bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–10–12
forty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
  2. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  3. Acidosis orchestrates adaptations of energy metabolism in tumors.
  4. Translational regulation in stress biology.
  5. Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
  6. Infant ketones set the thermogenic tone.
  7. Multifaceted mitochondria in innate immunity.
  8. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  9. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  10. Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
  11. Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
  12. Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.
  13. Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.
  14. Caspase-8 expression and its Src dependent phosphorylation on Tyrosine 380 triggers NRF2 signaling activation in glioblastoma.
  15. Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
  16. Decoding ferroptosis for cancer therapy.
  17. PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
  18. The energy resistance principle.
  19. The SWEET spot for weight maintenance.
  20. Ultra-sensitive DNA sequencing maps mutations that precede cancer.
  21. A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.
  22. The dissipation theory of aging: a quantitative analysis using a cellular aging map.
  23. Activity-dependent citrate dynamics in neurons.
  24. Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
  25. Mapping the evolution of mitochondrial complex I through structural variation.
  26. Imperial strategy of cancer cells through mitochondrial transfer.
  27. Somatic mutation and selection at population scale.
  28. Methionine restriction and mimetics to ameliorate human aging and disease.
  29. Creatine Kinase B promotes non-small cell lung cancer survival and metastasis.
  30. MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists.
  31. Quantitative CRACI reveals transcriptome-wide distribution of RNA dihydrouridine at base resolution.
  32. The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.
  33. Naked mole rats live for decades - genetic tweaks reveal insights into ageing.
  34. The cutting-edge medical approaches that could transform ageing.
  35. Keeping up with the nicotinamides: NADP(H), the forgotten circadian cofactor that keeps metabolic time.
  36. Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
  37. The biophysical mechanism of mitochondrial pearling.
  38. Histone acetylation modulation by a small molecule inhibitor recapitulates symbiont-induced cytoplasmic incompatibility.
  39. The differential regulation of the urea cycle in tumors goes awry.
  40. Physical traits of supercompetitors in cell competition.
  41. Clues to why the weight-loss condition cachexia arises when cancer occurs.
  42. Basal cells drive small cell lung cancer plasticity.
  43. Cancer-immune coevolution dictated by antigenic mutation accumulation.
  44. Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer.
  45. Integrating cross-sample and cross-modal data for spatial transcriptomics and metabolomics with SpatialMETA.
  1. Nat Commun. 2025 Oct 08. 16(1): 8952
    Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
    Vidhi Pareek, Stephen Benkovic.
      Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-025-64013-w
  2. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  3. Science. 2025 Oct 09. 390(6769): eadp7603
    Acidosis orchestrates adaptations of energy metabolism in tumors.
    Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.
      Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
    DOI:  https://doi.org/10.1126/science.adp7603
  4. Nat Cell Biol. 2025 Oct 07.
    Translational regulation in stress biology.
    Naomi R Genuth, Andrew Dillin.
      Organisms must constantly respond to stress to maintain homeostasis, and the successful implementation of cellular stress responses is directly linked to lifespan regulation. In this Review we examine how three age-associated stressors-loss of proteostasis, oxidative damage and dysregulated nutrient sensing-alter protein synthesis. We describe how these stressors inflict cellular damage via their effects on translation and how translational changes can serve as both sensors and responses to the stressor. Finally, we compare stress-induced translational programmes to protein synthesis alterations that occur with age and discuss whether these changes are adaptive or deleterious to longevity and healthy ageing.
    DOI:  https://doi.org/10.1038/s41556-025-01765-z
  5. Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00390-0. [Epub ahead of print]37(10): 1927-1928
    Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
    Joanne F Garbincius, John W Elrod.
      The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.1 propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.005
  6. Nat Metab. 2025 Oct 09.
    Infant ketones set the thermogenic tone.
    Jing Wang, Da Jia.
      
    DOI:  https://doi.org/10.1038/s42255-025-01357-z
  7. NPJ Metab Health Dis. 2024 May 27. 2(1): 6
    Multifaceted mitochondria in innate immunity.
    Eloïse Marques, Robbin Kramer, Dylan G Ryan.
      The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.
    DOI:  https://doi.org/10.1038/s44324-024-00008-3
  8. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
  9. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  10. Immunology. 2025 Oct 08.
    Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies.
    Sana Ahuja, Sufian Zaheer.
      Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine-tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia-inducible factor-1 (HIF-1), MYC, p53, peroxisome proliferator-activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element-binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal-tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single-cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin-modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.
    Keywords:  OXPHOS; glycolysis; mediators; metabolic reprogramming; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70045
  11. Metabolism. 2025 Oct 06. pii: S0026-0495(25)00282-3. [Epub ahead of print] 156413
    Mitochondrial phosphopantetheinylation is required for oxidative metabolism.
    Pieter R Norden, Riley J Wedan, Samuel E J Preston, Morgan Canfield, Naomi Graber, Jacob Z Longenecker, Olivia A Pentecost, Elizabeth McLaughlin, Madeleine L Hart, Sara M Nowinski.
      4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4'PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
    Keywords:  Electron transport chain; Fatty acid synthesis; Metabolism; Mitochondria; Phosphopantetheine; Reductive carboxylation; Respiration
    DOI:  https://doi.org/10.1016/j.metabol.2025.156413
  12. Cell Death Discov. 2025 Oct 06. 11(1): 430
    Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.
    Ziqian Ge, Martina Wallace, Rory Turner, Maureen Yin, Mary F Rooney, Richard K Porter.
      Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high recurrence rates and limited treatment options due to the absence of hormone receptors. Despite advancements in breast cancer research, effective therapies for TNBC remain inadequate, highlighting the need to elucidate subtype-specific metabolic vulnerabilities. TNBC cells exhibit a strong dependence on the exogenous amino acids cystine and glutamine, yet the interplay between these metabolic dependencies remains poorly understood. Here, we demonstrate that TNBC cells exhibit sensitivity to individual nutrient deprivation but can survive dual cystine and glutamine deprivation via distinct mechanisms. Exogenous glutamine primarily fuels glutamine anaplerosis, supporting TNBC cell proliferation. Notably, when exogenous glutamine is absent, restricted cystine uptake restores intracellular glutamate levels, fulfilling metabolic demands and sustaining TNBC cell growth. Under cystine deprivation, inhibition of glutaminolysis rescues TNBC cells by mitigating lipid peroxidation and reducing ROS production, whereas supplementation with the TCA cycle intermediates ɑ-ketoglutarate (ɑ-KG) and succinate induces profound cell death in both TNBC and luminal breast cancer cells under glutaminolysis blockade. Collectively, these findings highlight the metabolic interdependence of glutamine and cystine in TNBC, providing mechanistic insights into potential metabolic-targeted and dietary interventions for TNBC therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02714-3
  13. Life Metab. 2025 Dec;4(6): loaf032
    Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.
    Thomas Pfefer, Luke A J O'Neill.
      Clark et al. showcase that interferons (IFNs) trigger a functional reprogramming of tumor-associated macrophages (TAMs) by downregulating NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4), a key subunit of mitochondrial complex Ⅳ. This drives a transition from protumor TAMs to antitumor IFN-associated TAMs (IFN-TAMs) through activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This mechanism can be leveraged to boost antitumor immunity and improve responses to immune checkpoint blockade.
    DOI:  https://doi.org/10.1093/lifemeta/loaf032
  14. Cell Death Differ. 2025 Oct 06.
    Caspase-8 expression and its Src dependent phosphorylation on Tyrosine 380 triggers NRF2 signaling activation in glioblastoma.
    Claudia Cirotti, Claudia Di Girolamo, Irene Taddei, Claudia Contadini, Giorgia Massacci, Francesca Sacco, Donatella Del Bufalo, Illari Salvatori, Cristiana Valle, Daniela Barilà.
      Caspase-8 expression is upregulated in many tumors where, despite its canonical apoptotic pathway, it sustains cancer progression promoting cell migration, NF-kB activation and inflammation. Here, we provide the first evidence for a novel role of Caspase-8 in promoting the metabolic rewiring of cancer cells. By performing transcriptomic, proteomic and phosphoproteomic analyses on glioblastoma cellular models, we identify Caspase-8 as an unexpected modulator of NRF2. Here we show that Caspase-8 expression and phosphorylation affect NRF2 activity and mitochondrial homeostasis. Mechanistically, we demonstrate that Src-dependent phosphorylation of Caspase-8 on Tyrosine 380 (Y380), frequently reported in cancers including glioblastoma, sustains mTORC1 activation, thus promoting energy metabolism. mTORC1 activity results in p62 phosphorylation allowing its dependent sequestration of KEAP1 protein and constitutive NRF2 signaling activation, as a consequence. Overall, this work depicted a novel unexpected role for Caspase-8 in the modulation of cancer cell metabolism, bridging together Src, mTORC1 and NRF2 signaling.
    DOI:  https://doi.org/10.1038/s41418-025-01542-3
  15. Nat Commun. 2025 Oct 10. 16(1): 9022
    Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
    Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.
      Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.
    DOI:  https://doi.org/10.1038/s41467-025-64072-z
  16. Nat Rev Cancer. 2025 Oct 10.
    Decoding ferroptosis for cancer therapy.
    Adam Wahida, Marcus Conrad.
      Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis - the lethal outcome of iron-dependent (phospho)lipid peroxidation - stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.
    DOI:  https://doi.org/10.1038/s41568-025-00864-1
  17. J Cell Sci. 2025 Oct 09. pii: jcs.263903. [Epub ahead of print]
    PGAM5 cleavage and oligomerization equilibrates mitochondrial dynamics under stress by regulating DRP1 function.
    Sudeshna Nag, Kaitlin Szederkenyi, Christopher M Yip, G Angus McQuibban.
      Mitochondrial dynamics relies on the function of dynamin family GTPase proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1). The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) protein can regulate the phosphorylation levels and the function of both MFN2 and DRP1, however, the precise regulation of PGAM5 activity is unknown. We show that PGAM5 oligomerization and localization controls its function. Under depolarization and/or metabolic stress PGAM5 changes its association from dodecamers to dimers. These PGAM5 oligomers have differential affinity towards MFN2 and DRP1. Simultaneously, PGAM5 is cleaved by the inner mitochondrial membrane resident proteases PARL and OMA1 and a fraction of the cleaved PGAM5 translocates to the cytosol. These two events play an important role in regulating mitochondrial dynamics under depolarization and/or metabolic stress. Taken together, our results identify PGAM5 oligomerization and cleavage-induced relocalization as critical regulators of its function.
    Keywords:  DRP1; Glucose-Starvation; MFN2; Mitochondrial morphology; PGAM5
    DOI:  https://doi.org/10.1242/jcs.263903
  18. Cell Metab. 2025 Oct 06. pii: S1550-4131(25)00387-0. [Epub ahead of print]
    The energy resistance principle.
    Martin Picard, Nirosha J Murugan.
      Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss-all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.
    Keywords:  GDF15; biological circuits; biomarkers; cytokines; disease; energy; exercise; healing; inflammation; mitochondria; oxygen; physical laws; transformation
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.002
  19. Nat Metab. 2025 Oct 07.
    The SWEET spot for weight maintenance.
    Sarah H Schmitz, Louis J Aronne.
      
    DOI:  https://doi.org/10.1038/s42255-025-01382-y
  20. Nature. 2025 Oct 08.
    Ultra-sensitive DNA sequencing maps mutations that precede cancer.
    Jian Carrot-Zhang.
      
    Keywords:  Cancer; DNA sequencing; Epidemiology; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-02975-z
  21. Nat Cancer. 2025 Oct 07.
    A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma.
    William Zhao, Thinh T Nguyen, Atharva Bhagwat, Akhil Kumar, Bruno Giotti, Benjamin Kepecs, Jason L Weirather, Navin R Mahadevan, Asa Segerstolpe, Komal Dolasia, Jamshid Abdul-Ghafar, Naomi R Besson, Stephanie M Jones, Brian Y Soong, Chendi Li, Sebastien Vigneau, Michal Slyper, Isaac Wakiro, Mei-Ju Su, Karla Helvie, Allison Frangieh, Judit Jane-Valbuena, Orr Ashenberg, Mark Awad, Asaf Rotem, Raphael Bueno, Orit Rozenblatt-Rosen, Kathleen Pfaff, Scott Rodig, Aaron N Hata, Aviv Regev, Bruce E Johnson, Alexander M Tsankov.
      Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274-PDCD1 and PVR-TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.
    DOI:  https://doi.org/10.1038/s43018-025-01053-7
  22. NPJ Aging. 2025 Oct 09. 11(1): 86
    The dissipation theory of aging: a quantitative analysis using a cellular aging map.
    Farhan Khodaee, Rohola Zandie, Louis-Alexandre Leger, Yufan Xia, Pakaphol Thadawasin, Elazer R Edelman.
      We propose a new theory for aging based on dynamical systems and provide a data-driven computational method to quantify the changes at the cellular level. We use ergodic theory to decompose the dynamics of changes during aging and show that aging is fundamentally a dissipative process within biological systems, akin to dynamical systems where dissipation occurs due to non-conservative forces. To quantify the dissipation dynamics, we employ a transformer-based machine learning algorithm to analyze gene expression data, incorporating age as a token to assess how age-related dissipation is reflected in the embedding space. By evaluating the dynamics of gene and age embeddings, we provide a cellular aging map (CAM) and identify patterns indicative of divergence in gene embedding space, nonlinear transitions, and entropy variations during aging for various tissues and cell types. Our results provide a novel perspective on aging as a dissipative process and introduce a computational framework that enables measuring age-related changes with molecular resolution.
    DOI:  https://doi.org/10.1038/s41514-025-00277-2
  23. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2519902122
    Activity-dependent citrate dynamics in neurons.
    Paul C Rosen, Panhui Fu, Beatriz Ferrán, Erica Kim, Daniel J Brooks, Daniel C Lim, Carlos Manlio Díaz-García, Gary Yellen.
      Glycolytic enzymes sense metabolite levels to adapt rapidly to changing energy demands, but measuring the levels of these effectors with spatiotemporal precision in live cells has been challenging. We addressed this question in the context of neuronal depolarization, which activates glycolysis, focusing on the glycolysis inhibitor citrate. We engineered a pair of quantitative fluorescent biosensors for citrate that address several limitations (affinity, pH, Mg2+, and temperature) of existing citrate biosensors. Using two-photon fluorescence lifetime imaging, we found that free citrate in the cytosol of neurons in acute mouse brain slices declines two-to-threefold within seconds of neuronal activation and then returns to baseline over a few minutes. The stimulation-dependent citrate transient depends at least in part on the mitochondrial calcium uniporter. These types of live metabolite measurements are essential for achieving a nuanced understanding of the fast control of glycolysis.
    Keywords:  fluorescence lifetime; genetically encoded fluorescent biosensor; glycolytic regulation; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.1073/pnas.2519902122
  24. Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00363-4. [Epub ahead of print]33(10): 1645-1647
    Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
    Evie R Hodgson, Diana Stojanovski.
      In a recent Science paper, Medeiros et al. describe how infected cells use mitochondria as metabolic guardians, outcompeting Toxoplasma parasites for folate, an essential vitamin for DNA synthesis. This metabolic immunity strategy transforms the cell's powerhouse to an active defender, sequestering nutrients away from invaders in a metabolic tug-of-war.
    DOI:  https://doi.org/10.1016/j.chom.2025.09.002
  25. FEBS Lett. 2025 Oct 10.
    Mapping the evolution of mitochondrial complex I through structural variation.
    Dong-Woo Shin, Tingting Chen, James A Letts.
      Respiratory complex I (CI) is a multi-subunit membrane protein complex important for the production of ATP via the oxidative phosphorylation pathway. The structure of CI is roughly conserved across species and is composed of subunits that are either embedded in the membrane or are exposed to the aqueous environment that together form an overall L-shaped 'boot'. The conserved core of CI is generally composed of 14 subunits. Across species, various less conserved 'supernumerary' or 'accessory' subunits have been added. Accessory subunits vary in number across species and can include proteins that are unique to specific lineages. Additionally, there are structural variations in the core subunits between clades. In this Review, we compare seven representative CI structures from divergent eukaryotic lineages to identify what aspects of the CI core subunits are susceptible to variation and classify eukaryotic accessory subunits into those conserved from the last eukaryotic common ancestor (LECA) or those that are lineage specific. Impact statement Understanding the biodiversity and evolution of mitochondrial complex I will reveal patterns that may reflect metabolic niche and can be used to constrain quantitative models of molecular evolution.
    Keywords:  OXPHOS; bioenergetics; cellular respiration; complex I; cryoEM structures; evolution; last eukaryotic common ancestor; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/1873-3468.70181
  26. Mol Oncol. 2025 Oct 05.
    Imperial strategy of cancer cells through mitochondrial transfer.
    Takamasa Ishino, Yosuke Togashi.
      Mitochondria are essential organelles that regulate various biological processes including metabolism. Beyond their intracellular functions, intercellular mitochondrial transfer has emerged as a novel mechanism of intercellular communication. Notably, an increasing number of studies have reported its occurrence in the tumor microenvironment (TME), where it contributes to tumor progression. While previous studies largely characterized cancer cells as recipients of mitochondria, Cangkrama et al. demonstrated that cancer cells donate their mitochondria to fibroblasts via tunneling nanotubes. The mitochondrial transfer to fibroblasts reprogrammed them into cancer-associated fibroblasts exhibiting combined myofibroblastic and inflammatory characteristics, with enhanced oxidative metabolism and pro-tumorigenic activity. Our group has identified mitochondrial 'hijack' from cancer cells to tumor-infiltrating lymphocytes, leading to an impaired antitumor immunity. These insights underscore the need to recognize cancer cells as mitochondrial donors in the TME capable of reshaping the TME to their own advantage, resembling a dynastic expansion strategy that exerts influence by strategically placing lineages.
    Keywords:  cancer‐associated fibroblast; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70142
  27. Nature. 2025 Oct 08.
    Somatic mutation and selection at population scale.
    Andrew R J Lawson, Federico Abascal, Pantelis A Nicola, Stefanie V Lensing, Amy L Roberts, Georgios Kalantzis, Adrian Baez-Ortega, Natalia Brzozowska, Julia S El-Sayed Moustafa, Dovile Vaitkute, Belma Jakupovic, Ayrun Nessa, Samuel Wadge, Marc F Österdahl, Anna L Paterson, Doris M Rassl, Raul E Alcantara, Laura O'Neill, Sara Widaa, Siobhan Austin-Guest, Matthew D C Neville, Moritz J Przybilla, Wei Cheng, Maria Morra, Lucy Sykes, Matthew Mayho, Nicole Müller-Sienerth, Nicholas Williams, Diana Alexander, Luke M R Harvey, Thomas Clarke, Alex Byrne, Jamie R Blundell, Matthew D Young, Krishnaa T A Mahbubani, Kourosh Saeb-Parsy, Hilary C Martin, Michael R Stratton, Peter J Campbell, Raheleh Rahbari, Kerrin S Small, Iñigo Martincorena.
      As we age, many tissues become colonized by microscopic clones carrying somatic driver mutations1-7. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of this phenomenon remains limited due to the challenge of detecting mutations in small clones. Here we introduce a new version of nanorate sequencing (NanoSeq)8, a duplex sequencing method with an error rate lower than five errors per billion base pairs, which is compatible with whole-exome and targeted capture. Deep sequencing of polyclonal samples with single-molecule sensitivity simultaneously profiles large numbers of clones, providing accurate mutation rates, signatures and driver frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 blood samples from a twin cohort, we report an extremely rich selection landscape, with 46 genes under positive selection in oral epithelium, more than 62,000 driver mutations and evidence of negative selection in essential genes. High-resolution maps of selection across coding and non-coding sites are obtained for many genes: a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition or selection of somatic mutations. Accurate single-molecule sequencing provides a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09584-w
  28. Trends Endocrinol Metab. 2025 Oct 06. pii: S1043-2760(25)00198-5. [Epub ahead of print]
    Methionine restriction and mimetics to ameliorate human aging and disease.
    Andrey A Parkhitko, Sudipta Pathak, Jay E Johnson, Bettina Mittendorfer, Matthew L Steinhauser.
      Methionine restriction (MetR) attenuates the severity of numerous age-related diseases and extends lifespan across multiple species. Implementing MetR in humans remains challenging due to the low palatability of MetR diets, unfavorable side effects associated with continuous dietary MetR, and interindividual variation in factors that can diminish its efficacy, including microbiota activity, compensatory effects from cysteine, and methionine transfer from neighboring cells. Several novel approaches that target methionine metabolism have been developed - including small molecules, synthetic biotics, and xenotopic tools - with some already translated into early-stage clinical trials. In this review, we discuss a variety of approaches that either produce or mimic MetR, as well as their potential applications for human healthspan improvement.
    Keywords:  MetR; MetR mimetics; SAAR; cancer; cysteine; healthspan; lifespan; metabolic health
    DOI:  https://doi.org/10.1016/j.tem.2025.09.006
  29. J Biol Chem. 2025 Oct 08. pii: S0021-9258(25)02657-2. [Epub ahead of print] 110805
    Creatine Kinase B promotes non-small cell lung cancer survival and metastasis.
    Mouna Tlili, Bozena Samborska, Charlotte Girondel, Afnan Abu-Thuraia, Qiaoqiao Zhang, Jakub Bunk, Mohammed F Hussain, Peter M Siegel, Lawrence Kazak.
      Creatine kinase (CK) catalyzes the reversible transfer of a phosphoryl group from ATP to creatine. There are four distinct CK genes (CKM, CKB, CKMT1 and CKMT2) with cell-type selective expression and subcellular localization. In cancer, uncontrolled cell proliferation drives aggressive migration and invasion into nearby tissues and distant organs. While creatine metabolism is known to support cancer cell survival, the specific roles of individual CK isoenzymes remain unclear. Here, we demonstrate that CKB is essential for CK enzymatic activity in several cancer cell lines, including NSCLC (H1299), osteosarcoma (143B), and ovarian adenocarcinoma (OVCAR8). Moreover, we demonstrate that CKB promotes metastasis of H1299 cells to the lung and liver in vivo, a process associated with enhanced anoikis resistance.
    Keywords:  *Creatine; *lung cancer; *metastasis; *osteosarcoma; *ovarian cancer
    DOI:  https://doi.org/10.1016/j.jbc.2025.110805
  30. Science. 2025 Oct 09. 390(6769): eadl4089
    MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists.
    Jung-Mao Hsu, Chunxiao Liu, Weiya Xia, Chung-Yu Chen, Wei-Chung Cheng, Junwei Hou, Mien-Chie Hung.
      Cytosolic nucleic acid-sensing pathways are potential targets for cancer immunotherapy. Although stimulator of interferon genes (STING) agonists have shown substantial antitumor effects in animal models, their clinical efficacy in human tumors remains unclear. Deletion of methylthioadenosine phosphorylase (MTAP) is a common genomic alteration in human tumors but is rare in preclinical syngeneic mouse models. We found that homozygous MTAP deletion in human tumors creates a tumor microenvironment that obstructs cytosolic nucleic acid-sensing pathways by down-regulating interferon regulatory factor 3 (IRF3), leading to resistance to STING agonists. Targeting polyamine biosynthesis reverses IRF3 down-regulation, restoring sensitivity to STING agonists in MTAP-deficient tumors. Our findings suggest that MTAP genetic status may inform patient responses to STING agonist therapy and offer an alternative strategy for boosting antitumor immune responses using STING agonists in MTAP-deleted tumors.
    DOI:  https://doi.org/10.1126/science.adl4089
  31. Nat Commun. 2025 Oct 06. 16(1): 8863
    Quantitative CRACI reveals transcriptome-wide distribution of RNA dihydrouridine at base resolution.
    Cheng-Wei Ju, Han Li, Bochen Jiang, Xuanhao Zhu, Liang Cui, Zhanghui Han, Junxi Zou, Yunzheng Liu, Shenghai Shen, Hardik Shah, Chang Ye, Yuhao Zhong, Ruiqi Ge, Peng Xia, Yiyi Ji, Shun Liu, Fan Yang, Bei Liu, Yuzhi Xu, Jiangbo Wei, Li-Sheng Zhang, Chuan He.
      Dihydrouridine (D) is an abundant RNA modification, yet its roles in mammals remain poorly understood due to limited detection methods. We even do not have a comprehensive profile of D site location and modification stoichiometry in tRNA. Here, we introduce Chemical Reduction Assisted Cytosine Incorporation sequencing (CRACI), a highly sensitive, quantitative approach for mapping D at single-base resolution. Using CRACI, we generate the transcriptome-wide maps of D in both cytoplasmic and mitochondrial tRNAs from mammals and plants. We uncover D sites in mitochondrial tRNAs and identify DUS2L as the 'writer' protein responsible for human mitochondrial tRNAs. Furthermore, we demonstrate that most D modifications have a limited impact on tRNA stability, except for D20a, which also exhibits cis-regulation of adjacent D20 sites. Application of CRACI to human mRNA reveals that D modifications are present but rare and occur at very low stoichiometry. CRACI thus provides a powerful platform for investigating D biology across species.
    DOI:  https://doi.org/10.1038/s41467-025-63918-w
  32. Nat Aging. 2025 Oct 08.
    The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan.
    Motohiro Sekiya, Kenta Kainoh, Wanpei Chen, Daichi Yamazaki, Tomomi Tsuyuzaki, Yuto Kobari, Ayumi Nakata, Kenji Saito, Nao Aono-Soma, Ali Majid, Hiroshi Ohno, Takafumi Miyamoto, Takashi Matsuzaka, Rikako Nakajima, Takaaki Matsuda, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Hitoshi Shimano.
      Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.
    DOI:  https://doi.org/10.1038/s43587-025-00973-4
  33. Nature. 2025 Oct 09.
    Naked mole rats live for decades - genetic tweaks reveal insights into ageing.
    Mohana Basu.
      
    Keywords:  Ageing; Cancer; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-03279-y
  34. Nature. 2025 Oct;646(8084): 281-283
    The cutting-edge medical approaches that could transform ageing.
    Coleen T Murphy.
      
    Keywords:  Ageing; Medical research; Policy
    DOI:  https://doi.org/10.1038/d41586-025-03225-y
  35. Life Metab. 2025 Dec;4(6): loaf034
    Keeping up with the nicotinamides: NADP(H), the forgotten circadian cofactor that keeps metabolic time.
    Lauren Palluth, Joseph S Takahashi, Carla B Green.
      The hierarchical relationship between the core circadian clock of the suprachiasmatic nucleus and peripheral clocks throughout the body is tightly regulated. Nicotinamide adenine dinucleotide phosphate (NADP(H)) is a rhythmic cofactor used in hundreds of metabolic reactions. The cellular NADP(H) pool is not only regulated by several clock-controlled enzymes, but also responsive to peripheral "zeitgebers" such as food intake and oxidative stress. This positions NADP(H) as a potential harbinger between core and peripheral metabolic rhythms. While discussion in recent years has focused on its unphosphorylated counterpart, NAD(H), this review aims to highlight the roles of NADP(H) in circadian metabolism. This review discusses the multilayered regulation of cellular NADP(H), how the total pool size, redox ratio, and rhythmicity of NADP(H) impact core and peripheral rhythms, and how disruption of its rhythmic regulation can lead to metabolic disease.
    Keywords:  NAD kinase; NADP(H); NAMPT; circadian; metabolism; nocturnin
    DOI:  https://doi.org/10.1093/lifemeta/loaf034
  36. Nat Commun. 2025 Oct 10. 16(1): 9053
    Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
    Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.
      Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.
    DOI:  https://doi.org/10.1038/s41467-025-64147-x
  37. Mol Biol Cell. 2025 Oct 08. mbcE25060302
    The biophysical mechanism of mitochondrial pearling.
    Gabriel Sturm, Kayley Hake, Austin E Y T Lefebvre, Caleb J Rux, Daria Ivanova, Alfred Millett-Sikking, Kevin M Tharp, Beiduo Rao, Michael Closser, Adam James Waite, Magdalena Precido-Lopez, Alex T Ritter, Sophie Dumont, Wen Lu, Suliana Manley, Juan C Landoni, Wallace F Marshall.
      Mitochondrial networks exhibit remarkable dynamics that are driven in part by fission and fusion events. However, there are other reorganizations of the network that do not involve fission and fusion. One such exception is the elusive, "beads-on-a-string" morphological transition of mitochondria. During such transitions, the cylindrical tubes of the mitochondrial membrane transiently undergo shape changes to a string of "pearls" connected along thin tubes. These dynamics have been observed in many contexts and given disparate explanations. Here we unify these observations by proposing a common underlying mechanism based on the biophysical properties of tubular fluid membranes for which it is known that, under particular regimes of tension and pressure, membranes reach an instability and undergo a shape transition to a string of connected pearls. First, we use high-speed light-sheet microscopy to show that transient, short-lived pearling events occur spontaneously in the mitochondrial network in every cell type we have examined, including during T cell activation, neuronal firing, and replicative senescence. This high-temporal data reveals two distinct classes of spontaneous pearling, triggered either by ionic flux or cytoskeleton tension. We then induce pearling with chemical, genetic, and mechanical perturbations and establish three main physical causes of mitochondrial pearling, i) ionic flux producing internal osmotic pressure, ii) membrane packing lowering bending elasticity, and iii) external mechanical force increasing membrane tension. Pearling dynamics thereby reveal a fundamental biophysical facet of mitochondrial biology. We suggest that pearling should take its place beside fission and fusion as a key process of mitochondrial dynamics, with implications for physiology, disease, and aging.
    DOI:  https://doi.org/10.1091/mbc.E25-06-0302
  38. Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01187-8. [Epub ahead of print]44(10): 116416
    Histone acetylation modulation by a small molecule inhibitor recapitulates symbiont-induced cytoplasmic incompatibility.
    Rupinder Kaur, Mahip Kalra, Madangchanok Imchen, Bailey L Crowley, Angelina McGarry, Leah Carpenter, Seth R Bordenstein.
      Symbiotic relationships between arthropod hosts and microorganisms have garnered global attention for their influence on host ecology, evolution, and vector control. A major gap in the field is to mechanistically define and reconstitute symbiotic traits in the absence of microbes. Here, we address this omission by identifying an evolutionarily conserved host mechanism that recapitulates Wolbachia-induced cytoplasmic incompatibility (CI)-a paternal-effect embryonic lethality trait. We first show that Wolbachia alter histone acetylation during sperm development in Drosophila melanogaster. By chemically inhibiting histone acetyltransferase (HAT) activity in aposymbiotic males, we reprogram the chromatin landscape of developing sperm to induce a rescuable CI phenotype. This phenotype is further modulated through transgenic knockdown of HAT and histone deacetylase enzymes, providing tunable control over natural CI intensity. Our findings uncover histone acetylation as a key host-intrinsic pathway, capable of inducing symbiont-independent CI for new avenues of basic and applied studies.
    Keywords:  CP: Developmental biology; CP: Molecular biology; Drosophila spermatogenesis; Wolbachia symbiosis; anacardic acid; cytoplasmic incompatibility; histone acetylation; spermiogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116416
  39. Biochem Pharmacol. 2025 Oct 07. pii: S0006-2952(25)00630-6. [Epub ahead of print] 117365
    The differential regulation of the urea cycle in tumors goes awry.
    Ahmed M Abou-Shanab, Mennatallah A Khedr, Sandro Matosevic.
      Cancer cells exhibit significant metabolic reprogramming to support their rapid proliferation and survival. Most of the normal and cancer cells are glucose avid, which is metabolized, producing lactate (the Warburg effect). The urea cycle (UC) is traditionally associated with nitrogen detoxification in the liver. UC is boosted in normally proliferating cells; however, disruptions in UC activity are frequently observed in various cancers, leading to altered nitrogen metabolism and the accumulation of ammonia. This review covers the intricate relationship between the UC and cancer progression. We discuss how UC dysregulation contributes to tumorigenesis by promoting pyrimidine synthesis, altering amino acid metabolism, and modulating the tumor microenvironment. Additionally, we explore the impact of ammonia accumulation on cancer cell proliferation, stemness, and immune evasion. Understanding the metabolic rewiring of the UC in cancer offers novel therapeutic opportunities. Targeting UC enzymes or ammonia detoxification pathways may provide effective strategies to inhibit tumor growth and enhance the efficacy of immunotherapeutics.
    Keywords:  Ammonia; Cancer; Metabolism; Tumor microenvironment; Urea cycle
    DOI:  https://doi.org/10.1016/j.bcp.2025.117365
  40. J R Soc Interface. 2025 Oct;22(231): 20250638
    Physical traits of supercompetitors in cell competition.
    Logan C Carpenter, Shiladitya Banerjee.
      Cell competition is a fitness control mechanism in tissues, where less fit cells are eliminated to maintain tissue homeostasis. Two primary mechanisms of cell competition have been identified: contact-dependent apoptosis and mechanical stress-induced competition. While both operate in tissues, their combined impact on population dynamics is unclear. Here, we present a cell-based computational model that integrates cellular mechanics with proliferation, contact-induced apoptosis and mechanically triggered apoptosis to investigate competition between two distinct cell types. Using this framework, we systematically examine how differences in physical traits-such as stiffness, adhesion and crowding sensitivity-govern competitive outcomes. Our results show that apoptosis rates alone are insufficient to predict cell fate; differences in proliferation and contact inhibition play equally important, context-dependent roles. Notably, we find that increased cell stiffness can confer a fitness advantage, enabling stiffer cells to outcompete softer neighbours. However, cells with reduced stiffness can become 'soft' supercompetitors if they exhibit faster growth and lower sensitivity to crowding. We also demonstrate that colony size critically influences competition: a minimum size is required for mutant expansion, below which elimination becomes stochastic. This stochastic clearance is driven by a protrusive instability in the interface between two cells that promotes invasion of the supercompetitors.
    Keywords:  apoptosis; cancer; cell competition; cell growth; cellular Potts model; tissue homeostasis
    DOI:  https://doi.org/10.1098/rsif.2025.0638
  41. Nature. 2025 Oct 08.
    Clues to why the weight-loss condition cachexia arises when cancer occurs.
    Kerstin Haase, Mariam Jamal-Hanjani.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-02594-8
  42. Nat Genet. 2025 Oct;57(10): 2349
    Basal cells drive small cell lung cancer plasticity.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02387-9
  43. Elife. 2025 Oct 10. pii: RP103970. [Epub ahead of print]14
    Cancer-immune coevolution dictated by antigenic mutation accumulation.
    Long Wang, Christo Morison, Weini Huang.
      The immune system is one of the first lines of defence against cancer. When effector cells attempt to suppress tumour, cancer cells can evolve methods of escape or inhibition. Knowledge of this coevolutionary system can help to understand tumour-immune dynamics both during tumourigenesis and during immunotherapy treatments. Here, we present an individual-based model of mutation accumulation, where random mutations in cancer cells trigger specialised immune responses. Unlike previous research, we explicitly model interactions between cancer and effector cells and incorporate stochastic effects, which are important for the expansion and extinction of small populations. We find that the parameters governing interactions between the cancer and effector cells induce different outcomes of tumour progress, such as suppression and evasion. While it is hard to measure the cancer-immune dynamics directly, genetic information of the cancer may indicate the presence of such interactions. Our model demonstrates signatures of selection in sequencing-derived summary statistics, such as the single-cell mutational burden distribution. Thus, bulk and single-cell sequencing may provide information about the coevolutionary dynamics.
    Keywords:  cancer biology; cancer–immune interaction; effector cells; evolutionary biology; mutation accumulation; none; single-cell mutation burden distribution; site frequency spectrum; stochastic modelling
    DOI:  https://doi.org/10.7554/eLife.103970
  44. Cell Rep. 2025 Oct 04. pii: S2211-1247(25)01155-6. [Epub ahead of print]44(10): 116384
    Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer.
    Xinpei Jiang, Xueying Ma, Yunyun Zhou, Xiaodan Liu, Ting Zhang, William Kim, Siddharth Balachandran, Israel Cañadas.
      Spliceosome inhibitors emerged as promising anticancer agents. Recent studies have demonstrated that spliceosome-targeted therapies (STTs) trigger antitumor immune responses by inducing the accumulation of right-handed double-stranded (ds)RNA (A-RNA), resulting in the activation of RIG-I-like receptors (RLRs) and type I interferon-driven antiviral responses. Here, we show that spliceosome inhibition by pharmacological or genetic neutralization of SF3B1 activity induces the accumulation of endogenous left-handed dsRNAs (Z-RNAs) derived from intron-retained RNAs. These Z-RNAs activate the Z-form nucleic acid-sensor ZBP1, which triggers cell death in mouse embryonic fibroblasts and small cell lung cancer (SCLC) cells. Spliceosome inhibition induced potent ZBP1-dependent cell death in cancer-associated fibroblasts, which was essential for enhancing immunotherapy response in mouse models of SCLC. Collectively, these results demonstrate that spliceosome inhibitors can be used to generate Z-RNA and trigger on-demand ZBP1-dependent cell death in cells of the tumor microenvironment (TME) as a therapeutic strategy to enhance immunotherapy responses in resistant cancers.
    Keywords:  CP: Cancer; CP: Molecular biology; SCLC; SF3B1; STTs; Z-RNA; ZBP1; immunotherapy; necroptosis; small cell lung cancer; spliceosome; spliceosome-targeted therapy
    DOI:  https://doi.org/10.1016/j.celrep.2025.116384
  45. Nat Commun. 2025 Oct 06. 16(1): 8855
    Integrating cross-sample and cross-modal data for spatial transcriptomics and metabolomics with SpatialMETA.
    Ruonan Tian, Ziwei Xue, Yiru Chen, Yicheng Qi, Jian Zhang, Jie Yuan, Dengfeng Ruan, Junxin Lin, Jia Liu, Di Wang, Youqiong Ye, Wanlu Liu.
      Simultaneous profiling of spatial transcriptomics (ST) and spatial metabolomics (SM) on the same or adjacent tissue sections offers a revolutionary approach to decode tissue microenvironment and identify potential therapeutic targets for cancer immunotherapy. Unlike other spatial omics, cross-modal integration of ST and SM data is challenging due to differences in feature distributions of transcript counts and metabolite intensities, and inherent disparities in spatial morphology and resolution. Furthermore, cross-sample integration is essential for capturing spatial consensus and heterogeneous patterns but is often complicated by batch effects. Here, we introduce SpatialMETA, a conditional variational autoencoder (CVAE)-based framework for cross-modal and cross-sample integration of ST and SM data. SpatialMETA employs tailored decoders and loss functions to enhance modality fusion, batch effect correction and biological conservation, enabling interpretable integration of spatially correlated ST-SM patterns and downstream analysis. SpatialMETA identifies immune spatial clusters with distinct metabolic features in cancer, revealing insights that extend beyond the original study. Compared to existing tools, SpatialMETA demonstrates superior reconstruction capability and fused modality representation, accurately capturing ST and SM feature distributions. In summary, SpatialMETA offers a powerful platform for advancing spatial multi-omics research and refining the understanding of metabolic heterogeneity within the tissue microenvironment.
    DOI:  https://doi.org/10.1038/s41467-025-63915-z
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