bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–07–27
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.
  2. mTORC1 senses glutamine and other amino acids through GCN2.
  3. The peculiar properties of mitochondrial carriers of the SLC25 family.
  4. Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
  5. PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
  6. Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
  7. Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
  8. Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
  9. Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
  10. Metabolic adaptations of brain metastasis.
  11. Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
  12. Decoding subclonal anti-tumor immunity.
  13. Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
  14. Uridine phosphorylase-1 supports metastasis by altering immune and extracellular matrix landscapes.
  15. T cell InaDAGquacy in the TME driven by phosphoethanolamine.
  16. LARP4-mediated hypertranslation drives T cell dysfunction in tumors.
  17. From Harmony to Discord: Multicellular Coordination in Tissues and Its Rewiring in Cancer.
  18. Regulation of inflammatory responses by pH-dependent transcriptional condensates.
  19. N-acetylaspartate from fat cells regulates postprandial body temperature.
  20. High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
  21. Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
  22. The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer.
  23. Early methionine availability attenuates T cell exhaustion.
  24. Much ado about NAA-thing.
  25. De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.
  26. PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate.
  27. Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.
  28. α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.
  29. Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
  30. Primary and metastatic cellular landscapes in human pancreatic cancer.
  31. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
  32. Specific oncogene activation of the cell of origin in mucosal melanoma.
  33. O-GlcNAcylation of Fatty Acid Synthase is required for its proper subcellular localization, expression level and activity.
  34. Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.
  35. Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.
  36. Microbial trash to metabolic treasure.
  37. Developing serum proteomics based prediction models of disease progression in ADPKD.
  38. YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression.
  39. TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
  40. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
  41. The mammalian protein MTCH1 can function as an insertase.
  42. Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma.
  1. J Cell Physiol. 2025 Jul;240(7): e70066
    Metabolic Effects of Succinate Dehydrogenase Loss in Cancer.
    Adam Chatoff, Daniel S Kantner, Nathaniel W Snyder, Lori Rink.
      Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH2 and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.
    Keywords:  Complex II; clear cell renal cell carcinoma; electron transport chain; gastrointestinal stromal tumors; leigh syndrome; pheochromocytomas/paragangliomas; succinate dehydrogenase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1002/jcp.70066
  2. EMBO J. 2025 Jul 21.
    mTORC1 senses glutamine and other amino acids through GCN2.
    Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.
      mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.
    Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1
    DOI:  https://doi.org/10.1038/s44318-025-00505-1
  3. Biochem J. 2025 Jul 23. pii: BCJ20253171. [Epub ahead of print]482(15):
    The peculiar properties of mitochondrial carriers of the SLC25 family.
    Edmund R S Kunji, Vasiliki Mavridou, Martin S King, Camila Cimadamore-Werthein, Stephany Jaiquel Baron, Scott A Jones, Alannah C King, Roger Springett, Deepak Chand, Shane M Palmer, Denis Lacabanne, Sotiria Tavoulari, Jonathan J Ruprecht.
      With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.
    Keywords:  bioenergetics; mitochondria; oxidative phosphorylation; translocases; translocators; transport mechanism
    DOI:  https://doi.org/10.1042/BCJ20253171
  4. Nat Commun. 2025 Jul 21. 16(1): 6700
    Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex.
    Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P Tu, Xiaofeng Qi.
      The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.
    DOI:  https://doi.org/10.1038/s41467-025-61939-z
  5. Clin Transl Med. 2025 Jul;15(7): e70404
    PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
    Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.
       BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
    METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
    RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
    CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.
    Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.1002/ctm2.70404
  6. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2505704122
    Cell type-specific purifying selection of synonymous mitochondrial DNA variation.
    Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy.
      While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing used for m.7076A. Mitochondrial ribosome profiling confirmed stalled translation of the m.7076G allele. Functional analyses demonstrated that the elevated translational and metabolic demands of short-lived effector T cells (SLECs) amplify dependence on MT-CO1, driving this selective pressure. These findings suggest that synonymous variants can alter codon syntax, impacting mitochondrial physiology in a cell type-specific manner.
    Keywords:  immunology; mitochondria; selection; single-cell
    DOI:  https://doi.org/10.1073/pnas.2505704122
  7. Cell Metab. 2025 Jul 14. pii: S1550-4131(25)00324-9. [Epub ahead of print]
    Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
    Tiezhu Shi, Jialiang Shao, Yufeng Ding, Hong Tang, Xiangyin Tan, Sisi Zhou, Shaoqing Yu, Xiang Wang, Guanzhen Yu, Ninghan Feng, Xiongjun Wang.
      Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using in vivo metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8+ T cell cytotoxicity. Mechanistically, CD8+ T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8+ T cell response by promoting Xu5P-responsive progenitor-like SLC35E2+ CD8+ exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the Tcf7 promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8+ T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.
    Keywords:  Xu5P; dietary metabolite; immunotherapy; progenitor-like CD8(+) T cells; tumor metastasis
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.011
  8. Cell Chem Biol. 2025 Jul 17. pii: S2451-9456(25)00201-6. [Epub ahead of print]32(7): 902-904
    Powering the powerhouse: Mitochondrial NADPH propels oxidative metabolism.
    Riley J Wedan, Sara M Nowinski.
      Mitochondrial NADPH is abundant, but the reason why was uncertain. In a study published in Nature Cell Biology, Kim et al.1 identified an important role of NADK2-derived mitochondrial NADPH in mitochondrial fatty acid synthesis (mtFAS) through direct quantification of the products built by mtFAS. This work opens the door to understanding how NADK2, mitochondrial NADPH, and mtFAS regulate mitochondrial function.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.06.006
  9. J Clin Invest. 2025 Jul 22. pii: e190215. [Epub ahead of print]
    Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
    Chao-Chieh Lin, Yi-Tzu Lin, Ssu-Yu Chen, Yasaman Setayeshpour, Yubin Chen, Denise E Dunn, Taylor Nguyen, Alexander A Mestre, Adrija Banerjee, Lalitha Guruprasad, Erik J Soderblom, Guo-Fang Zhang, Chen-Yong Lin, Valeriy Filonenko, Suh Young Jeong, Scott R Floyd, Susan J Hayflick, Ivan Gout, Jen-Tsan Chi.
      The cystine-xCT transporter-glutathione (GSH)-GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrated increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated post-translational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.
    Keywords:  Amino acid metabolism; Cell biology; Cell stress; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI190215
  10. Nat Rev Cancer. 2025 Jul 24.
    Metabolic adaptations of brain metastasis.
    Pravat Kumar Parida, Srinivas Malladi.
      Brain metastases remain a major clinical challenge, characterized by high mortality rates and often limited therapeutic options. The cellular and molecular processes that drive brain metastases are highly intricate, underscored by dynamic metabolic adaptations that enable tumour cells to thrive in the unique microenvironment of the brain. Emerging clinical and preclinical evidence reveals that these metabolic adaptations are not uniform but vary based on the tumour's tissue of origin, oncogenomic landscape and capacity to endure nutrient stress. Notably, proliferative and dormant metastatic cells within the brain exhibit distinct metabolic profiles, highlighting the complexity of targeting these cells. Key metabolic pathways, including glucose, fatty acid and amino acid metabolism, are co-opted not only to sustain cancer cell survival and growth but also to modulate interactions with resident brain cells, reshaping their function to support metastasis. Importantly, this metabolic heterogeneity underscores the inadequacy of a one-size-fits-all therapeutic approach. Here, we review the adaptive metabolic reprogramming that facilitates brain metastases and discuss emerging strategies to tailor interventions aimed at preventing and treating overt brain metastases.
    DOI:  https://doi.org/10.1038/s41568-025-00848-1
  11. Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]
    Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
    Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.
      Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.
    DOI:  https://doi.org/10.21203/rs.3.rs-7042684/v1
  12. Cancer Cell. 2025 Jul 11. pii: S1535-6108(25)00268-5. [Epub ahead of print]
    Decoding subclonal anti-tumor immunity.
    Jason E Chan, Tuomas Tammela.
      Subclonal evolution allows tumors to evade the immune system. In this issue of Cancer Cell, Dijkstra et al. combine the TRACERx cohort with co-cultures of autologous tumors and immune cells to functionally profile subclonal immune escape at the single-clone resolution. This work highlights cancer-intrinsic immune-escape mechanisms that can be interrogated on a co-culture platform.
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.018
  13. Cell Death Dis. 2025 Jul 21. 16(1): 539
    Metastatic breast cancer cells are selectively dependent on the mitochondrial cristae-shaping protein OPA1.
    Antigoni Diokmetzidou, Aurora Maracani, Anna Pellattiero, Mauricio Cardenas-Rodriguez, Erwan A Rivière, Luca Scorrano.
      In breast cancer, the inner mitochondrial membrane fusion protein Optic Atrophy 1 (OPA1) is upregulated and its inhibition reverses acquired chemoresistance. However, it remains unclear whether OPA1 inhibition also targets normal breast cells. We show that OPA1 upregulation is a hallmark of metastatic breast cancer cells, which are selectively susceptible to OPA1 inhibition compared to isogenic normal or localized tumor cells. In an isogenic model spanning normal, transformed, and metastatic breast cancer cells, levels of Mitofusin 1 (MFN1) progressively declined while dynamin related protein 1 (DRP1) became increasingly active, correlating with fragmented mitochondria during cancer progression. Meanwhile, OPA1 levels were elevated in invasive cells characterized by mitochondrial fragmentation, tight cristae, and high respiration. OPA1 deletion selectively reduced metastatic cells mitochondrial respiration, proliferation, and migration. Specific OPA1 inhibitors MYLS22 and Opitor-0 diminished migration and increased death of metastatic cells, underscoring OPA1 as a selective vulnerability of metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07878-5
  14. EMBO Rep. 2025 Jul 23.
    Uridine phosphorylase-1 supports metastasis by altering immune and extracellular matrix landscapes.
    Declan Whyte, Sophie L Fisher, Christopher G J McKenzie, David Sumpton, Sandeep Dhayade, Emmanuel Dornier, Madeleine Moore, David Novo, Jasmine Peters, Robert Wiesheu, Michalis D Gounis, Dale M Watt, John B G Mackey, Amanda J McFarlane, Frédéric Fercoq, Carolina Dehesa Caballero, Keara L Redmond, Louise E Mitchell, Eve Anderson, Gemma Thomson, Ann Hedley, William Clark, Shannen Leroi, Lindsey N Dzierozynski, Juan J Apiz Saab, Caroline A Lewis, Alexander Muir, Christopher J Halbrook, Douglas Strathdee, Rene Jackstadt, Colin Nixon, Philip Dunne, Leo M Carlin, Iain R Macpherson, Edward W Roberts, Seth B Coffelt, Karen Blyth, Owen J Sansom, Jim C Norman, Johan Vande Voorde, Cassie J Clarke.
      Understanding mechanisms that facilitate early events in metastatic seeding is key to developing therapeutic approaches to reduce metastasis. Here we identify uracil as a metastasis-associated metabolite in genetically engineered mouse models of cancer and in patients with metastatic breast cancer. Uracil is generated by the enzyme uridine phosphorylase-1 (UPP1), and we find that neutrophils are a significant source of UPP1 in metastatic cancer. Mammary tumours increase expression of adhesion molecules on the neutrophil surface, in a UPP1-dependent manner, leading to decreased neutrophil motility in the pre-metastatic lung. UPP1-expressing neutrophils suppress T-cell proliferation, and the UPP1 product uracil increases fibronectin deposition in the extracellular microenvironment. Knockout or inhibition of UPP1 in mice with mammary tumours increases T-cell numbers and reduces fibronectin content in the lung, and decreases the proportion of mice that develop lung metastasis. These data indicate that UPP1 influences neutrophil behaviour and extracellular matrix deposition in the lung, and suggest that circulating uracil could be a marker of metastasis, and that pharmacological inhibition of UPP1 could be a strategy to reduce recurrence.
    Keywords:  Fibronectin; Metastasis; Neutrophils; T Cells; Uridine Phosphorylase
    DOI:  https://doi.org/10.1038/s44319-025-00520-7
  15. Dev Cell. 2025 Jul 21. pii: S1534-5807(25)00400-9. [Epub ahead of print]60(14): 1934-1935
    T cell InaDAGquacy in the TME driven by phosphoethanolamine.
    Erica G Brown, Roddy S O'Connor.
      In a recent issue of Nature Cell Biology, Wang et al. identify phosphoethanolamine as an onco-metabolite that disrupts T cell function through the depletion of diacylglycerol in the Kennedy cycle. These results highlight the substantial role of metabolites in the tumor microenvironment on T cell function.
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.022
  16. Nat Immunol. 2025 Jul 22.
    LARP4-mediated hypertranslation drives T cell dysfunction in tumors.
    Yi Liu, Haochen Ni, Jie Li, Jing Yang, Ivann Sekielyk, Bryan E Snow, Zihao Zhang, Feifan Zhang, Michael St Paul, Jinyi Han, Meghan Kates, Shaofeng Liu, Yawei Zhang, Zurui Huang, Yin Xu, Samuel D Saibil, Tak W Mak, Dali Han, Meng Michelle Xu.
      Adoptive T cell therapies have therapeutic potential for treating solid tumors, but long-term efficacy is limited by reduced functional fitness and poor persistence within the tumor microenvironment. Here we show that intratumoral T cells undergo translatome remodeling, transitioning into a hypertranslational state as they acquire dysfunctional traits. The RNA-binding protein LARP4 is a translation regulator that drives hypertranslation and dysfunction by selectively enhancing the translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor T cells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of T cell dysfunction in tumors.
    DOI:  https://doi.org/10.1038/s41590-025-02232-5
  17. Cancer Res. 2025 Jul 23.
    From Harmony to Discord: Multicellular Coordination in Tissues and Its Rewiring in Cancer.
    Merve Dede, Vakul Mohanty, Ken Chen.
      Tissue function emerges from coordinated interactions among diverse cell types, but how these interactions are structured and rewired in disease remains unclear. In a recent study, Shi and colleagues introduce CoVarNet, a computational framework that maps reproducible multicellular modules (CMs) across 35 human tissues using single-cell and spatial transcriptomics. These CMs, spanning immune, stromal, and endothelial cells, exhibit functional organization across tissue systems and dynamically respond to biological transitions such as aging and menopause. Importantly, cancer progression is marked by a breakdown of tissue-specific CMs and the emergence of a convergent cancer-associated ecosystem, cCM02. This rewiring reflects a fundamental reorganization of tissue architecture during malignancy and provides new opportunities for diagnostics and therapeutic targeting. The study signifies a conceptual advance from cell-centric to ecosystem-level biology and offers a generalizable framework for integrating multimodal data to dissect tissue-level coordination. Here, we discuss how CoVarNet redefines our understanding of tissue organization, its translational implications in oncology, and unresolved questions in modular tissue biology.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3155
  18. Cell. 2025 Jul 12. pii: S0092-8674(25)00735-4. [Epub ahead of print]
    Regulation of inflammatory responses by pH-dependent transcriptional condensates.
    Zhongyang Wu, Scott D Pope, Nasiha S Ahmed, Diana L Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M Anand, Elizabeth B Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C Kagan, Jay R Thiagarajah, Diana C Hargreaves, Ruslan Medzhitov, Xu Zhou.
      Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.
    Keywords:  BRD4; IDR; acidosis; gene expression; histidine; inflammatory response; innate immunity; macrophage; pH; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.cell.2025.06.033
  19. Nat Metab. 2025 Jul 23.
    N-acetylaspartate from fat cells regulates postprandial body temperature.
    Jessica B Felix, Pradip K Saha, Evelyn L de Groot, Lin Tan, Robert Sharp, Elizabeth S Anaya, Yafang Li, Holly Quang, Nooshin Saidi, Layla Abushamat, Christie M Ballantyne, Christopher I Amos, Philip L Lorenzi, Samuel Klein, Xia Gao, Sean M Hartig.
      N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis1. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine intermediate orotidine 5'-monophosphate, and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we observed that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Moreover, unopposed NAA from adipocytes greatly enhanced whole-body glucose disposal exclusively in WAT. Exogenous NAA also increased plasma pyrimidines and lowered body temperature. These data place WAT-derived NAA as an endocrine regulator of postprandial body temperature and define broader roles for metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01334-6
  20. Science. 2025 Jul 24. eadx3800
    High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
    Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.
      Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.
    DOI:  https://doi.org/10.1126/science.adx3800
  21. Nat Commun. 2025 Jul 24. 16(1): 6819
    Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
    Noa Yehoshua, Ahlam Khamaysi, Liana Shimshilashvili, Aharon Keshet, Mahmoud Taha, Moran Fremder, Hadar Eini-Rider, Ehud Ohana.
      The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metabolites and glucose balance, thus driving key energy management processes in response to nutrient availability in the liver.
    DOI:  https://doi.org/10.1038/s41467-025-62103-3
  22. Mol Cell. 2025 Jul 12. pii: S1097-2765(25)00550-7. [Epub ahead of print]
    The SWI/SNF-related protein SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer.
    Ifé Akano, Jakob M Hebert, Rochelle L Tiedemann, Qingzeng Gao, Yang Xiao, Nicholas A Prescott, Yanqing Liu, Kay See Tan, Ryan M Bastle, Aarthi Ramakrishnan, Ian Maze, Simone Sidoli, Richard P Koche, Karuna Ganesh, Scott B Rothbart, Yael David.
      Histone ubiquitination is a crucial post-translational modification (PTM) regulating chromatin function, yet many histone ubiquitination sites and the enzymes that control them remain poorly understood. Here, we identify SMARCA3, a SWI/SNF-related protein frequently downregulated in colorectal cancer (CRC), as an E3 ubiquitin ligase that targets histone H3 at lysine 23 (H3K23). We demonstrate that SMARCA3 histone ubiquitination activity is stimulated by the repressive H3K9me3 mark. Loss of SMARCA3 reduces both H3K23Ub and H3K9me3, increasing chromatin accessibility at promoters and enhancers enriched for pioneer transcription factor motifs. This chromatin "rewiring" alters the transcriptional landscape, driving upregulation of cancer-promoting genes. We validate this mechanism in CRC cell lines and patient-derived organoids, where SMARCA3 loss reduces H3K23Ub and H3K9me3. In xenograft mouse models, overexpression of wild-type SMARCA3, but not a RING domain mutant, suppresses tumor growth. Together, our findings define SMARCA3 as a key chromatin regulator contributing to CRC pathogenesis through epigenetic mechanisms.
    Keywords:  epigenetics, histone, ubiquitination, methylation, chromatin, accessibility, cancer, RING, E3 ligase
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.020
  23. Nat Immunol. 2025 Jul 23.
    Early methionine availability attenuates T cell exhaustion.
    Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.
      T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.
    DOI:  https://doi.org/10.1038/s41590-025-02223-6
  24. Nat Metab. 2025 Jul 23.
    Much ado about NAA-thing.
    Jan-Bernd Funcke, Philipp E Scherer.
      
    DOI:  https://doi.org/10.1038/s42255-025-01327-5
  25. EMBO Mol Med. 2025 Jul 24.
    De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.
    Duo Xu, Yanyun Gao, Shengchen Liu, Shiyuan Yin, Tong Hu, Haibin Deng, Tuo Zhang, Balazs Hegedüs, Thomas M Marti, Patrick Dorn, Shun-Qing Liang, Ralph A Schmid, Ren-Wang Peng, Yongqian Shu.
      Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.
    Keywords:  De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality
    DOI:  https://doi.org/10.1038/s44321-025-00278-4
  26. Nat Commun. 2025 Jul 22. 16(1): 6736
    PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate.
    Pianpian Lin, Yijun Qi, Huiying Chu, Hongyu Wu, Yajuan Zhang, Xiaolan Huang, Chen Li, Xiaoyan Xu, Hong Gao, Rong Zeng, Guohui Li, Weiwei Yang.
      Emerging evidence indicates that metabolic signals-including nutrient availability, biosynthetic intermediates, and energy balance-are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation.
    DOI:  https://doi.org/10.1038/s41467-025-62111-3
  27. Trends Pharmacol Sci. 2025 Jul 22. pii: S0165-6147(25)00139-7. [Epub ahead of print]
    Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.
    Allegra C Minor, Evan Couser, Lillian J Eichner.
      Despite the development of new classes of therapeutics in oncology, patients with tumors harboring mutations in the tumor suppressor gene STK11/LKB1 continue to exhibit poor clinical response and therapeutic resistance. Recent advances in the understanding of LKB1-mutant tumor biology have illuminated how metabolism and the tumor microenvironment (TME) function as effectors of the aggressive nature of this tumor type. New findings have revealed how metabolic reprogramming, a hallmark of LKB1-mutant tumor biology, can be exploited as a potential targetable liability in these tumors. Characterization of the distinctly immunosuppressive LKB1-mutant TME has motivated multiple discoveries of new approaches for rewiring the microenvironment to overcome immunotherapy resistance. Indeed, overcoming therapeutic resistance in LKB1-deficient tumors continues to be a major research focus, and some preclinical studies have advanced to clinical trials. In this review, we critically analyze these findings and discuss therapies in development that aim to leverage this new understanding for clinical benefit.
    Keywords:  LKB1/STK11; cancer; kinase; lung cancer; metabolism; therapeutic resistance; tumor microenvironment; tumor suppressor
    DOI:  https://doi.org/10.1016/j.tips.2025.06.008
  28. Blood. 2025 Jul 23. pii: blood.2024028069. [Epub ahead of print]
    α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.
    Carine Jaafar, Purushoth Ethiraj, Zhijun Qiu, An-Ping Lin, Pedro Simonis Seabra Martins Ferrari, Ricardo Aguiar.
      Targeting metabolic dependencies and "starving" malignant cells have long been considered as potential strategies to treat cancer. However, with rare exceptions, the implementation of these maneuvers has been fraught with limited activity and lack of specificity. Multiple cytoplasmic and mitochondrial transaminases catalyze reactions that lead to amino acid catabolism. These enzymes use alpha-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-HG perturbs their function. We postulated that exogenous αKG supplementation would influence the directionality of these reactions and deplete amino acids in cancer cells. Using B cell lymphoma as a model system, we found that αKG mediates a rapid and sustained amino acid depletion, principally of aspartate and branched-chain leucine, valine and isoleucine. The decrease in leucine levels influenced MTORC1 sub-cellular movement, suppressed its activity and associated with inhibition of B cell lymphoma growth in vitro and in vivo Increasing import of aspartate or leucine levels in the lymphoma cells, genetically forcing MTORC1 lysosomal localization or blocking leucine catabolism through BCAT2 deletion, all blunted the anti-lymphoma effects of αKG. In addition, long term dietary supplementation of αKG, a toxicity free strategy, significantly hindered lymphoma development in Eµ-Myc mice, in association with amino acid perturbation and impaired energy generation. We posit that αKG supplementation, which has been shown to improve health and lifespan in mice, also encodes marked anti-cancer properties.
    DOI:  https://doi.org/10.1182/blood.2024028069
  29. Cell. 2025 Jul 18. pii: S0092-8674(25)00741-X. [Epub ahead of print]
    Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
    Doris Kaltenecker, Søren Fisker Schmidt, Peter Weber, Anne Loft, Pauline Morigny, Juliano Machado, Julia Geppert, Kerstin Beate Saul, Pia Benedikt, Claudia-Eveline Molocea, Rachel Scott, Kerstin Haase, Marc E Martignoni, Ana Jimena Alfaro, Kan Kau Chow, Estefania Simoes, José Pinhata Otoch, Joanna D C C Lima, Charles Swanton, Nadine Spielmann, Martin Hrabé de Angelis, Markus Elsner, Ali Ertürk, Kenneth A Dyar, Maria Rohm, Olga Prokopchuk, Mariam Jamal-Hanjani, Marilia Seelaender, Johannes Backs, Stephan Herzig, Mauricio Berriel Diaz.
      In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.
    Keywords:  INTACT; REV-ERB; adipose tissue wasting; cachexia; circadian clock; hepatic reprogramming; liver-secreted factors; muscle atrophy
    DOI:  https://doi.org/10.1016/j.cell.2025.06.039
  30. iScience. 2025 Aug 15. 28(8): 113012
    Primary and metastatic cellular landscapes in human pancreatic cancer.
    Nina G Steele, Veerin R Sirihorachai, Ahmed M Elhossiny, Ian M Loveless, Padma Kadiyala, Monica Bonilla, Emily L Lasse-Opsahl, Carinna Solano Vargas, Katelyn L Donahue, Samantha B Kemp, Valerie Gunchick, Yatrik M Shah, Timothy L Frankel, Filip Bednar, Arvind Rao, Benjamin L Allen, Jiaqi Shi, Vaibhav Sahai, Howard C Crawford, Eileen S Carpenter, Marina Pasca di Magliano.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a complex tumor microenvironment (TME). We utilized single cell RNA sequencing to compare the TMEs of metastatic sites and primary tumors. We detected increased prevalence of exhausted CD8+ T cells in metastases, as well as the enrichment of complement pathway encoding genes in immunosuppressive tumor-associated macrophages, consistent with profound immunosuppression in metastatic disease. In cancer-associated fibroblasts, we identified a unique upregulation of metabolic genes, including UPP1, in metastasis. In cancer cells, we uncovered a specific gene signature upregulated in liver metastases; this signature was present in a proportion of primary tumors in the TCGA dataset, where it correlated with worse survival. Overall, our analysis of primary and metastatic PDAC defines a "high-risk" gene signature, metabolic reprogramming, and increased immune suppression in metastasis.
    Keywords:  Cancer; Integrative aspects of cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113012
  31. Nat Metab. 2025 Jul 21.
    LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
    Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.
      Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01333-7
  32. Nat Commun. 2025 Jul 22. 16(1): 6750
    Specific oncogene activation of the cell of origin in mucosal melanoma.
    Swathy Babu, Jiajia Chen, Chloé S Baron, Kaiwen Sun, Emily Robitschek, Alicia M McConnell, Constance Wu, Aikaterini Dedeilia, Moshe Sade-Feldman, Rodsy Modhurima, Michael P Manos, Kevin Y Chen, Anna M Cox, Calvin G Ludwig, Manolis Kellis, Elizabeth I Buchbinder, Nir Hacohen, Jiekun Yang, Genevieve M Boland, Brian J Abraham, David Liu, Leonard I Zon, Megan L Insco.
      Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we develop a zebrafish model in which all melanocytes experience CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only develops from melanocytes lining internal organs, analogous to the location of patient MM. We find that zebrafish MMs have a unique chromatin landscape from cutaneous melanomas. Internal melanocytes are labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes share a gene expression signature with MMs. Patient and zebrafish MMs show increased migratory neural crest and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests that the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery. As this is a non-MAPK driven genetically engineered model of melanoma, our work also has implications for the 15% of cutaneous melanoma patients who lack MAPK-driving mutations.
    DOI:  https://doi.org/10.1038/s41467-025-61937-1
  33. J Biol Chem. 2025 Jul 18. pii: S0021-9258(25)02347-6. [Epub ahead of print] 110497
    O-GlcNAcylation of Fatty Acid Synthase is required for its proper subcellular localization, expression level and activity.
    Dimitri Vanauberg, Céline Schulz, Sadia Raab, Gabriela Fuentes-Garcia, Emilie Cadart, Quentin Lemaire, Stéphanie Olivier-Van Stichelen, Fabrice Bray, Guillaume Brysbaert, Yannick Rossez, Stéphan Hardivillé, Tony Lefebvre.
      Fatty Acid Synthase (FASN) is involved in various fundamental cellular processes through its pivotal role in producing fatty acids through the de novo lipogenesis pathway. FASN is frequently overexpressed in tumors and participates in cancer cell proliferation. Little has been documented regarding post-translational modifications of FASN. We previously demonstrated that O-GlcNAcylation regulates FASN in mice livers and in the HepG2 hepatic cancer cell line. In the present study, we show that modulation of global O-GlcNAcylation levels impacts fatty acids production in HepG2 cells. We identified serine 595 and threonine 980 as major O-GlcNAcylation sites. While mutation of S595 moderately affects FASN behavior, T980 is crucial for FASN expression, membrane localization, homodimerization, stability and activity in Hep3B cells. This residue is necessary for FASN properties, promoting cell survival, cell proliferation and cell cycle progression. Our results suggest that targeting FASN at T980, may open an interesting path for controlling its catalytic activity.
    Keywords:  Fatty acid synthase; O-GlcNAc transferase; O-GlcNAcylation; fatty acids; liver cancer cells
    DOI:  https://doi.org/10.1016/j.jbc.2025.110497
  34. Nat Commun. 2025 Jul 22. 16(1): 6765
    Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.
    Julian R Buissant des Amorie, Max A Betjes, Jochem H Bernink, Joris H Hageman, Veerle E Geurts, Harry Begthel, Dimitrios Laskaris, Maria C Heinz, Ingrid Jordens, Tiba Vinck, Ronja M Houtekamer, Ingrid Verlaan-Klink, Sascha R Brunner, Jacco van Rheenen, Martijn Gloerich, Hans Clevers, Sander J Tans, Jeroen S van Zon, Hugo J G Snippert.
      Intestinal tuft cells are epithelial sentinels that trigger host defense upon detection of parasite-derived compounds. While they represent potent targets for immunomodulatory therapies in inflammation-driven intestinal diseases, their functioning and differentiation are poorly understood. Here, we reveal common intermediary transcriptomes among the previously described tuft-1 and tuft-2 subtypes in mouse and human. Tuft cell subtype-specific reporter knock-ins in organoids show that the two subtypes reflect successive post-mitotic maturation stages within the tuft cell lineage. In vitro stimulation with interleukin-4 and 13 is sufficient to fuel the generation of new Nrep+ tuft-1 cells, arising from tuft precursors (tuft-p). Subsequently, changes in crypt-villus signaling gradients, such as BMP, and cholinergic signaling, are required to advance maturation towards Chat+ tuft-2 phenotypes. Functionally, we find chemosensory capacity to increase during maturation. Our tuft subtype-specific reporters and optimized differentiation strategy in organoids provide a platform to study immune-related tuft cell subtypes and their unique chemosensory properties.
    DOI:  https://doi.org/10.1038/s41467-025-61878-9
  35. FASEB J. 2025 Jul 31. 39(14): e70834
    Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency-Driven Congenital Malformation Risk.
    Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Alena Sipka, Antonia W Shand, Natasha Nassar, Sally L Dunwoodie.
      Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in hundreds of cellular processes. Genetic disruption of NAD de novo synthesis causes congenital NAD deficiency disorder (CNDD), characterized by multiple congenital malformations or death in utero. Patient outcomes are highly variable, likely due to differences in the availability of maternal NAD precursors vitamin B3 and tryptophan to the embryo and its extraembryonic tissues. Here, maternal plasma and yolk sac NAD metabolomes, embryonic NAD levels, and pregnancy outcomes were quantified in a CNDD mouse model to determine how maternal circulatory NAD precursor provision affects pregnancy outcome and to identify metabolic markers of CNDD risk. Maternal levels of nicotinamide positively correlated with embryonic NAD levels, highlighting its central role for embryonic NAD metabolism. Levels of nicotinamide-derived excretion metabolites were the best predictors of adverse pregnancy outcome. NAD metabolomic analysis of pregnant women confirmed the relationship between dietary NAD precursor intake and circulatory nicotinamide and derived excretion product levels seen in mice, as women taking vitamin B3 supplements had elevated levels. Furthermore, mouse embryos with genetic disruption of NAD de novo synthesis (Haao-/-) were more susceptible to CNDD when maternal circulatory nicotinamide was limited, as their yolk sacs cannot generate NAD de novo from tryptophan. Metabolites originating from Haao-/- embryos were detectable in maternal plasma, showing that embryonic NAD metabolism also affects maternal circulation. Together, our findings elucidate the complex interplay between NAD metabolism of mother and conceptus and identify metabolic markers in maternal circulation that predict risk of NAD deficiency-related adverse pregnancy outcomes.
    Keywords:  NAD; congenital malformation; embryonic development; metabolism; pregnancy
    DOI:  https://doi.org/10.1096/fj.202500708RR
  36. Immunometabolism (Cobham). 2025 Jul;7(3): e00067
    Microbial trash to metabolic treasure.
    Alexander S Dowdell, Sean P Colgan.
      In a recent Nature publication, Lesbats et al uncover the molecular fate of phagocytosed bacterial contents. The authors observed incorporation of bacterial biomolecules (amino acids, metabolites) into those of the host macrophage through stable isotope labeling and mass spectrometry. Further, the authors found that the state of the phagocytosed bacteria, living or dead, dramatically alters the macrophage's metabolic program toward either a pro-inflammatory or a "recycling" direction, respectively. This commentary summarizes these findings and further discusses the implications of this work in a broader sense.
    Keywords:  AMPK; autophagy; dendritic cell; mTORC1; macrophage; neutrophil; phagocytosis
    DOI:  https://doi.org/10.1097/IN9.0000000000000067
  37. Nat Commun. 2025 Jul 19. 16(1): 6646
    Developing serum proteomics based prediction models of disease progression in ADPKD.
    Hande Ö Aydogan Balaban, Sita Arjune, Franziska Grundmann, Jan-Wilm Lackmann, Thomas Rauen, Philipp Antczak, Roman-Ulrich Müller.
      Autosomal Dominant Polycystic Kidney Disease is the most common genetic cause of kidney failure. Outcome prediction is essential to guide therapeutic decisions. However, currently available models are of limited accuracy. We aimed to examine the potential of serum proteomics for improved risk stratification. Here we show that 29 proteins are significantly associated with yearly kidney function decline. Functional enrichment on these 29 proteins reveals GO:BP terms related to immune response, lipoproteins and metabolic processes. A comparison to an Immunoglobulin A nephropathy cohort provides information regarding the eGFR-dependency and disease specificity of these proteins. The final outcome prediction model (adjusted R² 0.31) contains six proteins, namely Endothelial Plasminogen Activator Inhibitor (SERPINF1), Glutathione Peroxidase 3 (GPX3), Afamin (AFM), FERM Domain Containing Kindlin-3 (FERMT3), Complement Factor H Related 1 (CFHR1), and Retinoic Acid Receptor Responder 2 (RARRES2), the predictive value of which is independent from the clinical and imaging parameters currently used in clinical care. The validation of these models in different cohorts indicates the accuracy of the models. It will now be important to move towards targeted validation in a prospective study.
    DOI:  https://doi.org/10.1038/s41467-025-61887-8
  38. Mol Cell. 2025 Jul 17. pii: S1097-2765(25)00546-5. [Epub ahead of print]85(14): 2733-2748.e7
    YTHDC1 lactylation regulates its phase separation to enhance target mRNA stability and promote RCC progression.
    Chenyun Dai, Yuangui Tang, Huihui Yang, Junfang Zheng.
      The hypoxic and lactate-enriched microenvironment of renal cell carcinoma (RCC) provides favorable conditions for aberrant lysine lactylation (Kla). However, the functional role and mechanistic basis of Kla in RCC progression remain elusive. Here, we showed an elevated global Kla level in human RCC tissues and cells, which promoted RCC malignancy. Through lactylome analysis of human RCC cells under hypoxia-mimicking conditions, we found that the m6A reader YT521-B homology (YTH) domain-containing 1 (YTHDC1) is modified by Kla at K82. YTHDC1K82la, mediated by p300 under hypoxia, promotes RCC malignancy both in vitro and in vivo. Mechanistically, YTHDC1K82la increases YTHDC1 phase separation, leading to the expansion of nuclear condensates and safeguarding oncogenic transcripts BCL2 and E2F2 from degradation by the poly A-tail exosome targeting (PAXT)-exosome complex in human RCC cells. Our results demonstrated that augmented Kla advances RCC progression by modulating phase separation and thereby regulating the stability of YTHDC1 target genes.
    Keywords:  BCL2; E2F2; YTHDC1; lactylation; phase-separated condensate; renal cancer
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.017
  39. Nat Cell Biol. 2025 Jul 21.
    TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger.
    Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai.
      Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.
    DOI:  https://doi.org/10.1038/s41556-025-01721-x
  40. Nature. 2025 Jul 23.
    NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity.
    Janna Heide, Agnes J Bilecz, Samarjit Patnaik, Maria Francesca Allega, Leonhard Donle, Kaiting Yang, Ethan Teich, Yan Li, Qiaoshan Lin, Ke Kong, Li Liu, Tae Gyun Yang, Ken Chih-Chien Cheng, Jonathan H Shrimp, Quinlin M Hanson, Min Shen, Hongmao Sun, Hardik Shah, Lisa Schweizer, Katarzyna Zawieracz, Andrea Olland, Andre White, Robert K Suto, Razzaq Alhunayan, Medine Taşdemir, Noa Longman, Hua Liang, Matthias Mann, Gordon M Stott, Matthew D Hall, Simon Schwörer, Ralph R Weichselbaum, András Piffkó, Ernst Lengyel.
      Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking1,2. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour. Nnmt knockout in immunocompetent mice impairs tumour growth in syngeneic ovarian, breast and colon tumour models through enhanced CD8+ T cell activation. Using high-throughput screening, we develop a potent and specific NNMT inhibitor that reduces the tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated recruitment of MDSCs and reinvigorating CD8+ T cell activation. Our findings establish NNMT as a central CAF regulator and a promising therapeutic target to mitigate immunosuppression in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41586-025-09303-5
  41. J Cell Sci. 2025 Jul 24. pii: jcs.263736. [Epub ahead of print]
    The mammalian protein MTCH1 can function as an insertase.
    Anna Roza Dimogkioka, Anni Elias, Doron Rapaport.
      The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae, the MIM complex, consisting of Mim1 and Mim2, mediates the insertion of α-helical proteins into the OMM. Until recently, it was unclear which proteins serve this function in higher eukaryotes. Recent studies identified MTCH2 as the insertase of α-helical proteins into the OMM in mammals. MTCH1 is a paralogue of MTCH2 but its general function and contribution to the biogenesis process are not clear. To better characterize MTCH1, we explored whether MTCH1 or MTCH2 could functionally replace Mim1/Mim2 in yeast. Expression of MTCH1 and MTCH2 in yeast cells lacking Mim1, Mim2, or both revealed that MTCH1, but not MTCH2, could compensate the growth defects upon deleting the MIM complex. Furthermore, MTCH1 could restore the biogenesis of MIM substrates, TOM complex stability, and morphology of mitochondria. These findings indicate that MTCH1 by itself has insertase activity and is a functional homologue of the MIM complex, despite the absence of any evolutionary relation between the mammalian and yeast insertases.
    Keywords:  Insertase; MIM; MTCH1; MTCH2; Mitochondria; Outer membrane
    DOI:  https://doi.org/10.1242/jcs.263736
  42. Nat Commun. 2025 Jul 23. 16(1): 6770
    Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma.
    Tianhao Chu, Guiqi Zhu, Zheng Tang, Weifeng Qu, Rui Yang, Haiting Pan, Yi Wang, Ruilin Tian, Leilei Chen, Zhiqi Guan, Yichao Bu, Qianfu Zhao, Jiafeng Chen, Shengwei Mao, Yuan Fang, Jun Gao, Xiaoling Wu, Jian Zhou, Weiren Liu, Dan Ye, Jia Fan, Yinghong Shi.
      The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2+ TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2+ TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8+ T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2+ TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2+ TAMs, offering a promising therapeutic avenue for HCC immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-62132-y
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