression of integrin α2/α3 subunits, leading to FAK activation and elongation factor eEF1A2 upregulation. Pharmacological inhibition of HBP noticeably enhanced the efficacy of immune checkpoint blockade in vivo. Together, these findings unravel how immune checkpoint proteins are manipulated by metabolic dysregulation, which can be exploited as metabolic vulnerability for improving immunotherapies.
    Keywords:  CP: Cancer; PD-L1; glycosylation; hexosamine biosynthetic pathway; immune evasion; protein synthesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116249
  19. Nat Cell Biol. 2025 Sep;27(9): 1543-1554
    Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.
    Taslim A Al-Hilal, Maria-Anna Chrysovergi, Paula E Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K Probst, Vladimir Vrbanac, Tejaswini S Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R Yates, Kaveh Daneshvar, Allan C Mullen, David Ting, Eric S White, Raghu Kalluri, Christina M Woo, Ellen Puré, Wolfgang H Goldmann, Jose Luis Alonso, Andrew M Tager, Adam J Engler, Daniel J Tschumperlin, David Lagares.
      Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)-paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FATL994E knock-in mouse, which disrupts FAK-paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK-paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01697-8
  20. J Biomed Sci. 2025 Sep 10. 32(1): 87
    TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
    Shukla Sarkar, Chien-I Chang, Jussekia Jean, Meng-Ju Wu.
      Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.
    Keywords:  2-hydroxyglutarate; Epigenetic regulation; Fumarate; Itaconate; Metabolic reprogramming; Oncometabolites; Succinate; TCA cycle; Tumor immunity; α-ketoglutarate
    DOI:  https://doi.org/10.1186/s12929-025-01186-y
  21. Nature. 2025 Sep 10.
    Fluctuating DNA methylation tracks cancer evolution at clinical scale.
    Calum Gabbutt, Martí Duran-Ferrer, Heather E Grant, Diego Mallo, Ferran Nadeu, Jacob Househam, Neus Villamor, Madlen Müller, Simon Heath, Emanuele Raineri, Olga Krali, Jessica Nordlund, Thorsten Zenz, Ivo G Gut, Elias Campo, Armando Lopez-Guillermo, Jude Fitzgibbon, Chris P Barnes, Darryl Shibata, José I Martin-Subero, Trevor A Graham.
      Cancer development and response to treatment are evolutionary processes1,2, but characterizing evolutionary dynamics at a clinically meaningful scale has remained challenging3. Here we develop a new methodology called EVOFLUx, based on natural DNA methylation barcodes fluctuating over time4, that quantitatively infers evolutionary dynamics using only a bulk tumour methylation profile as input. We apply EVOFLUx to 1,976 well-characterized lymphoid cancer samples spanning a broad spectrum of diseases and show that initial tumour growth rate, malignancy age and epimutation rates vary by orders of magnitude across disease types. We measure that subclonal selection occurs only infrequently within bulk samples and detect occasional examples of multiple independent primary tumours. Clinically, we observe faster initial tumour growth in more aggressive disease subtypes, and that evolutionary histories are strong independent prognostic factors in two series of chronic lymphocytic leukaemia. Using EVOFLUx for phylogenetic analyses of aggressive Richter-transformed chronic lymphocytic leukaemia samples detected that the seed of the transformed clone existed decades before presentation. Orthogonal verification of EVOFLUx inferences is provided using additional genetic data, including long-read nanopore sequencing, and clinical variables. Collectively, we show how widely available, low-cost bulk DNA methylation data precisely measure cancer evolutionary dynamics, and provides new insights into cancer biology and clinical behaviour.
    DOI:  https://doi.org/10.1038/s41586-025-09374-4
  22. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  23. Oncogene. 2025 Sep 06.
    Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma.
    Samer Salem, Tiegang Han, Michel Alchoueiry, Nadine Mahmoud, Wafaa Bzeih, Joelle Chami, Damir Khabibullin, Hadi Mansour, Yan Tang, Thai H Ho, Jessalyn M Ubellacker, Carmen Priolo, Elizabeth P Henske.
      There are no proven therapies for metastatic or unresectable Chromophobe Renal Cell Carcinoma (ChRCC). ChRCC is characterized by high glutathione levels and hypersensitivity to ferroptosis, an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. The underlying mechanisms leading to ferroptosis hypersensitivity are unknown. Ferroptosis suppressor protein (FSP1) is a glutathione-independent suppressor of ferroptosis whose role in ChRCC is unexplored. In The Cancer Genomic Atlas (TCGA), we find that ChRCC exhibits the second highest upregulation of FSP1 relative to healthy organ out of all cancers, and that higher FSP1 expression correlates with poorer patient outcomes. We also define a ferroptosis signature combining FSP1 and Solute Carrier Family 7 Member 11 (SLC7A11) that predicts patient survival across all TCGA tumor types. Data queried from the Dependency Map and the Cancer Target Discovery and Development indicate that high FSP1 expression correlates with resistance to cell death induced by disruption of glutathione homeostasis via inhibition of glutathione peroxidase 4 (GPX4) or SLC7A11. Studies using ChRCC cell lines in vitro reveal that genetic inhibition of GPX4 or FSP1 individually does not induce substantial cell death, while inhibition of both results in near-complete loss of viability. Consistent with these genetic data, combining pharmacologic inhibition of GPX4 or SLC7A11 with inhibition of FSP1 demonstrates synergistic loss of viability. Strikingly, inhibition of FSP1 alone in vivo is sufficient to decrease ChRCC tumor growth by 69%, consistent with recent studies in lung and colorectal cancer showing similar effects. Taken together, these data establish FSP1 as targetable vulnerability in ChRCC.
    DOI:  https://doi.org/10.1038/s41388-025-03562-2
  24. Redox Biol. 2025 Sep 04. pii: S2213-2317(25)00372-6. [Epub ahead of print]86 103859
    Mitochondrial membrane potential and compartmentalized signaling: Calcium, ROS, and beyond.
    Nada Ahmed Selim, Andrew P Wojtovich.
      Mitochondria are central to cellular function, acting as metabolic hubs that regulate energy transduction to communicate cellular status. A key component of this energetic regulation is the mitochondrial membrane potential (MMP), a charge separation across the inner mitochondrial membrane generated by the electron transport chain. Beyond MMP's canonical role in driving ATP synthesis, MMP acts as a dynamic signaling hub. MMP rapidly adjusts to acute changes in cellular energy demand and undergoes sustained modifications during developmental processes, such as neuronal remodeling. Changes in MMP influence reactive oxygen species (ROS) production, calcium handling, and mitochondrial quality control, enabling localized and time-sensitive regulation of cellular function. In neurons, changes in MMP coordinate synaptic plasticity by linking metabolic state to structural changes at synapses. This review highlights the non-canonical roles of MMP in signal integration, spatial organization, and stress adaptation, providing a broader framework for understanding mitochondrial contributions to health and disease.
    Keywords:  Bioenergetics; Metabolic specialization; Mitochondria; Mitophagy; Neuron plasticity
    DOI:  https://doi.org/10.1016/j.redox.2025.103859
  25. Immunity. 2025 Sep 03. pii: S1074-7613(25)00371-1. [Epub ahead of print]
    Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer.
    Dayana B Rivadeneira, Sanjana Thosar, Kevin Quann, William G Gunn, Victoria G Dean, Bingxian Xie, Angelina Parise, Andrew C McGovern, Kellie Spahr, Konstantinos Lontos, Ryan P Barnes, Marcel P Bruchez, Patricia L Opresko, Greg M Delgoffe.
      The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.
    Keywords:  DNA damage; ROS; T cell dysfunction; adoptive cell therapy; mitochondria; telomere; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2025.08.008
  26. Cell Rep. 2025 Sep 05. pii: S2211-1247(25)01001-0. [Epub ahead of print]44(9): 116230
    ADSL deficiency is a secondary mitochondrial disease affecting organelle homeostasis and ERK2/AKT signaling in a linear genotype-phenotype relation.
    Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi.
      Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.
    Keywords:  ADSL; CP: Metabolism; ERK; mitochondria; purine metabolism; rare genetic disease
    DOI:  https://doi.org/10.1016/j.celrep.2025.116230
  27. EMBO Rep. 2025 Sep 08.
    Brief but not bland.
    Howy Jacobs.
      
    DOI:  https://doi.org/10.1038/s44319-025-00570-x
  28. FEBS J. 2025 Sep 12.
    Activator of apoptosis harakiri (HRK) localisation at mitochondria alters mitochondrial morphology independently of other BCL-2 proteins.
    Louise E King, Lukas Faber, Ana J García-Sáez.
      The activator of apoptosis harakiri (HRK) is a pro-apoptotic BCL-2 homology 3 (BH3)-only protein of the apoptosis regulator Bcl-2 (BCL-2) family that is mainly expressed in neuronal and haematopoietic tissues. How specific HRK protein domains contribute to its pro-apoptotic function, and what other non-apoptotic roles HRK performs within cells, remain poorly understood. Here, we evaluated the apoptosis sensitivity, and mitochondrial shape and function of HCT116 human colorectal cells lacking all BH3-only proteins as well as all relevant BCL-2 proteins. By reconstituting individual BH3-only proteins on this genetic background, we observed that HRK induces apoptosis in a manner dependent on its BH3 domain, and the presence of the apoptosis regulator BAX and BCL-2 homologous antagonist/killer (BAK), but independent of its transmembrane domain. Intriguingly, HRK also causes mitochondrial aggregation without altering cristae structure or respiration. Although the BH3 domain is not required for mitochondrial reorganisation, we found that the transmembrane domain requires additional upstream amino acids for HRK mitochondrial localisation and reorganisation. These observations uncover a previously unknown role of HRK in modulating mitochondrial morphology that is independent of its BH3 domain and pro-death function.
    Keywords:  BH3; Harakiri; apoptosis; mitochondria; transmembrane
    DOI:  https://doi.org/10.1111/febs.70255
  29. EMBO Rep. 2025 Sep 12.
    CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
    Mengting Liu, Aoxing Cheng, Weiyi You, Jiaxin Wu, Chenxu Dai, Ting Wang, Ying Wu, Fumei Zhong, Jue Shi, Yingying Du, Zhonghuai Hou, Ping Gao, Ke Ruan, Yi Yang, Yuzheng Zhao, Kaiguang Zhang, Zhenye Yang, Jing Guo.
      While cancer cells overexpress lactate dehydrogenase A (LDHA) to support glycolytic flux and lactate production, the role of LDHB-which preferentially catalyzes lactate oxidation-remains unclear. Here, we demonstrate that LDHB, but not LDHA, is essential for mitotic progression in cancers. During mitosis, CDK1 phosphorylates LDHA at threonine 18, reducing its incorporation into the lactate dehydrogenase (LDH) tetramer. This results in LDHB-enriched tetramers that shift catalytic activity toward lactate oxidation, converting lactate and NAD⁺ into pyruvate and NADH. The generated NADH fuels oxidative phosphorylation and ATP production, thereby sustaining mitosis. Notably, LDHA-T18 phosphorylation occurs exclusively in tumor tissues. Our findings reveal a tumor-specific mechanism in which CDK1 reprograms LDH isoenzyme composition to direct lactate toward NADH production, ensuring energy homeostasis during mitosis. This underscores the therapeutic necessity of targeting both LDHA and LDHB in cancer.
    Keywords:  ATP; Lactate; Lactate Dehydrogenase; Mitosis; NADH
    DOI:  https://doi.org/10.1038/s44319-025-00573-8
  30. Nat Aging. 2025 Sep 11.
    Are we getting closer to understanding why we age?
    Felipe Sierra.
      
    DOI:  https://doi.org/10.1038/s43587-025-00969-0
  31. Nat Rev Immunol. 2025 Sep 08.
    Metabolic control of innate-like T cells.
    Thomas Riffelmacher, Mitchell Kronenberg.
      Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-025-01219-5
  32. Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00708-7. [Epub ahead of print]
    Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
    Yaqin Deng, Goncalo Vale, Yonggang Liang, Shaojie Cui, Shimeng Xu, Jeffrey G McDonald, Jin Ye.
      Although polyunsaturated phospholipids are vital for cellular functions, their overaccumulation renders cells vulnerable to ferroptosis. It remains unclear how cells exposed to excess polyunsaturated fatty acids (PUFAs) prevent their over-incorporation into phospholipids. Here, we identified a mechanism by which ubiquitin regulatory X domain-containing protein 8 (UBXD8), a fatty acid (FA)-interacting protein, prevents overaccumulation of phospholipids containing docosahexaenoate (DHA), one of the most abundant PUFAs in mammalian cells. UBXD8 binds to and activates 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which specifically incorporates DHA into phospholipids. Thus, cultured cells and mouse livers deficient in UBXD8 were resistant to ferroptosis because of reduced production of DHA-containing phospholipids. Excess unsaturated FAs, including DHA, through their interaction with UBXD8, disrupt the UBXD8/AGPAT3 complex, thereby inhibiting AGPAT3-catalyzed synthesis of DHA-containing phospholipids. This FA-sensing mechanism prevents overaccumulation of DHA-containing phospholipids in cells exposed to excess DHA, thus reducing the ferroptotic potency of DHA, a property that might contribute to the health benefits of this ω-3 PUFA.
    Keywords:  AA; AGPAT3; DHA; UBXD8; ferroptosis; phospholipids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.023
  33. Nat Med. 2025 Sep 12.
    Mending a mother's mitochondrial DNA.
    Mike May.
      
    DOI:  https://doi.org/10.1038/d41591-025-00056-2
  34. Dev Cell. 2025 Sep 08. pii: S1534-5807(25)00410-1. [Epub ahead of print]60(17): 2218-2236
    Defining breast epithelial cell types in the single-cell era.
    G Kenneth Gray, Eric G Carlson, Tatyana Lev, Bailey Marshall, Austin D Reed, Alex P Sánchez-Covarrubias, Alecia-Jane Twigger, Aleix Puig-Barbe, Aatish Thennavan, Ayodele Omotoso, Lyndsay M Murrow, Deeptiman Chatterjee, Siyuan He, Sara Pensa, Brian Aevermann, Norbert K Tavares, Natalie Chen, Jason A Hilton, Kerrigan Blake, Yunlong Liu, Kiet Phong, Zev J Gartner, Devon A Lawson, Alexander Swarbrick, Camila O Dos Santos, Sophia H L George, Joan S Brugge, Mark A LaBarge, Harikrishna Nakshatri, Nicholas Navin, Kai Kessenbrock, Walid T Khaled.
      Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors. Our proposals and their underlying thought processes aim to catalyze the adoption of a shared model for this tissue and to serve as guidance for other investigators facing similar challenges.
    Keywords:  breast; hierarchical differentiation; human biology; lactation; mammary gland; nomenclature; single-cell biology; tissue organization
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.032
  35. Neurophotonics. 2025 Jun;12(Suppl 2): S22805
    Genetically encoded biosensors of metabolic function for the study of neurodegeneration, a review and perspective.
    Minglei Zhao, Saman Behboudi Tanourlouee, Sean McCracken, Philip R Williams.
      Nervous system tissue is the most metabolically active in the body and neurons are the primary consumers of oxygen and metabolites in nervous tissue. Many processes support neuronal metabolism, and dysregulation of these processes or intrinsic neuronal metabolism is often tied to neurodegenerative diseases. While many techniques are available to query metabolic function and disease (e.g. Seahorse XF, histology, immunostaining), almost all of these approaches are destructive and few offer cellular resolution. However, genetically encoded biosensors can optically measure metabolic features in any tissue with optical access. Biosensors represent an approach to non-destructively monitor metabolic components and regulatory signaling repeatedly over time in intact tissues. In this review, we discuss the application of genetically encoded biosensors that measure metabolites and metabolic processes as applied to studies of neurodegeneration.
    Keywords:  genetically encoded biosensors; metabolism; neurodegeneration
    DOI:  https://doi.org/10.1117/1.NPh.12.S2.S22805
  36. BMC Res Notes. 2025 Sep 08. 18(1): 385
    Imaging mass cytometry dataset of small-cell lung cancer tumors and tumor microenvironments.
    France Rose, Olta Ibruli, Luca Lichius, Martha Kiljan, Gokcen Gozum, Manoela Iannicelli Caiaffa, Jiali Cai, Li-Na Niu, Jan M Herter, Holger Grüll, Reinhard Büttner, Filippo Beleggia, Graziella Bosco, Julie George, Grit S Herter-Sprie, Hans Christian Reinhardt, Katarzyna Bozek.
       OBJECTIVES: Small cell lung cancer (SCLC) accounts for approximately 15% of lung tumors and is marked by aggressive growth and early metastatic spread. In this study, we used two SCLC mouse models with differing tumor mutation burdens (TMB). To investigate tumor composition, spatial architecture, and interactions with the surrounding microenvironment, we acquired multiplexed images of mouse lung tumors using imaging mass cytometry (IMC). These data build upon a previously published characterization of the mouse model.
    DATA DESCRIPTION: After tumor detection, mice were assigned to one of five treatment groups. Lung tumor tissues were imaged with a 37-marker IMC panel designed to identify major cell types-tumor, immune, and structural-as well as their functional states. When possible, each tumor was sampled both at its center and border regions. Tumor masks in the form of binary images are provided to delineate tumor areas. Additional metadata include tumor onset and endpoint dates to support downstream correlation or predictive analyses based on the image data. This dataset offers a valuable resource for studying the histological and cellular complexity of SCLC in a genetically controlled mouse model across multiple therapeutic conditions.
    Keywords:  Hyperion; IMC; MIBI-TOF; Mouse models; SCLC; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13104-025-07460-4
  37. JCI Insight. 2025 Sep 09. pii: e187758. [Epub ahead of print]10(17):
    Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia.
    Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig.
      Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic disorders. Metabolic flux analyses confirmed robust BCAT inhibition, with reduction of labeling of proximal and distal BCAA-derived metabolites in MMA hepatocytes. In vivo experiments verified the BCAT inhibition, but total levels of distal BCAA catabolite disease markers and clinical symptoms were not normalized, indicating contributions of substrates other than BCAA to these distal metabolite pools. Our study demonstrates the importance of understanding the underlying pathology of metabolic disorders for identification of therapeutic targets and the use of multiple, complementary models to evaluate them.
    Keywords:  Amino acid metabolism; Genetics; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.187758
  38. Nat Rev Cancer. 2025 Sep 08.
    Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
    Hariharan Easwaran, Ashani T Weeraratna.
      Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50-60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.
    DOI:  https://doi.org/10.1038/s41568-025-00868-x
  39. Cell. 2025 Sep 10. pii: S0092-8674(25)00978-X. [Epub ahead of print]
    Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.
    Travis E Faust, Yi-Han Lee, Ciara D O'Connor, Margaret A Boyle, Georgia Gunner, Violeta Durán-Laforet, Loris L Ferrari, Robert E Murphy, Ana Badimon, Kristina Sakers, Cagla Eroglu, Pinar Ayata, Anne Schaefer, Dorothy P Schafer.
      Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediated synapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on the release of Wnts from microglia downstream of neuron-to-microglia fractalkine ligand-receptor (CX3CL1-CX3CR1) signaling. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and that this signaling is upregulated in several disease contexts.
    Keywords:  Wnt; astrocyte; microglia; synapse remodeling
    DOI:  https://doi.org/10.1016/j.cell.2025.08.023
  40. Sci Adv. 2025 Sep 12. 11(37): eadx4511
    The citrullinating enzyme PADI4 governs progenitor cell proliferation and translation in developing hair follicles.
    Kim Vikhe Patil, Nil Campamà Sanz, Kylie Hin-Man Mak, Wei Yang, Karl Annusver, Jasson Makkar, David Grommisch, Li Lei, Priyanka Sharma, Ryan R Driskell, Maria Kasper, Maria Genander.
      Posttranslational protein modifications have emerged as a mechanism regulating progenitor cell state transitions during tissue formation. Herein, we exploit the stereotyped hair follicle development to delineate the function of PADI4, an enzyme converting peptidylarginine to citrulline. Single-cell sequencing places Padi4 in both progenitor and differentiated hair lineage cells and indicates that PADI4 acts to repress transcription during hair follicle development. We establish PADI4 as a negative regulator of proliferation, acting on LEF1-positive hair shaft committed progenitor cells. Mechanistically, PADI4 citrullinates proteins associated with mRNA processing and ribosomal biogenesis, and lack of PADI4 promotes protein synthesis and ribosomal RNA transcription in vivo. Characterizing key translational effectors, we demonstrate that PADI4 citrullinates the translational repressor 4E-BP1 and reveal a cross-talk between PADI4 activity and 4E-BP1 phosphorylation. This work sheds light on how posttranslational modifications affect progenitor cell states and tissue formation.
    DOI:  https://doi.org/10.1126/sciadv.adx4511
  41. EMBO J. 2025 Sep 11.
    BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.
    Michael G Hanna, Hely O Rodriguez Cruz, Kenshiro Fujise, Yumei Wu, C Shan Xu, Song Pang, Zhuonging Li, Mara Monetti, Pietro De Camilli.
      Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show that one such protein, bridge-like lipid transfer protein 3A (BLTP3A)/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region, and anchors them to lysosomes via its chorein domain-containing N-terminal region binding to Rab7. Upon lysosome damage, BLTP3A-positive vesicles rapidly (within minutes) dissociate from lysosomes. Lysosome damage is known to activate the CASM (Conjugation of ATG8 to Single Membranes) pathway, leading to lipidation and lysosomal recruitment of mammalian ATG8 (mATG8) proteins. We find that this process drives the reassociation of BLTP3A with damaged lysosomes via an interaction of its LIR motif with mATG8 which coincides with a dissociation from the vesicles. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage.
    Keywords:  BLTP3; LC3; Lysosome; Rab45; Urate Crystals
    DOI:  https://doi.org/10.1038/s44318-025-00543-9
  42. Nat Metab. 2025 Sep 12.
    Redox-dependent pathways in the pro-thermogenic effects of cysteine restriction.
    Daniele Lettieri-Barbato, Katia Aquilano.
      
    DOI:  https://doi.org/10.1038/s42255-025-01384-w
  43. Trends Cancer. 2025 Sep 05. pii: S2405-8033(25)00210-9. [Epub ahead of print]
    Glucose restriction: double edged sword in cancer treatment.
    Shenglong Xia, Dingjiacheng Jia.
      Glucose restriction generally limits tumor growth. Recently, Wu et al. reported that glucose restriction inhibits primary tumors but promotes lung metastasis by forming a macrophage-dominated, natural killer (NK) cell-deficient pre-metastatic niche (PMN). This finding provides a new perspective on understanding the dual role of glucose metabolism regulation in cancer treatment.
    Keywords:  cancer metastasis; exosomal TRAIL; low-carbohydrate diet; macrophages; natural killer cells; pre-metastatic niche
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.012
  44. Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01037-X. [Epub ahead of print]44(9): 116266
    Coordination of autophagosome closure and release by the Alzheimer's disease-associated protein BIN1.
    Jennifer E Palmer, Claudia Puri, Ryan S O'Rourke, Sung Min Son, Chun Sang, Yu-Wen Alvin Huang, David C Rubinsztein.
      Autophagosome closure by the endosomal sorting complex required for transport (ESCRT) complex is a prerequisite for their dynamin 2 (DNM2)-dependent release from the recycling endosome and subsequent lysosomal clearance. However, the mechanism that coordinates autophagosome closure and release is unknown. We identified that the Alzheimer's disease-associated protein bridging integrator 1 (BIN1) is a critical mediator of this coordination. Prior to autophagosome closure, BIN1 is held at autophagosomes by ESCRT-III and inhibits DNM2. Once the autophagosome has closed and ESCRT-III disassembles, BIN1 is released, removing the inhibition of DNM2. This mechanism provides insight into the functional consequences of increased BIN1 expression, as this occurs in microglia with Alzheimer's disease risk-associated polymorphisms. We find that the overexpression of BIN1 microglial isoforms inhibits DNM2-mediated autophagosome release and autophagic clearance. This provides a coherent explanation for the increased Alzheimer's disease risk associated with BIN1, as impaired microglial autophagy alters phagocytosis and is associated with microglial senescence and neuroinflammation.
    Keywords:  Alzheimer’s disease; BIN1; CP: Cell biology; CP: Neuroscience; DNM2; ESCRT-III; autophagy; microglia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116266
  45. J Clin Invest. 2025 Sep 16. pii: e184172. [Epub ahead of print]
    Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
    Thomas Mandel Clausen, Ryan J Weiss, Jacob R Tremblay, Benjamin P Kellman, Joanna Coker, Leo A Dworkin, Jessica P Rodriguez, Ivy M Chang, Timothy Chen, Vikram Padala, Richard Karlsson, Hyemin Song, Kristina L Peck, Satoshi Ogawa, Daniel R Sandoval, Hiren J Joshi, Gaowei Wang, L Paige Ferguson, Nikita Bhalerao, Allison Moores, Tannishtha Reya, Maike Sander, Thomas C Caffrey, Jean L Grem, Alexandra Aicher, Christopher Heeschen, Dzung Le, Nathan E Lewis, Michael A Hollingsworth, Paul M Grandgenett, Susan L Bellis, Rebecca L Miller, Mark M Fuster, David W Dawson, Dannielle D Engle, Jeffrey D Esko.
      3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of Antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues, but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions (PanINs), but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. Furthermore, plasma from PDAC patients showed accumulation of HSAT suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.
    Keywords:  Cancer; Cell biology; Coagulation; Glycobiology; Oncology
    DOI:  https://doi.org/10.1172/JCI184172
  46. Nature. 2025 Sep 10.
    Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis.
    Solomiia Savchuk, Kaylee M Gentry, Wengang Wang, Elana Carleton, Carlos A O Biagi-Junior, Karan Luthria, Belgin Yalçın, Lijun Ni, Hannah C Farnsworth, Rachel A Davis, Richard Drexler, Johannes C Melms, Yin Liu, Lehi Acosta-Alvarez, Griffin G Hartmann, Elisa C Pavarino, Jenna LaBelle, Pamelyn J Woo, Angus M Toland, Fangfei Qu, Yoon Seok Kim, Mariella G Filbin, Mark A Krasnow, Keith L Ligon, Benjamin Izar, Julien Sage, Bernardo L Sabatini, Michelle Monje, Humsa S Venkatesh.
      Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms1 and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses2,3. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression4-12. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron-cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.
    DOI:  https://doi.org/10.1038/s41586-025-09492-z
  47. Methods. 2025 Sep 10. pii: S1046-2023(25)00201-4. [Epub ahead of print]
    Optimization of 13C stable isotope labeling for the study of tricarboxylic cycle intermediates in mouse models.
    Jarrod Laro, Monica Ness, Joseane Godinho, Randy Coats, Laura-Isobel McCall.
      The tricarboxylic acid cycle (TCA), also known as the Krebs Cycle or the citric acid cycle, is an essential metabolic pathway involved in energy production that is often impacted by disease, making it of key interest to identify effective, affordable, and simple ways to monitor the impact of disease on TCA metabolism. 13C-based stable isotope labeling is a useful technique to track pathway alterations in living hosts. However, infusion-based methodologies are slow and expensive despite achieving steady-state labeling. Bolus-based methods are cheaper, faster, and compatible with biohazardous models, but require optimization to achieve maximum labeling. Herein, we performed bolus-based stable isotope labeling experiments in mouse models to identify the optimal dosage amount, label administration length, fast length prior to label administration, 13C-labeled precursor, and route of administration for the TCA cycle in the esophagus, heart, kidney, liver, plasma, and proximal colon. 13C-glucose at a concentration of 4 mg/g administered via intraperitoneal injection followed by a 90 min label incorporation period achieved the best overall TCA labeling. For most organs, a 3 h fast prior to label administration improved labeling, but labeling in the heart was better with no fasting period, showcasing the need to optimize methodology on an organ-by-organ basis. We also identified that bolus administration of glucose provided little impact on metabolism compared to vehicle control. The experiments outlined here provide critical information for designing in vivo stable isotope labeling experiments for the study of the TCA cycle.
    Keywords:  Bolus; Carbon-13; Fasting; Glucose; Labeling; Mice; TCA cycle
    DOI:  https://doi.org/10.1016/j.ymeth.2025.09.004
  48. Cell Genom. 2025 Sep 02. pii: S2666-979X(25)00236-8. [Epub ahead of print] 100980
    Single-cell analysis of Barrett's esophagus and carcinoma reveals cell types conferring risk via genetic predisposition.
    Marten C Wenzel, Pouria Dasmeh, Patrick S Plum, Ann-Sophie Giel, Sascha Hoppe, Marek Franitza, Christoph Jonas, René Thieme, Yue Zhao, Dominik Heider, Claire Palles, Rebecca Claire Fitzgerald, Christiane J Bruns, Reinhard Buettner, Alexander Quaas, Ines Gockel, Carlo Maj, Seung-Hun Chon, Johannes Schumacher, Axel M Hillmer.
      Inherited genetic variants contribute to Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but it is unknown which cell types are involved in this process. We performed single-cell RNA sequencing of BE, EAC, and paired normal tissues and integrated genome-wide association data to determine cell-type-specific genetic risk and cellular processes that contribute to BE and EAC. The analysis reveals that EAC development is driven to a greater extent by local cellular processes than BE development and suggests that one cell type of BE origin (intestinal metaplasia cells) and cellular processes that control the differentiation of columnar cells are of particular relevance for EAC development. Specific subtypes of fibroblasts and endothelial cells likely contribute to BE and EAC development, while dendritic cells and CD4+ memory T cells seem to contribute to BE development. The diagnostic value of markers characterizing the cell types and cellular processes should be explored for EAC prediction.
    Keywords:  Barrett’s esophagus; cancer development; esophageal adenocarcinoma; genetic risk; genome-wide association study; intestinal metaplasia; partitioned heritability; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.xgen.2025.100980
  49. Nat Aging. 2025 Sep 10.
    Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.
    DOI:  https://doi.org/10.1038/s43587-025-00942-x
  50. EMBO J. 2025 Sep 08.
    Nuclear glycine decarboxylase suppresses STAT1-dependent MHC-I and promotes cancer immune evasion.
    Rui Liu, Hui-Fang Li, Qi Jiang, Jun-Ge Shi, Zi-Lun Ruan, Peng Ren, Yi-Nuo Li, Hong-Bing Shu, Shu Li.
      Inadequate antigen presentation by MHC-I in tumor microenvironment (TME) is a common immune escape mechanism. Here, we show that glycine decarboxylase (GLDC), a key enzyme in glycine metabolism, functions as an inhibitor of MHC-I expression in EGFR-activated tumor cells to induce immune escape by a mechanism independent of its enzymatic activity. Upon EGFR activation, GLDC is phosphorylated by SRC and subsequently translocated to the nucleus in human NSCLC cells. Nuclear GLDC sequesters STAT1 co-activator SMARCE1, inhibiting STAT1-dependent transcription of the inflammatory genes IRF1 and NLRC5. Further, GLDC recruits DNMT1 to the IRF1/NLRC5 promoter inducing DNA hypermethylation, suppressing transcription of downstream MHC-I genes. Inhibition of GLDC restores MHC-I levels in tumor cells, improves tumor-specific CD8+ T cells functions in the TME, and rescues anti-tumor effects of PD-1 blockade therapy in mice. Our findings reveal a non-enzymatic nuclear function for GLDC in the suppression of MHC-I antigen presentation, suggesting new strategies for ICB-based combination immunotherapy.
    Keywords:  EGFR Activation; GLDC; ICB Therapy; Immune Escape; MHC-I Antigen Presentation
    DOI:  https://doi.org/10.1038/s44318-025-00557-3
  51. Trends Immunol. 2025 Sep 09. pii: S1471-4906(25)00201-7. [Epub ahead of print]
    Mitochondrial dysfunction in myeloid cells: a central deficit in autoimmune diseases.
    Chun-Ting J Kwong, Mariana J Kaplan.
      Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.
    Keywords:  autoimmune diseases; mitochondrial dysfunction; myeloid cells
    DOI:  https://doi.org/10.1016/j.it.2025.08.003
  52. Invest New Drugs. 2025 Sep 12.
    Comparative analysis of the effects of PSPH and PHGDH inhibitors on tumor cell proliferation.
    Yanbing Wang, Longze Sha.
      Serine metabolism plays a pivotal role in supporting the rapid proliferation of tumor cells, with PHGDH recognized as a key rate-limiting enzyme and therapeutic target. However, whether its antitumor effects rely exclusively on serine metabolism remains controversial. In this study, we compared the effects of PHGDH and PSPH inhibitors on serine metabolism and cell proliferation in the breast cancer cell lines HCC-70 and BT-20. While two PSPH inhibitors markedly reduced cellular serine M + 3 levels, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-supplemented conditions. Furthermore, supplementation with α-ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings indicate that the antitumor activity of PHGDH inhibition cannot be solely attributed to blockade of serine biosynthesis, but rather arises from the coordinated disruption of multiple metabolic pathways. This provides new insights into the potential of metabolic targeting strategies for cancer therapy.
    Keywords:  Cell proliferation; PHGDH; PSPH; Serine biosynthesis; Tumor metabolism
    DOI:  https://doi.org/10.1007/s10637-025-01581-0
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