bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–02–23
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
  2. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
  3. RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
  4. Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
  5. An organism-level quantitative flux model of energy metabolism in mice.
  6. Cooperative nutrient scavenging is an evolutionary advantage in cancer.
  7. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
  8. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  9. Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
  10. Querying stool for dietary information.
  11. ImmuneLENS characterizes systemic immune dysregulation in aging and cancer.
  12. How are mitochondrial nucleoids trafficked?
  13. Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
  14. A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
  15. Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
  16. TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
  17. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
  18. Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
  19. Clonal driver neoantigen loss under EGFR TKI and immune selection pressures.
  20. Role of aconitase in plant stress response and signaling.
  21. Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.
  22. Linking macrophage metabolism to function in the tumor microenvironment.
  23. Structural dynamics of human fatty acid synthase in the condensing cycle.
  24. A novel biosensor for the spatiotemporal analysis of STING activation during innate immune responses to dsDNA.
  25. Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.
  26. Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism.
  27. Mechanism for local attenuation of DNA replication at double-strand breaks.
  28. Intratumour oxidative hotspots provide a niche for cancer cell dissemination.
  29. CDKN2ALow cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance.
  30. Overfeeding induces adipose tissue release of distinct mitochondria.
  31. Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
  32. Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.
  33. Solute carriers: The gatekeepers of metabolism.
  34. AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
  35. Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
  36. Human-correlated genetic models identify precision therapy for liver cancer.
  37. High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.
  38. Uridine Metabolism as a Targetable Metabolic Achilles' Heel for chemo-resistant B-ALL.
  39. Identification and characterization of cell niches in tissue from spatial omics data at single-cell resolution.
  40. Compositionally unique mitochondria in filopodia support cellular migration.
  41. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer.
  42. Helminths target macrophage epigenetics and metabolism to evade immunity.
  43. Metabolic and stress response adaptations in T cells to fever and physiological heat.
  44. GDP-mannose 4,6-dehydratase is a key driver of MYCN-amplified neuroblastoma core fucosylation and tumorigenesis.
  45. Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation.
  46. Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties.
  47. Enhanced flux potential analysis links changes in enzyme expression to metabolic flux.
  48. HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
  49. Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.
  50. B cell immunometabolism in health and disease.
  1. Nat Metab. 2025 Feb 19.
    Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
    Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.
      Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.
    DOI:  https://doi.org/10.1038/s42255-025-01224-x
  2. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]
    Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    Keywords:  MPST; ergothioneine; exercise; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
  3. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]
    RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
    Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.
      Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.
    Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
  4. J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00155-3. [Epub ahead of print] 108307
    Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
    Hannah M German, Jolita Ciapaite, Nanda M Verhoeven-Duif, Judith J M Jans.
      The constant replenishment of tricarboxylic acid (TCA) cycle intermediates, or anaplerosis, is crucial to ensure optimal TCA cycle activity in times of high biosynthetic demand. In inborn metabolic diseases, anaplerosis is often affected, leading to impaired TCA cycle flux and ATP production. In these cases, anaplerotic compounds can be a therapy option. Triheptanoin, a triglyceride containing three heptanoate chains, is thought to be anaplerotic through production of propionyl- and acetyl-CoA. However, the precise mechanism underlying its anaplerotic action remains poorly understood. In this study, we performed a comprehensive in vitro analysis of heptanoate metabolism and compared it to that of octanoate, an even-chain fatty acid which only provides acetyl-CoA. Using stable isotope tracing, we demonstrate that both heptanoate and octanoate contribute carbon to the TCA cycle in HEK293T cells, confirming direct anaplerosis. Furthermore, by using labeled glucose and glutamine, we show that heptanoate and octanoate decrease the contribution of glucose-derived carbon and increase the influx of glutamine-derived carbon into the TCA cycle. Our findings also point towards a change in redox homeostasis, indicated by an increased NAD+/NADH ratio, accompanied by a decreased lactate/pyruvate ratio and increased de novo serine biosynthesis. Taken together, these results highlight the broad metabolic effects of heptanoate and octanoate supplementation, suggesting that therapeutic efficacy may strongly depend on specific disease pathophysiology. Furthermore, they underline the need for careful selection of fatty acid compound and concentration to optimize anaplerotic action.
    Keywords:  Anaplerosis; fatty acids; isotopic tracer; mass spectrometry (MS); metabolic disease; metabolomics; redox regulation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108307
  5. Cell Metab. 2025 Feb 13. pii: S1550-4131(25)00008-7. [Epub ahead of print]
    An organism-level quantitative flux model of energy metabolism in mice.
    Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.
      Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.
    Keywords:  energy metabolism; futile cycle; high-fat diet; isotope tracing; metabolic flux analysis; ob/ob; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.008
  6. Nature. 2025 Feb 19.
    Cooperative nutrient scavenging is an evolutionary advantage in cancer.
    Gizem Guzelsoy, Setiembre D Elorza, Manon Ros, Logan T Schachtner, Makiko Hayashi, Spencer Hobson-Gutierrez, Parker Rundstrom, Julia S Brunner, Ray Pillai, William E Walkowicz, Lydia W S Finley, Maxime Deforet, Thales Papagiannakopoulos, Carlos Carmona-Fontaine.
      The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.
    DOI:  https://doi.org/10.1038/s41586-025-08588-w
  7. bioRxiv. 2025 Feb 08. pii: 2025.02.07.637120. [Epub ahead of print]
    Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
    Kimberly S Huggler, Carlos A Mellado Fritz, Kyle M Flickinger, Gavin R Chang, Meghan F McGuire, Jason R Cantor.
      Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.
    DOI:  https://doi.org/10.1101/2025.02.07.637120
  8. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  9. Cell Death Dis. 2025 Feb 19. 16(1): 116
    Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
    Mengfei Yao, Xingming Zhang, Tianqi Wu, Tao Feng, Xiaojie Bian, Mierxiati Abudurexiti, Wenfeng Wang, Guohai Shi, Gong-Hong Wei, Qin Zhang, Xiangyun Li, Gang Feng, Leilei Du, Jianhua Wang.
      Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors; however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.
    DOI:  https://doi.org/10.1038/s41419-025-07449-8
  10. Nat Metab. 2025 Feb 18.
    Querying stool for dietary information.
    Lars O Dragsted, Henrik M Roager, Catalina Cuparencu.
      
    DOI:  https://doi.org/10.1038/s42255-025-01219-8
  11. Nat Genet. 2025 Feb 18.
    ImmuneLENS characterizes systemic immune dysregulation in aging and cancer.
    TRACERx Consortium
      Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.
    DOI:  https://doi.org/10.1038/s41588-025-02086-5
  12. Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]
    How are mitochondrial nucleoids trafficked?
    Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.
      Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.
    Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
  13. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635929. [Epub ahead of print]
    Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues.
    Janell Lm Smith, Kamaryn Tanner, Jack Devine, Anna S Monzel, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to metabolic perturbations, we develop an ISR GDF15 index quantifying the GDF15 arm of the ISR activation in human cells. Validation of ISR GDF15 index across 44 postmortem human tissues illustrates how this index can be applied to investigate tissue-specific and age-related ISR activation.
    DOI:  https://doi.org/10.1101/2025.01.31.635929
  14. bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]
    A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
    Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.
      Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.
    DOI:  https://doi.org/10.1101/2025.02.03.635951
  15. bioRxiv. 2025 Jan 30. pii: 2025.01.30.635785. [Epub ahead of print]
    Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
    Iryna Bohovych, Gabriella Menezes da Silva, Saieeda Fabia Ali, Emma J Bergmeyer, Edward M Germany, Adarsh Mayank, James A Wohlschlegel, Jason C Casler, Muhammad Arifur Rahman, Taras Y Nazarko, Maureen Tarsio, Takuya Shiota, Laura L Lackner, Steven M Claypool, Patricia M Kane, Antoni Barrientos, Oleh Khalimonchuk.
      The mitochondrial inner membrane is among the most protein-dense cellular membranes. Its functional integrity is maintained through a concerted action of several conserved mechanisms that are far from clear. Here, using the baker's yeast model, we functionally characterize Mdm38/LETM1, a disease-related protein implicated in mitochondrial translation and ion homeostasis, although the molecular basis of these connections remains elusive. Our findings reveal a novel role for Mdm38 in maintaining protein homeostasis within the inner membrane. Specifically, we demonstrate that Mdm38 is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles. These processes are linked to the m- AAA quality control protease, whose unrestrained activity disrupts the assembly and stability of respiratory chain complexes in Mdm38-deficient cells. Our study highlights the central role of Mdm38 in mitochondrial biology and reveals how it couples proteostatic mechanisms to ion homeostasis across subcellular compartments.
    DOI:  https://doi.org/10.1101/2025.01.30.635785
  16. Sci Adv. 2025 Feb 21. 11(8): eadr3723
    TRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
    Pradeep K Sheokand, Andrew M James, Benjamin Jenkins, Pawel K Lysyganicz, Denis Lacabanne, Martin S King, Edmund R S Kunji, Symeon Siniossoglou, Albert Koulman, Michael P Murphy, Kasparas Petkevicius.
      The diversity of cellular phospholipids, crucial for membrane homeostasis and function, arises from enzymatic remodeling of their fatty acyl chains. In this work, we reveal that poorly understood TRAM-LAG1-CLN8 domain (TLCD)-containing proteins are phospholipid remodeling enzymes. We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates previously undescribed fatty acid and thiamine (vitamin B1) esters as its secondary products. Furthermore, we establish that human TLCD protein CLN8, mutations of which cause fatal neurodegenerative Batten disease, is a lysophosphatidylglycerol acyltransferase. We show that CLN8 catalyzes the essential step in the biosynthesis of bis(monoacylglycero)phosphate, a phospholipid critical for lysosome function. Our study unveils a family of acyltransferases integral to cellular membrane phospholipid homeostasis and human disease.
    DOI:  https://doi.org/10.1126/sciadv.adr3723
  17. Nature. 2025 Feb 19.
    Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
    Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.
      Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
    DOI:  https://doi.org/10.1038/s41586-025-08590-2
  18. Nature. 2025 Feb 20.
    Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
    Kollin Schultz, Pedro Costa-Pinheiro, Lauren Gardner, Laura V Pinheiro, Julio Ramirez-Solis, Sarah M Gardner, Kathryn E Wellen, Ronen Marmorstein.
      The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP-DH and ACP-ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.
    DOI:  https://doi.org/10.1038/s41586-025-08587-x
  19. Nature. 2025 Feb 19.
    Clonal driver neoantigen loss under EGFR TKI and immune selection pressures.
    Maise Al Bakir, James L Reading, Samuel Gamble, Rachel Rosenthal, Imran Uddin, Andrew Rowan, Joanna Przewrocka, Amber Rogers, Yien Ning Sophia Wong, Amalie K Bentzen, Selvaraju Veeriah, Sophia Ward, Aaron T Garnett, Paula Kalavakur, Carlos Martínez-Ruiz, Clare Puttick, Ariana Huebner, Daniel E Cook, David A Moore, Chris Abbosh, Crispin T Hiley, Cristina Naceur-Lombardelli, Thomas B K Watkins, Marina Petkovic, Roland F Schwarz, Felipe Gálvez-Cancino, Kevin Litchfield, Peter Meldgaard, Boe Sandahl Sorensen, Line Bille Madsen, Dirk Jäger, Martin D Forster, Tobias Arkenau, Clara Domingo-Vila, Timothy I M Tree, Mohammad Kadivar, Sine Reker Hadrup, Benny Chain, Sergio A Quezada, Nicholas McGranahan, Charles Swanton.
      Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.
    DOI:  https://doi.org/10.1038/s41586-025-08586-y
  20. Physiol Plant. 2025 Jan-Feb;177(1):177(1): e70128
    Role of aconitase in plant stress response and signaling.
    Moona Rahikainen, Oliver Berkowitz, James Whelan, Saijaliisa Kangasjärvi, Jesús Pascual.
      Mitochondria are the centres of carbon and energy metabolism in cells and are functionally integrated with other organelles. Under environmental stress, disturbances in organellar functions trigger stress signals that activate the necessary metabolic responses and maintain cell redox homeostasis. The tricarboxylic acid cycle enzyme aconitase has emerged as a key component in stress-induced organellar signalling and a regulator of metabolic and redox balance in photosynthetic organisms. Aconitase mediates mitochondrial and chloroplast retrograde signalling and contributes to the activation of the alternative oxidase (AOX) pathway in mitochondria. Aconitase-driven citrate metabolism plays a crucial role in providing reducing equivalents and metabolic precursors for cytosolic nitrogen metabolism and biosynthetic pathways relevant for stress acclimation. Besides its enzymatic activity, aconitase has a non-canonical function as it is a post-transcriptional regulator of specific gene transcripts. The varied functions of aconitase under stress are facilitated by the regulation of specific aconitase isoforms at multiple levels. This review discusses the emerging role of aconitase as a central regulator of stress responses and signalling in photosynthetic organisms.
    DOI:  https://doi.org/10.1111/ppl.70128
  21. FEBS Lett. 2025 Feb 21.
    Acute oxygen sensing by arterial chemoreceptors with a mutant mitochondrial complex I ND6 subunit lacking reverse electron transport.
    María Torres-López, Pedro F Spiller, Lin Gao, Paula García-Flores, Michael P Murphy, Patricia Ortega-Sáenz, José López-Barneo.
      Carotid body glomus cells are essential for stimulating breathing in response to hypoxia. They contain specialized mitochondria in which hypoxia induces the accumulation of NADH and H2O2 that modulate membrane ion channel activity. We investigated whether hypoxia induces reverse electron transport (RET) at mitochondrial complex I (MCI). We studied glomus cells from mice with a mutation in ND6, a core protein of MCI, which maintain normal MCI NADH dehydrogenase activity but cannot catalyze RET. The ND6 mutation increases the propensity of MCI to deactivate, and glomus cells with deactivated MCI are insensitive to acute hypoxia. These findings further indicate that MCI function is necessary for glomus cell responsiveness to hypoxia, although MCI RET does not seem to be required for this process.
    Keywords:  ND6 mutation; acute oxygen sensing; carotid body glomus cells; hypoxia; mitochondrial complex I deactivation; reverse electron transport
    DOI:  https://doi.org/10.1002/1873-3468.70017
  22. Nat Cancer. 2025 Feb 17.
    Linking macrophage metabolism to function in the tumor microenvironment.
    Robbie Jin, Luke Neufeld, Tracy L McGaha.
      Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.
    DOI:  https://doi.org/10.1038/s43018-025-00909-2
  23. Nature. 2025 Feb 20.
    Structural dynamics of human fatty acid synthase in the condensing cycle.
    Wooyoung Choi, Chengmin Li, Yifei Chen, Yongqiang Wang, Yifan Cheng.
      Long chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyze all chemical reactions needed for de novo fatty acid synthesis1. While the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyzes such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293 for single particle cryogenic electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured the conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyze particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, we reveal that FASN function does not require large rotational motion between its two major functional domains during the condensing cycle, and that the catalytic reactions in condensing cycle carried out by two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle.
    DOI:  https://doi.org/10.1038/s41586-025-08782-w
  24. EMBO J. 2025 Feb 21.
    A novel biosensor for the spatiotemporal analysis of STING activation during innate immune responses to dsDNA.
    Steve Smarduch, Sergio David Moreno-Velasquez, Doroteja Ilic, Shashank Dadsena, Ryan Morant, Anja Ciprinidis, Gislene Pereira, Marco Binder, Ana J García-Sáez, Sergio P Acebrón.
      The cGAS-STING signalling pathway has a central role in the innate immune response to extrinsic and intrinsic sources of cytoplasmic dsDNA. At the core of this pathway is cGAS-dependent production of the intra- and extra-cellular messenger cGAMP, which activates STING and leads to IRF3-dependent expression of cytokines and interferons. Despite its relevance to viral and bacterial infections, cell death, and genome instability, the lack of specific live-cell reporters has precluded spatiotemporal analyses of cGAS-STING signalling. Here, we generate a fluorescent biosensor termed SIRF (STING-IRF3), which reports on the functional interaction between activated STING and IRF3 at the Golgi. We show that cells harbouring SIRF react in a time- and concentration-dependent manner both to STING agonists and to microenvironmental cGAMP. We demonstrate that the new biosensor is suitable for single-cell characterisation of immune responses to HSV-1 infection, mtDNA release upon apoptosis, or other sources of cytoplasmic dsDNA. Furthermore, our results indicate that STING signalling is not activated by ruptured micronuclei, suggesting that other cytosolic pattern recognition receptors underlie the interferon responses to chromosomal instability.
    Keywords:  Biosensor; Innate Immune Response; Micronuclei; cGAMP; cGAS-STING Signalling
    DOI:  https://doi.org/10.1038/s44318-025-00370-y
  25. Semin Cancer Biol. 2025 Feb 13. pii: S1044-579X(25)00013-6. [Epub ahead of print]110 65-82
    Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential.
    Zhixue Chen, Lin Xu, Yejv Yuan, Si Zhang, Ruyi Xue.
      Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.
    Keywords:  Cancer therapy; Energy metabolism; Mitochondrial transfer; Platelet
    DOI:  https://doi.org/10.1016/j.semcancer.2025.02.001
  26. Cell. 2025 Feb 11. pii: S0092-8674(25)00095-9. [Epub ahead of print]
    Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism.
    Yiheng Lan, Zhen Xia, Qizhe Shao, Peng Lin, Jinhong Lu, Xiaoying Xiao, Mengyue Zheng, Di Chen, Yanmei Dou, Qi Xie.
      Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m6A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb m6A modification patterns, which we refer to as "m6A disruption mutations (m6A-DMs)." These are either synonymous m6A-DMs (sm6A-DMs) or missense m6A-DMs (mm6A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m6A levels at specific sm6A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm6A-DMs into cancer cells promotes tumor growth while BRCA2 sm6A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm6A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.
    Keywords:  cancer; epitranscriptomic; m(6)A; m(6)A-DMs; sm(6)A-DMs; synonymous mutation; tumor suppressor gene
    DOI:  https://doi.org/10.1016/j.cell.2025.01.026
  27. Nature. 2025 Feb 19.
    Mechanism for local attenuation of DNA replication at double-strand breaks.
    Robin Sebastian, Eric G Sun, Michael Fedkenheuer, Haiqing Fu, SeolKyoung Jung, Bhushan L Thakur, Christophe E Redon, Gianluca Pegoraro, Andy D Tran, Jacob M Gross, Sara Mosavarpour, Nana Afua Kusi, Anagh Ray, Anjali Dhall, Lorinc S Pongor, Rafael Casellas, Mirit I Aladjem.
      DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation1,2. However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown. Here we show that DSBs induce a local genome maintenance mechanism that inhibits replication initiation in DSB-containing topologically associating domains (TADs) without affecting DNA synthesis at other genomic locations. This process is facilitated by mediators of replication and DSBs (MRDs). In normal and cancer cells, MRDs include the TIMELESS-TIPIN complex and the WEE1 kinase, which actively dislodges the TIMELESS-TIPIN complex from replication origins adjacent to DSBs and prevents initiation of DNA synthesis at DSB-containing TADs. Dysregulation of MRDs, or disruption of 3D chromatin architecture by dissolving TADs, results in inadvertent replication in damaged chromatin and increased DNA damage in cancer cells. We propose that the intact MRD cascade precedes DSB repair to prevent genomic instability, which is otherwise observed when replication is forced, or when genome architecture is challenged, in the presence of DSBs3-5. These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.
    DOI:  https://doi.org/10.1038/s41586-024-08557-9
  28. Nat Cell Biol. 2025 Feb 21.
    Intratumour oxidative hotspots provide a niche for cancer cell dissemination.
    Yoshifumi Ueda, Shigeki Kiyonaka, Laura M Selfors, Keisuke Inoue, Hiroshi Harada, Tomohiro Doura, Kunishige Onuma, Makoto Uchiyama, Ryuhei Kurogi, Yuji Yamada, Jiacheng H Sun, Reiko Sakaguchi, Yuki Tado, Haruki Omatsu, Harufumi Suzuki, Mike Aoun, Takahiro Nakayama, Taketoshi Kajimoto, Tetsuya Yano, Rikard Holmdahl, Itaru Hamachi, Masahiro Inoue, Yasuo Mori, Nobuaki Takahashi.
      Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial-mesenchymal transition through p38-MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.
    DOI:  https://doi.org/10.1038/s41556-025-01617-w
  29. bioRxiv. 2025 Feb 08. pii: 2025.02.08.637227. [Epub ahead of print]
    CDKN2ALow cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance.
    Raquel Buj, Aidan R Cole, Jeff Danielson, Jimmy Xu, Drew Hurd, Akash Kishore, Katarzyna M Kedziora, Jie Chen, Baixue Yang, David Barras, Apoorva Uboveja, Amandine Amalric, Juan J Apiz Saab, Jayamanna Wickramasinghe, Naveen Kumar Tangudu, Evan Levasseur, Hui Wang, Aspram Minasyan, Rebekah E Dadey, Allison C Sharrow, Frank P Vendetti, Dayana B Rivadeneira, Christopher J Bakkenist, Greg M Delgoffe, Nadine Hempel, Nathaniel W Snyder, Riyue Bao, Adam C Soloff, John M Kirkwood, Denarda Dangaj Laniti, Andrew V Kossenkov, Alexander Muir, Jishnu Das, Diwakar Davar, Clementina Mesaros, Katherine M Aird.
      Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through a dietary intervention re-educates macrophages to a pro-phagocytic phenotype, sensitizing CDKN2A Low tumors to ICB. Unexpectedly, T cells are not required for this response. Clinically, macrophages from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete macrophages for zinc, directly disrupting their function and ICB efficacy.
    DOI:  https://doi.org/10.1101/2025.02.08.637227
  30. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318
    Overfeeding induces adipose tissue release of distinct mitochondria.
    Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.
      Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.
    Keywords:  CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.115318
  31. Nat Rev Cardiol. 2025 Feb 19.
    Roadmap for alleviating the manifestations of ageing in the cardiovascular system.
    Luca Liberale, Simon Tual-Chalot, Simon Sedej, Stefano Ministrini, Georgios Georgiopoulos, Myriam Grunewald, Magnus Bäck, Marie-Luce Bochaton-Piallat, Reinier A Boon, Gustavo Campos Ramos, Menno P J de Winther, Konstantinos Drosatos, Paul C Evans, Jane F Ferguson, Sofia K Forslund-Startceva, Claudia Goettsch, Mauro Giacca, Judith Haendeler, Marinos Kallikourdis, Daniel F J Ketelhuth, Rory R Koenen, Patrick Lacolley, Esther Lutgens, Pasquale Maffia, Satomi Miwa, Claudia Monaco, Fabrizio Montecucco, Giuseppe Danilo Norata, Elena Osto, Gavin D Richardson, Niels P Riksen, Oliver Soehnlein, Ioakim Spyridopoulos, Sophie Van Linthout, Gemma Vilahur, Jolanda J Wentzel, Vicente Andrés, Lina Badimon, Athanase Benetos, Christoph J Binder, Ralf P Brandes, Filippo Crea, David Furman, Vera Gorbunova, Tomasz J Guzik, Joseph A Hill, Thomas F Lüscher, María Mittelbrunn, Alessio Nencioni, Mihai G Netea, João F Passos, Kimon S Stamatelopoulos, Nektarios Tavernarakis, Zoltan Ungvari, Joseph C Wu, James L Kirkland, Giovanni G Camici, Stefanie Dimmeler, Guido Kroemer, Mahmoud Abdellatif, Konstantinos Stellos.
      Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
    DOI:  https://doi.org/10.1038/s41569-025-01130-5
  32. J Clin Invest. 2025 Feb 18. pii: e186648. [Epub ahead of print]
    Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.
    Wenjie Wei, Hongzhao Li, Shuo Tian, Chi Zhang, Junxiao Liu, Wen Tao, Tianwei Cai, Yuhao Dong, Chuang Wang, Dingyi Lu, Yakun Ai, Wanlin Zhang, Hanfeng Wang, Kan Liu, Yang Fan, Yu Gao, Qingbo Huang, Xin Ma, Baojun Wang, Xu Zhang, Yan Huang.
      Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
    Keywords:  Cell biology; Immunology; Immunotherapy; Therapeutics; Urology
    DOI:  https://doi.org/10.1172/JCI186648
  33. Cell. 2025 Feb 20. pii: S0092-8674(25)00044-3. [Epub ahead of print]188(4): 869-884
    Solute carriers: The gatekeepers of metabolism.
    Artem Khan, Yuyang Liu, Mark Gad, Timothy C Kenny, Kıvanç Birsoy.
      Solute carrier (SLC) proteins play critical roles in maintaining cellular and organismal homeostasis by transporting small molecules and ions. Despite a growing body of research over the past decade, physiological substrates and functions of many SLCs remain elusive. This perspective outlines key challenges in studying SLC biology and proposes an evidence-based framework for defining SLC substrates. To accelerate the deorphanization process, we explore systematic technologies, including human genetics, biochemistry, and computational and structural approaches. Finally, we suggest directions to better understand SLC functions beyond substrate identification in physiology and disease.
    Keywords:  SLC; deorphanization; metabolism; solute carriers
    DOI:  https://doi.org/10.1016/j.cell.2025.01.015
  34. Nat Commun. 2025 Feb 20. 16(1): 1804
    AIF3 splicing variant elicits mitochondrial malfunction via the concurrent dysregulation of electron transport chain and glutathione-redox homeostasis.
    Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang.
      Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases ROS generation, and simultaneously hinders antioxidant defense. Expression of NADH dehydrogenase NDI1 restores mitochondrial functions partially and protects neurons in AIF3-splicing mice. Our findings unveil an underrated role of AIF as a mammalian mitochondrial complex-I alternative NAD(P)H dehydrogenase and provide insights into pathologic AIF-variants in mitochondrial disorders and brain development.
    DOI:  https://doi.org/10.1038/s41467-025-57081-5
  35. Cell Stem Cell. 2025 Feb 13. pii: S1934-5909(25)00011-6. [Epub ahead of print]
    Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
    Frances J England, Ignacio Bordeu, Minn-E Ng, JaeHak Bang, Bumsoo Kim, Jinwook Choi, Erik C Cardoso, Bon-Kyoung Koo, Benjamin D Simons, Joo-Hyeon Lee.
      Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.
    Keywords:  AT2 clone dynamics; NF-κB activation; cell fate plasticity; cell plasticity; clonal modeling; lineage tracing; lung cancer; lung stem cells; regeneration program; stem cell competition; tumor ecosystem dynamics; tumor evolution
    DOI:  https://doi.org/10.1016/j.stem.2025.01.011
  36. Nature. 2025 Feb 19.
    Human-correlated genetic models identify precision therapy for liver cancer.
    Miryam Müller, Stephanie May, Holly Hall, Timothy J Kendall, Lynn McGarry, Lauriane Blukacz, Sandro Nuciforo, Anastasia Georgakopoulou, Thomas Jamieson, Narisa Phinichkusolchit, Sandeep Dhayade, Toshiyasu Suzuki, Júlia Huguet-Pradell, Ian R Powley, Leah Officer-Jones, Rachel L Pennie, Roger Esteban-Fabró, Albert Gris-Oliver, Roser Pinyol, George L Skalka, Jack Leslie, Matthew Hoare, Joep Sprangers, Gaurav Malviya, Agata Mackintosh, Emma Johnson, Misti McCain, John Halpin, Christos Kiourtis, Colin Nixon, Graeme Clark, William Clark, Robin Shaw, Ann Hedley, Thomas M Drake, Ee Hong Tan, Matt Neilson, Daniel J Murphy, David Y Lewis, Helen L Reeves, John Le Quesne, Derek A Mann, Leo M Carlin, Karen Blyth, Josep M Llovet, Markus H Heim, Owen J Sansom, Crispin J Miller, Thomas G Bird.
      Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.
    DOI:  https://doi.org/10.1038/s41586-025-08585-z
  37. Cancer Discov. 2025 Feb 17. OF1-OF15
    High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.
    Ling Cai, Nia G Hammond, Alpaslan Tasdogan, Massar Alsamraae, Chendong Yang, Robert B Cameron, Peiran Quan, Ashley Solmonson, Wen Gu, Panayotis Pachnis, Mayher Kaur, Brianna K Chang, Qin Zhou, Christopher T Hensley, Quyen N Do, Luiza Martins Nascentes Melo, Jessalyn M Ubellacker, Akash Kaushik, Maia G Clare, Isabel N Alcazar, Katarzyna Kurylowicz, Joseph D Marcuccilli, Gabriele Allies, Andrea Kutritz, Joachim Klode, Vijayashree Ramesh, Thomas J Rogers, Aparna D Rao, Hannah E Crentsil, Hong Li, Fang Brister, Phyllis McDaniel, Xiaohong Xu, Bret M Evers, Lauren G Zacharias, Jessica Sudderth, Jian Xu, Thomas P Mathews, Dwight Oliver, John D Minna, John Waters, Sean J Morrison, Kemp H Kernstine, Brandon Faubert, Ralph J DeBerardinis.
       SIGNIFICANCE: Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1319
  38. bioRxiv. 2025 Jan 30. pii: 2025.01.27.635108. [Epub ahead of print]
    Uridine Metabolism as a Targetable Metabolic Achilles' Heel for chemo-resistant B-ALL.
    Yuxuan Liu, Haowen Jiang, Jingjing Liu, Lucille Stuani, Milton Merchant, Astraea Jager, Abhishek Koladiya, Ti-Cheng Chang, Pablo Domizi, Jolanda Sarno, Tim Keyes, Dorra Jedoui, Ao Wang, Jodie Meng, Felix Hartmann, Sean C Bendall, Min Huang, Norman J Lacayo, Kathleen M Sakamoto, Charles G Mullighan, Mignon Loh, Jiyang Yu, Jun Yang, Jiangbin Ye, Kara L Davis.
      Relapse continues to limit survival for patients with B-cell acute lymphoblastic leukemia (B-ALL). Previous studies have independently implicated activation of B-cell developmental signaling pathways and increased glucose consumption with chemo-resistance and relapse risk. Here, we connect these observations, demonstrating that B-ALL cells with active signaling, defined by high expression of phosphorylated ribosomal protein S6 ("pS6+ cells"), are metabolically unique and glucose dependent. Isotope tracing and metabolic flux analysis confirm that pS6+ cells are highly glycolytic and notably sensitive to glucose deprivation, relying on glucose for de novo nucleotide synthesis. Uridine, but not purine or pyrimidine, rescues pS6+ cells from glucose deprivation, highlighting uridine is essential for their survival. Active signaling in pS6+ cells drives uridine production through activating phosphorylation of carbamoyl phosphate synthetase (CAD), the enzyme catalyzing the initial steps of uridine synthesis. Inhibition of signaling abolishes glucose dependency and CAD phosphorylation in pS6+ cells. Primary pS6+ cells demonstrate high expression of uridine synthesis proteins, including dihydroorotate dehydrogenase (DHODH), the rate-limiting catalyst of de novo uridine synthesis. Gene expression demonstrates that increased expression of DHODH is associated with relapse and inferior event-free survival after chemotherapy. Further, the majority of B-ALL genomic subtypes demonstrate activity of DHODH. Inhibiting DHODH using BAY2402232 effectively kills pS6+ cells in vitro , with its IC50 correlated with the strength of pS6 signaling across 14 B-ALL cell lines and patient-derived xenografts (PDX). In vivo DHODH inhibition prolongs survival and decreases leukemia burden in pS6+ B-ALL cell line and PDX models. These findings link active signaling to uridine dependency in B-ALL cells and an associated risk of relapse. Targeting uridine synthesis through DHODH inhibition offers a promising therapeutic strategy for chemo-resistant B-ALL as a novel therapeutic approach for resistant disease.
    DOI:  https://doi.org/10.1101/2025.01.27.635108
  39. Nat Commun. 2025 Feb 16. 16(1): 1693
    Identification and characterization of cell niches in tissue from spatial omics data at single-cell resolution.
    Jingyang Qian, Xin Shao, Hudong Bao, Yin Fang, Wenbo Guo, Chengyu Li, Anyao Li, Hua Hua, Xiaohui Fan.
      Deciphering the features, structure, and functions of the cell niche in tissues remains a major challenge. Here, we present scNiche, a computational framework to identify and characterize cell niches from spatial omics data at single-cell resolution. We benchmark scNiche with both simulated and biological datasets, and demonstrate that scNiche can effectively and robustly identify cell niches while outperforming other existing methods. In spatial proteomics data from human triple-negative breast cancer, scNiche reveals the influence of the microenvironment on cellular phenotypes, and further dissects patient-specific niches with distinct cellular compositions or phenotypic characteristics. By analyzing mouse liver spatial transcriptomics data across normal and early-onset liver failure donors, scNiche uncovers disease-specific liver injury niches, and further delineates the niche remodeling from normal liver to liver failure. Overall, scNiche enables decoding the cellular microenvironment in tissues from single-cell spatial omics data.
    DOI:  https://doi.org/10.1038/s41467-025-57029-9
  40. Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00125-3. [Epub ahead of print]
    Compositionally unique mitochondria in filopodia support cellular migration.
    Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.
      Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.
    Keywords:  MCU; MICOS; MYO19; calcium; cristae; filopodia; migration; mitochondria; organelle
    DOI:  https://doi.org/10.1016/j.cub.2025.01.062
  41. Nature. 2025 Feb 19.
    RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer.
    Zachary Sethna, Pablo Guasp, Charlotte Reiche, Martina Milighetti, Nicholas Ceglia, Erin Patterson, Jayon Lihm, George Payne, Olga Lyudovyk, Luis A Rojas, Nan Pang, Akihiro Ohmoto, Masataka Amisaki, Abderezak Zebboudj, Zagaa Odgerel, Emmanuel M Bruno, Siqi Linsey Zhang, Charlotte Cheng, Yuval Elhanati, Evelyna Derhovanessian, Luisa Manning, Felicitas Müller, Ina Rhee, Mahesh Yadav, Taha Merghoub, Jedd D Wolchok, Olca Basturk, Mithat Gönen, Andrew S Epstein, Parisa Momtaz, Wungki Park, Ryan Sugarman, Anna M Varghese, Elizabeth Won, Avni Desai, Alice C Wei, Michael I D'Angelica, T Peter Kingham, Kevin C Soares, William R Jarnagin, Jeffrey Drebin, Eileen M O'Reilly, Ira Mellman, Ugur Sahin, Özlem Türeci, Benjamin D Greenbaum, Vinod P Balachandran.
      A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.
    DOI:  https://doi.org/10.1038/s41586-024-08508-4
  42. Trends Parasitol. 2025 Feb 13. pii: S1471-4922(25)00034-0. [Epub ahead of print]
    Helminths target macrophage epigenetics and metabolism to evade immunity.
    Bart Everts.
      Parasitic helminths are well known master regulators of host immune responses. Yet, the underlying molecular principles remain largely enigmatic. Recent work from Bohnacker et al. reveals that glutamate dehydrogenase (GDH), a metabolic enzyme secreted by Heligmosomoides polygyrus, can suppress type 2 immunity by multimodal regulation of macrophage metabolism and epigenetics.
    Keywords:  epigenetics; helminth; immunomodulation; macrophage; metabolism; prostaglandin E2
    DOI:  https://doi.org/10.1016/j.pt.2025.01.012
  43. Trends Immunol. 2025 Feb 20. pii: S1471-4906(25)00025-0. [Epub ahead of print]
    Metabolic and stress response adaptations in T cells to fever and physiological heat.
    Benjamin A Wilander, Jeffrey C Rathmell.
      Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.
    Keywords:  T cells; fever; immunometabolism; stress
    DOI:  https://doi.org/10.1016/j.it.2025.01.007
  44. Oncogene. 2025 Feb 16.
    GDP-mannose 4,6-dehydratase is a key driver of MYCN-amplified neuroblastoma core fucosylation and tumorigenesis.
    Beibei Zhu, Michelle G Pitts, Michael D Buoncristiani, Lindsay T Bryant, Oscar Lopez-Nunez, Juan P Gurria, Cameron Shedlock, Roberto Ribas, Shannon Keohane, Jinpeng Liu, Chi Wang, Matthew S Gentry, Nathan R Shelman, Derek B Allison, B Mark Evers, Ramon C Sun, Eric J Rellinger.
      MYCN-amplification is a genetic hallmark of ~40% of high-risk neuroblastomas (NBs). Altered glycosylation is a common feature of adult cancer progression, but little is known about how genetic signatures such as MYCN-amplification alter glycosylation profiles. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased core fucosylated glycan abundance within neuroblast-rich regions of human MYCN-amplified NB tumors. GDP-mannose 4,6-dehydratase (GMDS) is responsible for the first-committed and rate-limiting step of de novo GDP-fucose synthesis. High GMDS expression was found to be associated with poor patient survival, advanced stage disease, and MYCN-amplification in human NB tumors. Chromatin immunoprecipitation and promoter reporter assays demonstrated that N-MYC directly binds and activates the GMDS promoter in NB cells. When GMDS was blocked through either genetic or pharmacological mechanisms, NBs were found to be dependent upon de novo GDP-fucose production to sustain cell surface and secreted core fucosylated glycan abundance, as well as adherence and motility. Moreover, genetic knockdown of GMDS inhibited tumor formation and progression in vivo. These critical findings identify de novo GDP-fucose production as a novel metabolic vulnerability that may be exploited in designing new treatment strategies for MYCN-amplified NBs.
    DOI:  https://doi.org/10.1038/s41388-025-03297-0
  45. Nat Commun. 2025 Feb 19. 16(1): 1762
    Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation.
    Juan Liu, Yiyun Shen, Jie Liu, Dandan Xu, Chun-Yuan Chang, Jianming Wang, Jason Zhou, Bruce G Haffty, Lanjing Zhang, Jill Bargonetti, Subhajyoti De, Wenwei Hu, Zhaohui Feng.
      The tumor-suppressive function of p53 is frequently disrupted by mutations in cancers. Missense mutant p53 (mutp53) protein often stabilizes and accumulates to high levels in cancers to promote tumorigenesis through the gain-of-function (GOF) mechanism. Currently, the mechanism of mutp53 accumulation and GOF is incompletely understood. Here, we identify the lipogenic enzyme FASN as an important regulator of mutp53 accumulation and GOF. FASN interacts with mutp53 to enhance mutp53 palmitoylation, which inhibits mutp53 ubiquitination to promote mutp53 accumulation and GOF. Blocking FASN genetically or by small-molecule inhibitors suppresses mutp53 palmitoylation to inhibit mutp53 accumulation, which in turn inhibits the growth of mutp53 tumors in orthotopic and subcutaneous xenograft tumor models and transgenic mice, as well as the growth of human tumor organoids carrying mutp53. Our results reveal that mutp53 palmitoylation is an important mechanism underlying mutp53 accumulation and GOF, and targeting FASN is a potential therapeutic strategy for cancers carrying mutp53.
    DOI:  https://doi.org/10.1038/s41467-025-57099-9
  46. Nat Cell Biol. 2025 Feb 21.
    Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties.
    Dennis K Jeppesen, Zachary C Sanchez, Noah M Kelley, James B Hayes, Jessica Ambroise, Emma N Koory, Evan Krystofiak, Nilay Taneja, Qin Zhang, Matthew M Dungan, Olivia L Perkins, Matthew J Tyska, Ela W Knapik, Kevin M Dean, Amanda C Doran, Robert J Coffey, Dylan T Burnette.
      Cells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment.
    DOI:  https://doi.org/10.1038/s41556-025-01621-0
  47. Mol Syst Biol. 2025 Feb 17.
    Enhanced flux potential analysis links changes in enzyme expression to metabolic flux.
    Xuhang Li, Albertha J M Walhout, L Safak Yilmaz.
      Algorithms that constrain metabolic network models with enzyme levels to predict metabolic activity assume that changes in enzyme levels are indicative of flux variations. However, metabolic flux can also be regulated by other mechanisms such as allostery and mass action. To systematically explore the relationship between fluctuations in enzyme expression and flux, we combine available yeast proteomic and fluxomic data to reveal that flux changes can be best predicted from changes in enzyme levels of pathways, rather than the whole network or only cognate reactions. We implement this principle in an 'enhanced flux potential analysis' (eFPA) algorithm that integrates enzyme expression data with metabolic network architecture to predict relative flux levels of reactions including those regulated by other mechanisms. Applied to human data, eFPA consistently predicts tissue metabolic function using either proteomic or transcriptomic data. Additionally, eFPA efficiently handles data sparsity and noisiness, generating robust flux predictions with single-cell gene expression data. Our approach outperforms alternatives by striking an optimal balance, evaluating enzyme expression at pathway level, rather than either single-reaction or whole-network levels.
    Keywords:  Enzyme Expression; Flux Potential Analysis; Metabolic Flux; Metabolic Network Model; Single-cell Data
    DOI:  https://doi.org/10.1038/s44320-025-00090-9
  48. Cell. 2025 Feb 12. pii: S0092-8674(25)00098-4. [Epub ahead of print]
    HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity.
    Skyler Y Blume, Ankur Garg, Yolanda Martí-Mateos, Ayush D Midha, Brandon T L Chew, Baiwei Lin, Cecile Yu, Ryan Dick, Patrick S Lee, Eva Situ, Richa Sarwaikar, Eric Green, Vyas Ramanan, Gijsbert Grotenbreg, Maarten Hoek, Christopher Sinz, Isha H Jain.
      We have previously demonstrated that chronic inhaled hypoxia is remarkably therapeutic in the premier animal model of mitochondrial Leigh syndrome, the Ndufs4 knockout (KO) mouse. Subsequent work has extended this finding to additional mitochondrial diseases and more common conditions. However, challenges inherent to gas-based therapies have hindered the rapid translation of our findings to the clinic. Here, we tested a small molecule (hereafter termed HypoxyStat) that increases the binding affinity of hemoglobin for oxygen, thereby decreasing oxygen offloading to tissues. Daily oral dosing of HypoxyStat caused systemic hypoxia in mice breathing normoxic (21% O2) air. When administered prior to disease onset, this treatment dramatically extended the lifespan of Ndufs4 KO mice and rescued additional aspects of disease, including behavior, body weight, neuropathology, and body temperature. HypoxyStat was also able to reverse disease at a very late stage, thereby serving as a clinically tractable form of hypoxia therapy.
    Keywords:  Leigh syndrome; hemoglobin; hyperoxia; hypoxia; mitochondrial disease; oxygen; red blood cells; therapy
    DOI:  https://doi.org/10.1016/j.cell.2025.01.029
  49. Nat Commun. 2025 Feb 14. 16(1): 1394
    Matrix mechano-sensing at the invasive front induces a cytoskeletal and transcriptional memory supporting metastasis.
    Oscar Maiques, Marta C Sallan, Roman Laddach, Pahini Pandya, Adrian Varela, Eva Crosas-Molist, Jaume Barcelo, Olivia Courbot, Yanbo Liu, Vittoria Graziani, Youssef Arafat, Joanne Sewell, Irene Rodriguez-Hernandez, Bruce Fanshawe, Yaiza Jung-Garcia, Paul Rc Imbert, Eloise M Grasset, Jean Albrengues, Maria Santacana, Anna Macià, Jordi Tarragona, Xavier Matias-Guiu, Rosa M Marti, Sophia Tsoka, Cedric Gaggioli, Jose L Orgaz, Gilbert O Fruhwirth, Fredrik Wallberg, Kai Betteridge, Constantino Carlos Reyes-Aldasoro, Syed Haider, Andrejs Braun, Sophia N Karagiannis, Alberto Elosegui-Artola, Victoria Sanz-Moreno.
      The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-56299-7
  50. Nat Immunol. 2025 Feb 21.
    B cell immunometabolism in health and disease.
    Eleonora Martinis, Silvia Tonon, Alessandra Colamatteo, Antonio La Cava, Giuseppe Matarese, Carlo Ennio Michele Pucillo.
      B cells have crucial roles in the initiation and progression of many pathological conditions, and several therapeutic strategies have targeted the function of these cells. The advent of immunometabolism has provided compelling evidence that the metabolic reprogramming of immune cells can dramatically alter physiopathological immune activities. A better knowledge of the metabolic profiles of B cells can provide valuable means for developing therapies tuning defined cell pathways. Here we review the cellular and molecular mechanisms by which immunometabolism controls the physiology and pathophysiology of B cells and discuss the experimental evidence linking B cell metabolism to health, autoimmunity, and cancer. Considering that several metabolic pathways in B cells are involved differently, or even in opposite ways, in health and disease, we discuss how targeted modulation of B cell immunometabolism could be exploited mechanistically to rebalance abnormal B cell functions that have become altered in disease states.
    DOI:  https://doi.org/10.1038/s41590-025-02102-0
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