bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–11–02
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
  2. Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
  3. A carbon trail to follow: unveiling itaconate's metabolism in vivo.
  4. HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma.
  5. Longevity-promoting mitochondrial unfolded protein response activation requires elements of the PeBoW complex.
  6. Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.
  7. Single rate-limiting event of carcinogenesis.
  8. FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
  9. Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
  10. The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.
  11. Phagocytosis: a process that shapes immune responses to engulfed meals.
  12. Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
  13. Metabolic rewiring prevents neurodegeneration caused by chronic mitochondrial dysfunction.
  14. Mitochondrial organization in the developing proximal tubule is controlled by LRRK2.
  15. Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.
  16. A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
  17. A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
  18. Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.
  19. Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
  20. Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition.
  21. MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.
  22. Transcription factor switching drives subtype-specific pancreatic cancer.
  23. Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.
  24. Iron raider: Tumors in the bone marrow.
  25. SICyLIA-cTMT dissects redox proteome dynamics with high accuracy and depth at microgram scale.
  26. Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response.
  27. This whale lives for centuries: its secret could help extend human lifespan.
  28. Redox destabilization by ibrutinib promotes ferroptosis in diffuse large B-cell lymphoma (DLBCL).
  29. Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
  30. Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
  31. Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
  32. Extracellular matrix-driven metabolic control of pancreatic endocrine lineage allocation.
  33. BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability.
  34. Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
  35. DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation.
  36. Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.
  37. Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
  38. A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular L-lactate dynamics.
  39. A guide to reactive oxygen species in tumour hypoxia: measurement and therapeutic implications.
  40. Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria.
  41. Circadian clock control of ribosome composition promotes rhythmic translation and termination fidelity.
  42. Origins of chromosome instability unveiled by coupled imaging and genomics.
  43. Cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma.
  44. Remembering David Baltimore (1938-2025).
  45. Evidence for improved DNA repair in long-lived bowhead whale.
  46. Optimization-based framework with flux balance analysis (FBA) and metabolic pathway analysis (MPA) for identifying metabolic objective functions.
  47. p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer.
  1. Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]
    Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
    Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.
      The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.
    Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
  2. Nat Cell Biol. 2025 Oct 31.
    Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
    Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.
      The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01799-3
  3. Immunometabolism (Cobham). 2025 Oct;7(4): e00072
    A carbon trail to follow: unveiling itaconate's metabolism in vivo.
    Denis E Anisov, Sally A Clayton, Maxim A Nosenko.
      The discovery of itaconate as an immunoregulatory metabolite has transformed the field of immunometabolism and opened multiple therapeutic avenues over the past decade. While the immunological functions of itaconic acid have been extensively studied, several aspects of its biochemistry-particularly in vivo utilization pathways-have remained unclear. In a recent study published in Nature Metabolism, Willenbockel et al apply carbon tracing to uncover the metabolic fate of itaconate within the organism. Insights from this work have important implications for understanding the physiological roles of itaconate and for advancing itaconate-based therapeutic strategies.
    Keywords:  itaconate metabolism; stable isotope tracing; succinate dehydrogenase
    DOI:  https://doi.org/10.1097/IN9.0000000000000072
  4. JCI Insight. 2025 Oct 30. pii: e182711. [Epub ahead of print]
    HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma.
    Wencao Zhao, Sara M Demczyszyn, Nathan J Coffey, Yanqing Jiang, Boyoung Kim, Schuyler Bowers, Caitlyn E Bowman, Michael C Noji, Cholsoon Jang, M Celeste Simon, Zoltan Arany, Boa Kim.
      Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows significant but incomplete benefits. This highlights the need to better understand the interplay between glutamine metabolism and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria in diverse cell types, but not in ccRCC. GLS1 clustering occurs rapidly within 1 to 3 hours, is reversible, is specifically triggered by reduced intracellular glutamate, and is dependent on mitochondrial fission. Clustered GLS1 markedly enhances glutaminase activity and promotes cell death under glutamine-deprived conditions. HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby maintaining low GLS activity and protecting ccRCC cells from glutamine deprivation-induced cell death. Forced clustering of GLS1, using constitutively clustering mutants, restores high GLS activity, promotes apoptosis, and suppresses ccRCC tumor growth in vivo. These findings reveal multiple insights into cellular glutamine handling, including a previously unrecognized process by which HIF2α promotes ccRCC: by suppressing GLS1 clustering and maintaining low GLS activity. This mechanism provides a potential explanation for the lack of clinical efficacy of GLS inhibitors in ccRCC and suggests a therapeutic avenue to combine HIF2α inhibition with strategies that restore GLS1 clustering.
    Keywords:  Cancer; Cell biology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.182711
  5. Genes Dev. 2025 Oct 29.
    Longevity-promoting mitochondrial unfolded protein response activation requires elements of the PeBoW complex.
    Adebanjo Adedoja, Niclole Stuhr, Yifei Zhou, Yuyao Zhang, Armen Yerevanian, Alexander A Soukas.
      Mitochondria play a crucial role in cellular energy metabolism and homeostasis and are strongly implicated in aging and age-related diseases. The outer mitochondrial membrane protein voltage-dependent anion channel (VDAC) plays multiple roles in mitochondrial homeostasis, including transport of metabolites, ATP, and Ca2+ Dysregulation of VDAC levels has been associated with cancer, neurodegeneration, metabolic disorders, and aging. Previously, we demonstrated that elevated VDAC-1 levels in Caenorhabditis elegans lead to increased mitochondrial permeability and reduced life span. Here we demonstrate that reduced VDAC-1 function extends life span through the activation of the mitochondrial unfolded protein response (UPRmt), a conserved stress response that maintains mitochondrial proteostasis and is linked to life span extension in multiple species. Leveraging unbiased genomic discovery, we identified genes encoding several proteins in the PeBoW complex as a critical mediator of UPRmt activation following VDAC-1 loss. More broadly, we demonstrated a universal requirement for several PeBoW component genes across diverse mitochondrial stressors in order to fully animate the UPRmt Our findings reveal a heretofore unappreciated role for PeBoW components in UPRmt induction and life span extension in response to mitochondrial stress, highlighting its essential function in mitochondrial quality control and longevity pathways.
    Keywords:  PeBoW; mito-stress; mitoUPR; mitochondria
    DOI:  https://doi.org/10.1101/gad.352979.125
  6. Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00435-8. [Epub ahead of print]
    Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.
    Zhengwei Wu, Zhenxun Wang, Seow Qi Ng, Jessica Alice Lidster, Paul Schwerd-Kleine, Zi Jin Cheryl Phua, Kai Lay Esther Peh, Yin Ying Ho, Ju Yuan, S Shathishwaran, Xun Hui Yeo, Ying Zhang, Yui Hei Jasper Chiu, Li Yieng Eunice Lau, Tony Kiat Hon Lim, Angela Takano, Eng Huat Tan, Anders Jacobsen Skanderup, Vinay Tergaonkar, Weiping Han, Ying Swan Ho, Daniel Shao Weng Tan, Wai Leong Tam.
      Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.
    Keywords:  CD147; MCT1; glucose stress; ketogenic diet; ketone metabolism; lung cancer; metabolic reprogramming; monocarboxylate transporter; tumor-initiating cells
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.001
  7. Nat Commun. 2025 Oct 30. 16(1): 9596
    Single rate-limiting event of carcinogenesis.
    Yutaka Yasui, Qi Liu.
      Single-cell studies have discovered abundant cancer-associated genetic/phenotypic changes in non-cancerous cells, strikingly contrasting with the infrequency of cancer. Epidemiological data have revealed decades-long plateaus of breast cancer incidence in the contralateral breast and twins/relatives following the first/proband's diagnosis, unlike the well-known continuous increase of population-level incidence with age, the latter ostensibly attributable to the successive accumulation of multiple genetic/epigenetic changes necessary for transformation. Here, we explain these contradicting observations by differentiating cell-level, individual-level, and population-level evidence. First, we show the same decades-long incidence plateau for renal-cell carcinoma in the contralateral kidney following the first diagnosis, expanding the individual-level evidence from breast cancer. We then consider somatic evolution and cell competition in stem-cell compartments and their bounded nature in ageing as a hypothesized mechanism for the abundant cancer-associated cell-level changes and the prolonged constancy of individual-level incidence. Individual-specific propensity with heritable/familial components underlies this process, with which we show congruence between individual-level's constant incidence vs. population-level's increasing incidence. The resulting postulate, an extension of one by Peto and Mack 25 years ago, distinguishes the last multistage "hit" as the critically rate-limiting event in carcinogenesis. Its supporting evidence calls for a reappraisal of the precise nature of multistage carcinogenesis in cancer biology.
    DOI:  https://doi.org/10.1038/s41467-025-64613-6
  8. Nat Cell Biol. 2025 Oct 29.
    FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
    Mike Lange, Michele Wölk, Vivian Wen Li, Cody E Doubravsky, Joseph M Hendricks, Shunji Kato, Yurika Otoki, Benjamin Styler, Sean L Johnson, Cynthia A Harris, Kiyotaka Nakagawa, Isabel F Snodgrass, Dohee Kim, John W Newman, Maria Fedorova, James A Olzmann.
      Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-025-01790-y
  9. Nat Immunol. 2025 Oct 29.
    Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
    Haoxin Zhao, Jaeoh Park, Yuzhu Wang, Yi-Ju Chou, Lemin Li, Lydia N Raines, Michael Hsu, Ching-Cheng Lin, Wei Cao, Yuli Ouyang, Heng-Yi Chen, Linghua Zheng, Zihai Li, Alex Y Huang, Ping-Chih Ho, Chan-Wang Jerry Lio, Stanley Ching-Cheng Huang.
      Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02324-2
  10. Nat Metab. 2025 Oct 30.
    The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.
    Juan P Bolaños, Pierre J Magistretti.
      Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron-astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01404-9
  11. Nat Rev Immunol. 2025 Oct 31.
    Phagocytosis: a process that shapes immune responses to engulfed meals.
    Kai Li, David M Underhill.
      The process of phagocytosis creates intracellular compartments (organelles known as phagosomes) that are central hubs for innate immune sensing of potentially dangerous microorganisms, cells, cellular debris and foreign objects. Receptors, enzymes and signalling molecules are specifically enriched in these compartments, wherein they learn everything they can about the phagocytosed material and signal for the cell to mount appropriate responses. The phagosome organelle is also a compartment that facilitates nutrient and metabolite harvesting from internalized materials. This Review explores recent developments in our understanding of phagocytosis as a specific mechanism of innate immune sensing. We discuss efforts to identify the catalogue of proteins that are enriched in different types of phagosomes to learn how these molecules work together to tailor inflammatory and antimicrobial immune responses.
    DOI:  https://doi.org/10.1038/s41577-025-01231-9
  12. Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00395-X. [Epub ahead of print]
    Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
    Penghu Han, Shuzheng Chu, Jing Shen, Lixiang Li, Yan Zhang, Shiguan Wang, Yatai Chen, Yangchun Ma, Xiaolong Tang, Chao Gao, Xiangyun Zheng, Bowen Xu, Qiong Wang, Detian Yuan, Shiyang Li.
      Quercetin, a dietary flavonol, shows promise in cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy.
    Keywords:  BNIP3; CD8(+) T cells; DOPAC; NRF2; anti-tumor immunity; microbiota; mitophgagy; quercetin
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.010
  13. Curr Biol. 2025 Oct 27. pii: S0960-9822(25)01263-1. [Epub ahead of print]
    Metabolic rewiring prevents neurodegeneration caused by chronic mitochondrial dysfunction.
    Shlesha Richhariya, Daniel Shin, Matthias Schlichting, Michael Rosbash.
      The mitochondrial fission-fusion cycle is often disrupted in neurodegenerative diseases, but this important, dynamic process is not well characterized in healthy long-lived neurons of animals. We used an efficient cell-type-specific CRISPR strategy to knock out key fission and fusion genes in specific Drosophila neurons. Neither process is essential for neuronal survival and function, but the fusion knockouts had a larger impact than that of fission, especially in older animals. Mutations in the human mitochondrial inner membrane fusion gene Opa1 often cause the disease optic atrophy. Importantly, knockout of Opa1 in neurons causes a dramatic age-dependent transcriptomic response. This response resembles those of cancer cells and includes the upregulation of glycolytic genes, including Lactate dehydrogenase (Ldh). A novel double knockout strategy indicates that Ldh enhances the reduced ATP levels of the fusion mutants and is essential to prevent age-dependent neurodegeneration. This neuroprotective upregulation of Ldh is largely mediated by the transcription factor ATF4. The identified relationship-dysfunctional mitochondrial fusion alters metabolism-is reminiscent of Warburg's original cancer hypothesis, albeit in neurons. These data underscore the similarity of the two molecular programs, which promote growth in cancer and viability in the case of neurodegeneration.
    Keywords:  ATF4; CRISPR; Drosophila; Warburg effect; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.1016/j.cub.2025.09.063
  14. Nat Commun. 2025 Oct 30. 16(1): 9611
    Mitochondrial organization in the developing proximal tubule is controlled by LRRK2.
    Mohsina Khan, Kyle Bond, Elyse Grilli, Daniel Cameron, Liyang Zhao, Sunder Sims-Lucas, Andrew P McMahon, Thomas J Carroll, Leif Oxburgh.
      The proximal tubule of the nephron performs energy-demanding functions such as resorption of water, amino acids and glucose. Formation of the energy-producing machinery is an essential step in proximal tubule epithelial cell differentiation, and this report asks how mitochondria are localized within these cells. We show that mitochondria move from the apical to basolateral side of the proximal tubule cell coincident with the initiation of lumen flow and that proximal tubules deficient in filtration maintain mitochondria in the apical position. Mitochondrial localization depends on the activity of LRRK2 and modeling fluid flow on cultured proximal tubule epithelial cells demonstrates that LRRK2 activity is regulated by fluid shear stress, explaining how onset of flow in the newly differentiated proximal tubule may trigger the apical-to-basolateral dissemination of mitochondria. These findings indicate that mitochondrial redistribution is one component of a cellular program in the nascent proximal tubule that drives function and that this process is triggered by flow.
    DOI:  https://doi.org/10.1038/s41467-025-64598-2
  15. Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2419568122
    Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.
    Katharina Schindlmaier, Theresa Haitzmann, Visnja Bubalo, Barbara Konrad, Joseph Jelwan, Gabriele Bluemel, Sonja Rittchen, Vanessa Jäger, Michael A Dengler, Luka Brcic, Jörg Lindenmann, Leigh M Marsh, Thomas O Eichmann, Alexander Kirchmair, Zlatko Trajanoski, Julia Kargl, Cristina Muñoz-Pinedo, Katharina Leithner.
      Macrophages are recruited to sites of infection contributing to the killing of bacteria, but also to malignant tumors, where they promote angiogenesis and suppress antitumor immune responses. The metabolic microenvironment in tumors is frequently depleted of important nutrients such as glucose. Here, we investigated metabolic adaptation strategies of macrophages to glucose deprivation using stable isotopic tracing. Lactate production was decreased, potentially indicating a reduction of glycolysis. In contrast, the contribution of glutamine to the tricarboxylic acid cycle via α-ketoglutarate and reductive carboxylation were increased. Moreover, gluconeogenesis, the reverse pathway of glycolysis, was activated in glucose-deprived macrophages, proceeding partially to the generation of glycolytic intermediates and glycerol-3-phosphate. The partial gluconeogenesis pathway was abrogated in human and murine macrophages lacking the initial gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK2, mitochondrial isoform). Partial gluconeogenesis was higher in anti-inflammatory, interleukin-4-stimulated compared to proinflammatory, interferon-γ/lipopolysaccharide-stimulated macrophages. Single-cell analysis and immunostaining revealed expression of PCK2 in macrophages from both lung cancer and normal lung. Low glucose conditions only partially modulated macrophage phenotypes, leading to reduced CD80 surface marker levels in proinflammatory, and enhanced vascular endothelial growth factor expression in anti-inflammatory macrophages. Our study reveals partial gluconeogenesis in glucose-deprived macrophages and shows that this versatile type of immune cells exhibits remarkable metabolic flexibility.
    Keywords:  glucose deprivation; glycolysis; macrophages; metabolism; partial gluconeogenesis
    DOI:  https://doi.org/10.1073/pnas.2419568122
  16. Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496
    A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
    Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.
      Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.
    Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116496
  17. Nat Commun. 2025 Oct 31. 16(1): 9644
    A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
    Shu-Jing Huang, Dong-Fei Ma, Caiting Yu, Jing Li, Xinyu Tu, Zi Huang, Yuanbo Qi, Jun-Ying Ou, Jian-Xiong Feng, Bing Yu, Yu-Lu Cao, Jia-Xing Yue, Junjie Hu, Ming Li, Ying Lu, Liming Yan, Song Gao.
      The mitochondrion is a highly dynamic organelle, constantly undergoing fusion and fission, which are critical processes for the health of cells. Fusion of the outer mitochondrial membrane (OMM) is mediated by the mitofusins belonging to the dynamin superfamily of GTPases. Most eukaryotic organisms possess two cooperatively functioning mitofusins, but yeast has only one mitofusin (Fzo1). How Fzo1 solely catalyzes OMM fusion is unclear. Here, we present crystal structures of truncated Fzo1 (Fzo1IM) in different nucleotide-loading states and report a special mechanistic feature of Fzo1 through systematic functional studies. Differing from mammalian mitofusins, Fzo1 contains an extra latch bulge (LB) that is essential for the viability of yeast. Upon GTP loading, Fzo1IM dimerizes via the GTPase domain and prefers the closed conformation. This state is then locked by the subsequent trans interaction mediated by the LB of each protomer, so that Fzo1IM remains dimerized in the closed conformation even after GTP hydrolysis. This special mechanistic feature may be relevant to the previous observation that degradation of Fzo1 by the ubiquitin-proteasome system is required for mitochondrial fusion. Our study reveals how mitochondrial fusion in yeast is efficiently ensured with limited GTP consumption, which broadens current understanding of this fundamental biological process.
    DOI:  https://doi.org/10.1038/s41467-025-64646-x
  18. Mol Biomed. 2025 Oct 27. 6(1): 87
    Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.
    Yongrui Hai, Ruizhuo Lin, Weike Liao, Shuo Fu, Renming Fan, Guiquan Ding, Junyan Zhuang, Bingjie Zhang, Yi Liu, Junke Song, Gaofei Wei.
      Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy.
    Keywords:  CGAS-STING pathway; DHODH; NK cells; Pyrimidine metabolism; Pyroptosis
    DOI:  https://doi.org/10.1186/s43556-025-00339-7
  19. EMBO J. 2025 Oct 30.
    Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
    Marlena Mucha, Zhihao Lai, Nicholas J McKenzie, Francesca Matrà, Marion Boudes, Sarena F Flanigan, Maria Teresa Alejo-Vinogradova, Craig Monger, Qi Zhang, Darragh Nimmo, Evan Healy, Ademar J Silva, Daniel Angelov, David M Reck, Gráinne Holland, Zeynep Eda Atmaca, Helen E King, Maeve Hamilton, Eleanor Glancy, James Nolan, Robert J Weatheritt, Oliver Bell, Michiel Vermeulen, Chen Davidovich, Adrian P Bracken.
      Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri-methylating H3K27. Control of PRC2 activity is a critical process in development and disease, yet no inhibitory cofactor has been identified in somatic cells. Here, we show that the alternative isoforms of its accessory subunit AEBP2, namely AEBP2S (short) and AEBP2L (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2L isoform inhibits it. AEBP2L is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2S, expressed during early embryogenesis, promotes PRC2 DNA-binding activity and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2L inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2L arose in vertebrates to restrain PRC2 activity in somatic cells.
    Keywords:  AEBP2; Cryo-EM; PRC2; Polycomb; Trithorax
    DOI:  https://doi.org/10.1038/s44318-025-00616-9
  20. Neoplasia. 2025 Oct 27. pii: S1476-5586(25)00123-X. [Epub ahead of print]70 101243
    Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition.
    Rachele Niccolai, Camiel Göbel, Klevis Ndoj, Maaike Kreft, Hendrik J Kuiken, Cor Lieftink, Ben Morris, Sietse D Yska, Sebastian Hendrix, Bram van den Broek, Vincent Pappalardo, Marie José Kersten, Roderick L Beijersbergen, Noam Zelcer, Fred van Leeuwen, Heinz Jacobs.
      The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.
    Keywords:  CRISPR-Cas9 screen; Cholesterol Biosynthesis; Diffuse large B cell lymphoma; EZH2; LDL-receptor
    DOI:  https://doi.org/10.1016/j.neo.2025.101243
  21. Cell Mol Life Sci. 2025 Oct 28. 82(1): 371
    MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.
    Bin Zhang, Anran Xu, Haowei Wang, Wei Yan, Qing Zhang, Shuang Wang.
      Lactate is an abundant oncometabolite in the tumor microenvironment (TME). Lactate driven by metabolic reprogramming leads to acidic microenvironment formation to promote the immune evasion of tumor cells and reduce the effectiveness of immunotherapy for patients with tumors. The expression of mitochondrial pyruvate carrier (MPC) is crucial for pyruvate metabolism, and its dysregulation can lead to the formation of an acidic microenvironment caused by excessive lactic acid. However, the impact of MPC on tumor metabolic processes and biological behavior, as well as how lactate impacts immunosuppression, remains unclear. Here, we found that MPC1 and MPC2, two subunits of MPC, were downregulated in patients with colorectal cancer (CRC). Co-overexpression of MPC1 and MPC2 decreased lactate levels and inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo in the setting of CRC. Knockdown of MPC1 or MPC2 increased lactate levels and promoted the proliferation, migration and invasion of CRC cells. Mechanistically, the accumulation of lactate promotes the elevation of histone lactylation levels, and MPC regulates the expression of CD33, a marker of dendritic cell (DC) maturation, via histone lactylation, decreasing CD8+ T cell functions. In addition, the overexpression of MPC increased the therapeutic effect of the anti-PD-1 antibody. Our findings reveal that MPC downregulation-mediated lactate production impacts DC maturation via histone lactylation-dependent transcriptional regulation to impair CD8+ T cell responses, suggesting that targeting MPC could enhance immunotherapy efficacy by modulating the TME.
    Keywords:  CD33; Colorectal cancer; Dendritic cell; Histone lactylation; Mitochondrial pyruvate transporter carrier
    DOI:  https://doi.org/10.1007/s00018-025-05881-9
  22. Nat Genet. 2025 Oct 30.
    Transcription factor switching drives subtype-specific pancreatic cancer.
    Shalini V Rao, Lisa Young, Danya Cheeseman, Sean Flynn, Niklas Krebs, Dominique-Laurent Couturier, Stephanie Mack, Rebecca Brais, Jill Temple, Amy Smith, Evangelia Papachristou, Catarina Pelicano, Chandra Sekhar Reddy Chilamakuri, Krzysztof Herka, Hideo Baba, Luay Farah, Phyllis F Cheung, Jens Siveke, Stéphane Guerrier, Luca Insolia, Michael Gill, Emily Archer Goode, Steven Kupczak, Yi Cheng, Giacomo Borsari, Duncan Jodrell, Clive D'Santos, Alasdair Russell, Barbara T Grünwald, Eva Serrao, Igor Chernukhin, Jason S Carroll.
      Emerging evidence suggests that lineage-specifying transcription factors control the progression of pancreatic ductal adenocarcinoma (PDAC). We have discovered a transcription factor switching mechanism involving the poorly characterized orphan nuclear receptor HNF4G and the putative pioneer factor FOXA1, which drives PDAC progression. Using our unbiased protein interactome discovery approach, we identified HNF4A and HNF4G as reproducible, FOXA1-associated proteins, in both preclinical models and Whipple surgical samples. In the primary tumor context, we consistently find that the dominant transcription factor is HNF4G, where it functions as the driver. A molecular switch occurs in advanced disease, whereby HNF4G expression or activity decreases, unmasking FOXA1's transcriptional potential. Derepressed FOXA1 drives late-stage disease by orchestrating metastasis-specific enhancer-promoter loops to regulate the expression of metastatic genes. Overall survival is influenced by HNF4G and FOXA1 activity in primary tumor growth and in metastasis, respectively. We suggest that the existence of stage-dependent transcription factor activity, triggered by molecular compartmentalization, mediates the progression of PDAC.
    DOI:  https://doi.org/10.1038/s41588-025-02389-7
  23. J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02712-7. [Epub ahead of print] 110860
    Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.
    Andrew N Bayne, Danielle M Simons, Naoto Soya, Karl Grenier, Gergely L Lukacs, Edward A Fon, Jean-François Trempe.
      Nuclear-encoded mitochondrial proteins rely on N-terminal targeting sequences (N-MTS) for their import. Most N-MTSs are cleaved in the matrix by the mitochondrial processing peptidase (MPP), a heterodimeric metalloprotease composed of (α) and catalytic (β) subunits, essential for the maturation of imported proteins. Import and processing of PINK1, a kinase implicated in Parkinson's disease, govern its ability to sense mitochondrial damage. The current paradigm suggests PINK1 undergoes two sequential processing steps: first, MPP removes the PINK1 N-MTS in the matrix; second, the inner mitochondrial membrane protease PARL cleaves the PINK1 transmembrane domain, leading to PINK1 degradation. Upon depolarization, PINK1 escapes proteolysis and accumulates on mitochondria to initiate mitophagy. However, the MPP cleavage site on PINK1, the role of MPP in PINK1 signalling, and the mechanisms of substrate recognition by human MPP remain unclear. Here, we define the MPP cleavage site on PINK1 between Ala28-Tyr29 and show it is inefficiently processed compared to canonical N-MTSs. In cells, MPP cleavage is dispensable for both PARL processing and PINK1 function, decoupling PINK1 import and damage sensing from its N-MTS removal. However, in vitro, the PINK1 N-MTS binds potently to MPP, inhibits the cleavage of other substrates, and traps MPP in a slowly processing complex. Exploiting PINK1 as a mechanistic probe, we use hydrogen-deuterium exchange mass spectrometry to map the PINK1 binding site on MPPα. We identify a two-step mechanism involving MPPα lid rearrangement followed by active site engagement, providing key insight into PINK1's unique import pathway and fundamental MPP processing mechanisms.
    Keywords:  PTEN-induced putative kinase 1 (PINK1); Parkinson disease; hydrogen-deuterium exchange; mitochondria; mitochondrial processing peptidase (MPP); protein import; protein processing
    DOI:  https://doi.org/10.1016/j.jbc.2025.110860
  24. Cell. 2025 Oct 30. pii: S0092-8674(25)01128-6. [Epub ahead of print]188(22): 6107-6108
    Iron raider: Tumors in the bone marrow.
    Jiashuo Zheng, Marcus Conrad.
      In this issue of Cell, Han et al. find that tumor cells metastasizing to the bone marrow hijack macrophages to seize iron from red blood cells. This metabolic plunder thereby fuels tumor progression while contributing to anemia.
    DOI:  https://doi.org/10.1016/j.cell.2025.09.028
  25. Cell Rep Methods. 2025 Oct 29. pii: S2667-2375(25)00246-2. [Epub ahead of print] 101210
    SICyLIA-cTMT dissects redox proteome dynamics with high accuracy and depth at microgram scale.
    Sergio Lilla, Samuel Atkinson, Sonja Radau, Ulla-Maja Bailey, Atul Shahaji Deshmukh, Jiska van der Reest, Joanna Kirkpatrick, Thomas MacVicar, Sara Zanivan.
      Cysteine oxidative modifications are critical signaling events regulating cellular functions, but their low abundance and dynamic nature pose technical challenges. We developed the SICyLIA-TMT workflow, which sequentially labels reduced and reversibly oxidized cysteines with light and heavy iodoacetamide (IAA) within the same sample. The inclusion of tandem mass tags (TMTs) enables simultaneous quantification of oxidative modification dynamics and protein levels across multiple conditions using micrograms of material. To improve the detection of low-abundance oxidized cysteines, a dedicated TMT channel serves as a carrier for heavy IAA-labeled peptides (SICyLIA-cTMT), enhancing quantification and enabling precise stoichiometry calculations. We demonstrate the workflow's applicability to cultured cells and full organs under stress. SICyLIA-cTMT achieves unprecedented depth and accuracy in redox proteome analysis while reducing mass spectrometry time. Combining SICyLIA-TMT with latest mass spectrometry technologies further halves the acquisition time without compromising coverage, improving throughput and enabling comprehensive studies of oxidative signaling.
    Keywords:  CP: biotechnology; cancer; cysteine oxidation; fibroblasts; mass spectrometry; obesity; oxidative signaling; post-translational modification; redox proteomics; redox stress
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101210
  26. Cell Rep. 2025 Oct 23. pii: S2211-1247(25)01249-5. [Epub ahead of print]44(11): 116478
    Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response.
    Abigail M Elliot, Isabel Ribeiro Bravo, Yiyi Zhao, Zhuorui Wang, Jeanette Astorga Johansson, Esme Hutton, Richard Cunningham, Henna Myllymäki, Kai Yee Chang, Justyna Cholewa-Waclaw, Lisa Kelly, Mariana Beltran, Amy Lewis, Philip M Elks, Carsten Gram Hansen, Neil C Henderson, Yi Feng.
      Oncogenic driver mutations are common in normal tissues, indicating that non-genetic factors are necessary for tumorigenesis. Phenotypic plasticity is a crucial gateway to malignancy, and inflammation can fuel tumorigenesis; however, little is known about the timing and mechanisms by which these hallmarks first emerge. Using single-cell transcriptomics and in vivo live imaging, we characterized the immediate cell-intrinsic and innate immune responses during the first 24 h following oncogenic Ras activation in a zebrafish model of HRASG12V-mediated skin tumor initiation. We found that in a subset of basal keratinocytes, RAS alone drives phenotypic plasticity, and these cells undergo dedifferentiation and partial epithelial-to-mesenchymal transition (EMT), resembling malignant cells in human squamous cell carcinoma. Strikingly, these cells also drive a tumor-promoting neutrophil program, which in turn enhances preneoplastic cell proliferation. Thus, oncogenic Ras effects are dictated by the cell of origin, and we revealed a link between unlocking plasticity and the onset of tumor-promoting inflammation.
    Keywords:  CP: Cancer; CP: Immunology; Ras; epithelial-mesenchymal transition; preneoplastic; tumor initiation; tumor-associated neutrophils; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2025.116478
  27. Nature. 2025 Oct 29.
    This whale lives for centuries: its secret could help extend human lifespan.
    Heidi Ledford.
      
    Keywords:  Ageing; Molecular biology; Zoology
    DOI:  https://doi.org/10.1038/d41586-025-03511-9
  28. Cell Death Discov. 2025 Oct 31. 11(1): 495
    Redox destabilization by ibrutinib promotes ferroptosis in diffuse large B-cell lymphoma (DLBCL).
    Anuschka Langpape, Debora Bonasera, Jenny Stroh, Moritz Reese, Maria Cartolano, Gianmaria Liccardi, Silvia von Karstedt.
      Diffuse large B-cell lymphoma (DLBCL) exhibits marked clinical heterogeneity and frequent treatment resistance, particularly in molecularly defined high-risk subtypes such as ABC-DLBCL. While current therapies largely rely on apoptosis induction, non-apoptotic cell death pathways remain underexplored in hematologic malignancies. Here, we identify ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated necrosis, as an effective baseline in additive therapy with ibrutinib for the treatment of DLBCL. Transcriptomic and lipidomic analyses revealed that DLBCL cells, despite lacking overt enrichment of polyunsaturated fatty acids (PUFAs), display elevated expression of the core ferroptosis protective machinery. Inhibition of GPX4 induced rapid and selective lipid ROS accumulation and cell death across a panel of human and murine DLBCL cellular models irrespective of subtype. Notably, the BTK inhibitor and clinical compound ibrutinib showed additive effects with GPX4 inhibition, even at concentrations below its cytotoxic threshold, expanding its therapeutic relevance beyond BTK inhibition. Mechanistically, we uncover two activities of ibrutinib to enhance ferroptosis sensitivity: First, chemical scavenging of glutathione and second the inhibition of GPX4 protein expression via translational repression. Thereby, our findings define ferroptosis as a basis for additive therapy in combination with ibrutinib in DLBCL and reveal a previously unrecognized role for ibrutinib in directly modulating anti-oxidant defense.
    DOI:  https://doi.org/10.1038/s41420-025-02826-w
  29. Nat Commun. 2025 Oct 27. 16(1): 9481
    Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
    Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis, Franz Hagn.
      The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.
    DOI:  https://doi.org/10.1038/s41467-025-65363-1
  30. EMBO Rep. 2025 Oct 30.
    Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
    Dongjing Cai, Cheng Chen, Piyanat Meekrathok, Weiqian Zeng, Zheng Wang, Zhigang Peng, Yunan Mo, Xia Xu, Junling Wang, Jian Qiu.
      Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction-observed over two decades ago-has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.
    Keywords:  Cytosolic TOP3α; Inflammation; Mitochondrial DNA; cGAS
    DOI:  https://doi.org/10.1038/s44319-025-00614-2
  31. J Immunol. 2025 Oct 31. pii: vkaf250. [Epub ahead of print]
    Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
    Emilie L Fisher-Gupta, Emma S Hathaway, Jeffrey M Perera, Erin Q Jennings, Channing Chi, Allison E Sewell, Spenser H Stone, Jason E Muka, Rachael C Sinard, Joseph A DeCorte, Heidi Chen, John T Wilson, Jens Meiler, Jeffrey C Rathmell.
      Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.
    Keywords:  T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism
    DOI:  https://doi.org/10.1093/jimmun/vkaf250
  32. EMBO Rep. 2025 Oct 27.
    Extracellular matrix-driven metabolic control of pancreatic endocrine lineage allocation.
    Christine Ebeid, Adam Rump, Chenglei Tian, Anant Mamidi, Adèle De Arcangelis, Gérard Gradwohl, Henrik Semb.
      The mechanical and metabolic states of progenitor and stem cells are emerging as key regulators of cell fate decisions. Lineage specification of pancreatic endocrine cells is promoted by reduced mechanical tension in vitro, but the underlying mechanism is poorly understood. Here, we show that heterogeneously deposited low-adhesion extracellular matrix (ECM) components, such as the laminin isoform LN411, trigger a local "soft" environment by broadly reducing the expression of integrins. Mimicking this low-tension state by in vitro knockdown and in vivo gene targeting of the LN-binding integrins Itga3 and Itga6 reveal their importance in inducing endocrinogenesis. Unexpectedly, the cell responds to this change in tensile forces by engaging a major metabolic enzyme, PDK4, to execute the resulting cell fate decision. PDK4 achieves this through two distinct mechanisms: a non-canonical action controlling YAP activity and a canonical metabolic function maintaining PDX1 expression. In sum, we believe our findings have broad relevance for how local changes in mechanical tension governs cell behaviour in many developmental and disease contexts.
    Keywords:  Laminin-411; Mechanotransduction; PDK4; Pancreatic Endocrinogenesis; YAP Signalling
    DOI:  https://doi.org/10.1038/s44319-025-00610-6
  33. Nat Commun. 2025 Oct 29. 16(1): 9544
    BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability.
    Kathy Situ, Haohui Duan, Stephen K Godin, Joshua Yang, Gabrielle Q McCloskey, Basim Naeem, Margaret K Gillis, Muhammad H Zeb, Silvi Salhotra, Pratha Rawal, Nisha Patel, Salome K Mouliere, Jie Chen, Angéla Békési, Hajnalka L Pálinkás, Subramanian Venkatesan, Abby M Green, Nicolai J Birkbak, Beáta G Vértessy, Charles Swanton, Shailja Pathania.
      BRCA2 plays a critical role in stabilizing stalled replication forks, yet critical gaps remain in understanding how BRCA2 deficiency triggers fork collapse and drives genomic instability. Here, we identify cytidine deaminase APOBEC3B as a key driver of this process. Using a unique uracil-in-DNA probe, we show that BRCA2 loss promotes APOBEC3B-mediated uracil accumulation in single-stranded DNA (U-ssDNA) at stalled forks. These lesions when processed by UNG2 and APE1, trigger fork collapse and release ssDNA fragments into the cytoplasm, activating NF-κB signaling. This in turn upregulates APOBEC3B expression, establishing a self-reinforcing loop that amplifies cytidine deamination at stalled forks and exacerbates genomic instability. Depletion of APOBEC3B, UNG2, or APE1 rescues these defects. Notably, BRCA1-deficient cells do not accumulate U-ssDNA or induce APOBEC3B under replication stress, highlighting a BRCA2-specific vulnerability. Clinically, low APE1 expression correlates with poor survival in patients with BRCA2-mutant tumors, with high APOBEC3 levels further worsening outcomes. Together, our findings establish that replication stress, whether intrinsic or therapy induced, triggers APOBEC3B overexpression and potentially activates an APOBEC3B-driven mutagenic loop in BRCA2-deficient cells. These results position APOBEC3B, UNG2 and APE1 as critical regulators of BRCA2-mutant tumor evolution and therapy resistance.
    DOI:  https://doi.org/10.1038/s41467-025-64578-6
  34. Nat Commun. 2025 Oct 27. 16(1): 9448
    Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
    Yi Wang, Hao-Yuan Yu, Zi-Juan Yi, Lian-Yu Qi, Jing-Song Yang, Hai-Xin Xie, Min Zhao, Na-Hui Liu, Jia-Qi Chen, Tian-Jiao Zhou, Lei Xing, Xian-Wu Cheng, Hu-Lin Jiang.
      Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber's hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-025-64486-9
  35. EMBO J. 2025 Oct 29.
    DNGR-1 signalling limits dendritic cell activation for optimal antigen cross-presentation.
    Michael D Buck, Tomás Castro-Dopico, Oliver Schulz, Ana Cardoso, Probir Chakravarty, Nathalie Legrave, Conor M Henry, Johnathan Canton, Estelle Wu, Sonia Lee, Neil C Rogers, Enzo Z Poirier, William Stainier, Victor Bosteels, Eleanor Childs, James I MacRae, J Mark Skehel, Santiago Zelenay, Caetano Reis E Sousa.
      Innate immune receptors often induce activation of conventional dendritic cells (cDCs) and enhance antigen (cross-)presentation, favouring immune responses. DNGR-1 (CLEC9A), a receptor expressed by type 1 cDCs (cDC1s) and implicated in immune responses to viruses and cancer, recognises F-actin exposed on dead cell remnants and promotes cross-presentation of associated antigens. Here, we show that recruitment of phosphatase SHIP1, a process governed by a single amino acid residue adjacent to the signalling motif of the receptor, partly explains how DNGR-1 fails to trigger cDC1 activation in vitro. Substituting this residue converts DNGR-1 into an activating receptor but decreases induction of cross-presentation of dead cell-associated antigens. Introducing the reverse mutation into the related receptor Dectin-1 impairs its activation capacity while enhancing its ability to promote cross-presentation. These findings reveal a functional trade-off in receptor signalling and suggest that DNGR-1 has evolved to prioritise antigen cross-presentation over cellular activation, possibly to minimise inflammatory responses to dead cells.
    Keywords:  Activation; CLEC9A; Cross-presentation; DNGR-1; cDC1
    DOI:  https://doi.org/10.1038/s44318-025-00620-z
  36. Nat Biotechnol. 2025 Oct 30.
    Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.
    Karin Gustafsson, Sergey Isaev, Kamdin Mirsanaye, Johanna Hofmann, Kameron A Kooshesh, Ninib Baryawno, Anna Kiem, Nicolas Severe, Ting Zhao, Elizabeth W Scadden, Joel A Spencer, Christian Burns, Kumaran Akilan, Nikolaos Barkas, Hayalneh Gessessew, Konstantinos D Kokkaliaris, Charles P Lin, Peter V Kharchenko, David T Scadden.
      Thymic atrophy and the progressive immune decline that accompanies it is a major health problem, chronically with age and acutely with immune injury. No definitive solution is available. Here we demonstrate that one of the three mesenchymal cell subsets identified by single-cell analysis of human and mouse thymic stroma is a critical niche component for T lymphopoiesis. The Postn+ subset is perivascular, and its depletion abrogates T cell progenitor recruitment, likely through production of the chemokine Ccl19. It markedly declines with age and in the acute setting of hematopoietic stem cell transplant conditioning. When isolated and adoptively transferred, Postn+ cells durably engraft the atrophic thymus, recruit early T progenitors, increase T cell neogenesis and enhance T cell response to vaccination. More readily available mesenchymal populations expressing Ccl19 provide similar effects. These data define a thymus lymphopoietic niche cell type that may be manipulated therapeutically to regenerate T lymphopoiesis.
    DOI:  https://doi.org/10.1038/s41587-025-02864-w
  37. Cell Mol Life Sci. 2025 Oct 30. 82(1): 380
    Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
    Indira Chavan, Arindam Bhattacharjee.
      Lysosomes respond to cellular nutrient availability and diverse oncoming vesicle traffic such as endocytosis and autophagy by switching between anabolic signaling or catabolic hydrolase activity, which coincides with a drastic shift in their cellular distribution, organelle contacts, ion homeostasis, membrane proteome and lipidome. Emerging evidence now reveals a dynamic remodeling of lysosomal membrane to counter membrane damage, acting via extensive lipid transfer from the endoplasmic reticulum or by localized membrane repair. Functionally, lysosomes play a key role in lipid metabolism and intracellular calcium signaling. Unsurprisingly, disease-associated lysosomes are either often hyperactive- thus promoting abnormal tissue growth, or hypoactive, promoting storage. Taken together, this presents an incredible functional diversity among the cellular population of lysosomes. Here, we discuss this intracellular heterogeneity and intercellular diversity in context of lysosomal function in health and disease.
    Keywords:  Lipid storage disorders; Lysosome plasticity; Lysosome quality control; Lysosome subpopulations; Phosphoinositides
    DOI:  https://doi.org/10.1007/s00018-025-05883-7
  38. Nat Commun. 2025 Oct 29. 16(1): 9531
    A red fluorescent genetically encoded biosensor for in vivo imaging of extracellular L-lactate dynamics.
    Yuki Kamijo, Philipp Mächler, Natalie Ness, Cong Quang Vu, Tsukasa Kusakizako, Jamsad Mannuthodikayil, Zaneta Ku, Marc Boisvert, Ekaterina Grebenik, Ikumi Miyazaki, Rina Hashizume, Haruaki Sato, Rui Liu, Yukiko Hori, Taisuke Tomita, Tetsuro Katayama, Akihiro Furube, Gabriela Caraveo, Marie-Eve Paquet, Mikhail Drobizhev, Osamu Nureki, Satoshi Arai, Marco Brancaccio, Robert E Campbell, David Kleinfeld, Yusuke Nasu.
      L-Lactate is increasingly recognized as an intercellular energy currency in mammals, but mysteries remain regarding the spatial and temporal dynamics of its release and uptake between cells via the extracellular environment. Here we introduce R-eLACCO2.1, a red fluorescent extracellular L-lactate biosensor that is superior to previously reported green fluorescent biosensors in in vivo sensitivity to increases in extracellular L-lactate and spectral orthogonality. R-eLACCO2.1 exhibits excellent fluorescence response in cultured cells, mouse brain slices, and live mice. R-eLACCO2.1 also serves as an effective fluorescence lifetime-based biosensor. Using R-eLACCO2.1, we monitor whisker stimulation and locomotion-induced changes in endogenous extracellular L-lactate in the somatosensory cortex of awake mice. To highlight the potential insights gained from in vivo measurements with R-eLACCO2.1, we perform dual-color imaging from the somatosensory cortex of actively locomoting mice. This enables us to simultaneously observe the neural activity, reported by a green fluorescent GCaMP calcium ion biosensor, and extracellular L-lactate. As the high-performance tool in the suite of extracellular L-lactate biosensors, R-eLACCO2.1 is ideally suited to delimit the emerging roles of L-lactate in mammalian metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-64484-x
  39. Mol Oncol. 2025 Oct 29.
    A guide to reactive oxygen species in tumour hypoxia: measurement and therapeutic implications.
    Lina Hacker, Elysia Sarsam, Stuart J Conway, Ester M Hammond.
      Reactive oxygen species (ROS) are a diverse group of molecules that serve as both essential signalling mediators and potential drivers of oxidative stress. In tumours, ROS influence critical processes such as proliferation, angiogenesis, metabolic adaptation and therapy resistance. These processes are further modulated by reduced oxygen availability (hypoxia), a defining feature of many solid tumours that can alter redox balance and cellular signalling. The interplay between ROS and hypoxia is highly dynamic, with both factors shaping tumour behaviour in complex and often unpredictable ways. Accurately measuring ROS and tumour oxygenation remains a significant challenge due to their transient nature and variability in levels across different tumour types. In this guide, we provide a comprehensive update on the dynamic interaction between ROS and hypoxia in tumours, evaluate current strategies for ROS detection and discuss emerging therapeutic approaches that target redox vulnerabilities in cancer. Understanding the intricate relationship between ROS and hypoxia is crucial for refining therapeutic strategies and improving patient outcomes.
    Keywords:  cancer; hypoxia; reactive oxygen species; tumour microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70151
  40. Sci Signal. 2025 Oct 28. 18(910): eadt3549
    Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria.
    Madelyn M Jackstadt, Ronald Fowle-Grider, Mun-Gu Song, Matthew H Ward, Madison Barr, Kevin Cho, Hector H Palacios, Samuel Klein, Leah P Shriver, Gary J Patti.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to a shift in the composition of the gut microbiome. Here, we found that depletion of the gut microbiome in adult zebrafish led to the development of steatotic liver disease in animals on standard diets. Using metabolomics and isotope tracing, we found that dietary glucose was converted to sorbitol by host intestinal cells. Although bacteria degraded sorbitol in control animals, sorbitol was transferred to the livers of fish when the gut microbiome had been depleted. Within the liver, sorbitol was converted into fructose 1-phosphate, which subsequently activated glucokinase and increased glycolytic flux, leading to increased hepatic glycogen and fat content. Inhibition of sorbitol production in microbiome-depleted animals was sufficient to prevent the development of steatotic liver, and colonizing the intestines of microbiome-depleted fish with sorbitol-degrading Aeromonas bacterial strains rescued the steatotic liver phenotype. Conversely, exogenous administration of high concentrations of sorbitol phenocopied gut microbiota depletion and induced hepatic steatosis. Together, these findings show that sorbitol-degrading bacteria in the gut protect against steatotic liver disease and suggest that excessive intake of dietary sorbitol may pose a risk for the development of MASLD.
    DOI:  https://doi.org/10.1126/scisignal.adt3549
  41. Cell Rep. 2025 Oct 28. pii: S2211-1247(25)01255-0. [Epub ahead of print]44(11): 116484
    Circadian clock control of ribosome composition promotes rhythmic translation and termination fidelity.
    Teresa M Lamb, Kathrina D Castillo, Rachel Porter, Cheng Wu, Samuel O Purvine, Griffin Best, Erika Zink, Ebimobowei O Preh, Lunda Shen, Matthew S Sachs, Deborah Bell-Pedersen.
      Ribosome composition is dynamic, shifting with cell state and stress, but whether it varies with circadian time is unknown. Here, we uncover circadian clock-driven changes in ribosome composition in Neurospora crassa. Mass spectrometry of ribosomes across circadian time identified six ribosomal proteins and one associated factor under clock control. Rhythms in eL31 abundance were validated in purified ribosomes, and deletion of el31 disrupted translation rhythms in nearly half of rhythmically translated mRNAs. N. crassa eL31 promotes circadian control of translation termination and impacts elongation fidelity while maintaining Mg homeostasis, a key determinant of translational accuracy. These findings reveal that the circadian clock reprograms ribosome composition to orchestrate rhythmic translation and fidelity, temporally expanding the proteome beyond the static genome to align cellular function with time of day.
    Keywords:  CP: Molecular biology; Zuotin; circadian clock; eL31; magnesium ion homeostasis; ribosome composition; translation; translation fidelity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116484
  42. Nature. 2025 Oct 29.
    Origins of chromosome instability unveiled by coupled imaging and genomics.
    Marco Raffaele Cosenza, Alice Gaiatto, Büşra Erarslan Uysal, Álvaro Andrades, Nina Luisa Sautter, Marina Simunovic, Michael Adrian Jendrusch, Sonia Zumalave, Tobias Rausch, Aliaksandr Halavatyi, Eva-Maria Geissen, Joshua Lucas Eigenmann, Thomas Weber, Patrick Hasenfeld, Eva Benito, Catherine Stober, Isidro Cortes-Ciriano, Andreas E Kulozik, Rainer Pepperkok, Jan O Korbel.
      Somatic chromosome instability results in widespread structural and numerical chromosomal abnormalities (CAs) during cancer evolution1-3. Although CAs have been linked to mitotic errors resulting in the emergence of nuclear atypia4-7, the underlying processes and rates of spontaneous CA formation in human cells are underexplored. Here we introduce machine-learning-assisted genomics and imaging convergence (MAGIC)-an autonomously operated platform that integrates live-cell imaging of micronucleated cells, machine learning on-the-fly and single-cell genomics to systematically investigate CA formation. Applying MAGIC to near-diploid, non-transformed cell lines, we track de novo CAs over successive cell cycles, highlighting the common role of dicentric chromosomes as initiating events. We determine the baseline CA mutation rate, which approximately doubles in TP53-deficient cells, and observe that chromosome losses arise more frequently than gains. The targeted induction of DNA double-strand breaks along chromosome arms triggers distinct CA processes, revealing stable isochromosomes, coordinated segregation and amplification of isoacentric segments in multiples of two, as well as complex CA outcomes, influenced by the chromosomal break location. Our data contrast de novo CA spectra from somatic mutational landscapes after selection occurred. The experimentation enabled by MAGIC advances the dissection of DNA rearrangement processes, shedding light on fundamental determinants of chromosomal instability.
    DOI:  https://doi.org/10.1038/s41586-025-09632-5
  43. Nat Genet. 2025 Oct 27.
    Cellular states associated with metastatic organotropism and survival in patients with pancreatic ductal adenocarcinoma.
    Morteza Chalabi Hajkarim, Michael May, Amit Dipak Amin, Jacob Jamison, Somnath Tagore, Edridge D'Souza, Lindsay Caprio, Zachary H Walsh, Joy Linyue Fan, Mingxuan Zhang, Parin Shah, Sinan Abuzaid, Alissa Michel, Sun Dajiang, Winston Wong, Neha Shaikh, Priyanka Ramaradj, Basil Bakir, Michael D Kluger, John Chabot, Elham Azizi, Hanina Hibshoosh, Anil K Rustgi, Alexander G Raufi, Gulam A Manji, Benjamin Izar.
      Most patients with localized pancreatic ductal adenocarcinoma (PDAC) experience recurrence after resection. Analysis of 744 patients with resected PDAC revealed that patients with initial isolated liver-metastatic recurrence (n = 100) had significantly worse overall survival than those with initial isolated lung-metastatic recurrence (n = 31). Using single-nucleus RNA sequencing in a representative cohort, we found that transcriptional profiles of primary cancer cells with liver-metastatic recurrence and lung-metastatic recurrence were correlated with those of normal liver and lung parenchymal cells, respectively, suggesting adoption of organ-specific metastatic programs at the primary site. These signatures were confirmed in transcriptomes of PDAC lung and liver metastases, primary lung and liver tumors, and organotropic PDAC xenograft models. These signatures were independent of large genomic events, and analysis of large-scale tumor profiling data showed no genetic alterations predictive of recurrence patterns. Additional analyses suggested that metastatic recurrence may be determined early in tumorigenesis and influenced by tumor-infiltrating immune cells. Thus, pre-existing cellular states within primary tumors appear to guide organ-specific metastatic relapse.
    DOI:  https://doi.org/10.1038/s41588-025-02345-5
  44. Cell. 2025 Oct 28. pii: S0092-8674(25)01180-8. [Epub ahead of print]
    Remembering David Baltimore (1938-2025).
    George Q Daley.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.10.015
  45. Nature. 2025 Oct 29.
    Evidence for improved DNA repair in long-lived bowhead whale.
    Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Gregory Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alexander Y Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric C Hillpot, John C Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ekaterina Strelkova, Ena Haseljic, Avnee Patel, Maggie E Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael R Hoopmann, Robert L Moritz, Shingo Fujii, Amandine Pelletier, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Carlo C Maley, Mauro Modesti, Giannicola Genovese, Mirre J P Simons, Jan Vijg, Andrei Seluanov, Vera Gorbunova.
      At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto's paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. However, bowhead whale cells exhibited enhanced DNA double-strand break repair capacity and fidelity, and lower mutation rates than cells of other mammals. We found the cold-inducible RNA-binding protein CIRBP to be highly expressed in bowhead fibroblasts and tissues. Bowhead whale CIRBP enhanced both non-homologous end joining and homologous recombination repair in human cells, reduced micronuclei formation, promoted DNA end protection, and stimulated end joining in vitro. CIRBP overexpression in Drosophila extended lifespan and improved resistance to irradiation. These findings provide evidence supporting the hypothesis that, rather than relying on additional tumour suppressor genes to prevent oncogenesis3-5, the bowhead whale maintains genome integrity through enhanced DNA repair. This strategy, which does not eliminate damaged cells but faithfully repairs them, may be contributing to the exceptional longevity and low cancer incidence in the bowhead whale.
    DOI:  https://doi.org/10.1038/s41586-025-09694-5
  46. PLoS Comput Biol. 2025 Oct;21(10): e1013635
    Optimization-based framework with flux balance analysis (FBA) and metabolic pathway analysis (MPA) for identifying metabolic objective functions.
    Ching-Mei Wen, Eleftherios Papoutsakis, Marianthi Ierapetritou.
      Metabolic network modeling, especially Flux Balance Analysis (FBA), plays a critical role in systems biology by providing insights into cellular behaviors. Although FBA is the main tool for predicting flux distributions, it can face challenges capturing flux variations under different conditions. Selecting an appropriate objective function is therefore important for accurately representing system performance. To address this, we introduce a novel framework (e.g., TIObjFind) that imposes Metabolic Pathway Analysis (MPA) with Flux Balance Analysis (FBA) to analyze adaptive shifts in cellular responses throughout different stages of a biological system. This framework determines Coefficients of Importance (CoIs) that quantify each reaction's contribution to an objective function, aligning optimization results with experimental flux data. By examining Coefficients of Importance, TIObjFind enhances the interpretability of complex metabolic networks and provides insights into adaptive cellular responses.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013635
  47. Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2522646122
    p53 regulates the expression of histone modifiers to restrict stemness and maintain differentiated luminal identity in breast cancer.
    Yael Aylon, Noa Furth, Anna C Pirona, Adi Lavie, Olga Fedorova, Ori Hassin, Nuno Padrão, Maxime Steinmetz, Avital Sarusi-Potuguez, Liat Fellus-Alyagor, Irit Shimoni, Bareket Dassa, Wilbert Zwart, Efrat Shema, Moshe Oren.
      Breast cancer is the leading cause of death in women under 50. The majority of breast cancers are estrogen receptor α-positive (ER+) and are commonly treated with hormonal therapies such as tamoxifen that inhibit ER activity. The TP53 tumor suppressor gene, encoding the p53 protein, is the most frequently mutated gene in breast cancer, and TP53 mutations are associated with diminished tamoxifen response and worse prognosis for breast cancer patients. Here, we report that in breast cancer cells p53 and ER cooperate to regulate the transcription of a set of genes encoding chromatin modifiers. The net result is a global increase in H3K4me3 and decrease in H3K9me3 chromatin marks. The resultant "open" chromatin is associated with increased transcription of luminal cell identity genes and enhanced tamoxifen sensitivity. Conversely, diminished p53 control of these chromatin modulators is associated with the evolution of tamoxifen resistance and cancer stem cell properties.
    Keywords:  breast cancer; estrogen receptor; histone modification; p53; tamoxifen
    DOI:  https://doi.org/10.1073/pnas.2522646122
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