bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–05–18
43 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
  2. Approaches to stable isotope tracing and in vivo metabolomics in the cancer clinic.
  3. Molecular machineries shaping the mitochondrial inner membrane.
  4. Mitochondria-membranous organelle contacts at a glance.
  5. ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
  6. To transfer mitochondria or not to transfer mitochondria: ADP does the trick.
  7. How cancer reduces motivation.
  8. A data-driven model for mitochondrial inner membrane remodeling as a driving force of organelle shaping.
  9. Adipocyte metabolic state regulates glial phagocytic function.
  10. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
  11. Three-dimensional genome landscape of primary human cancers.
  12. Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
  13. A fluorescent sensor for real-time monitoring of DPP8/9 reveals crucial roles in immunity and cancer.
  14. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
  15. Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling.
  16. Quality control of un-imported mitochondrial proteins at a glance.
  17. Metabolic pathway analysis of tumors using stable isotopes.
  18. Ageing lipids map melanoma's journey.
  19. Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis.
  20. Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones.
  21. Lysosomal Repair in Health and Disease.
  22. Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.
  23. Incomplete paralog compensation generates selective dependency on TRA2A in cancer.
  24. Interferon-γ orchestrates leptomeningeal anti-tumour response.
  25. Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
  26. TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.
  27. FGF21 reverses MASH through coordinated actions on the CNS and liver.
  28. Metabolic mapping of the human solute carrier superfamily.
  29. Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion.
  30. Computational modeling of cancer cell metabolism along the catabolic-anabolic axes.
  31. Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.
  32. Tryptophan Hydroxylase 1 Regulates Tryptophan and Its Metabolites.
  33. Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.
  34. Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.
  35. RNA transcripts serve as a template for double-strand break repair in human cells.
  36. Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.
  37. Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.
  38. Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
  39. Unlocking in vivo metabolic insights with vibrational microscopy.
  40. Spatial mapping of the brain metabolome lipidome and glycome.
  41. NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis.
  42. AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism.
  43. Data- and knowledge-derived functional landscape of human solute carriers.
  1. Mol Cancer Res. 2025 May 16.
    Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
    Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers.
      TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although glucose oxidation remains functional, TRAP1 KO reduces overall glucose uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases glucose uptake while preserving its metabolic fate, promoting glutamine conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis. Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0194
  2. EMBO J. 2025 May 12.
    Approaches to stable isotope tracing and in vivo metabolomics in the cancer clinic.
    Brandon Faubert, Alpaslan Tasdogan.
      
    Keywords:  Cancer Metabolism; Intraoperative Patient Infusions; Stable Isotope Tracing
    DOI:  https://doi.org/10.1038/s44318-025-00450-z
  3. Nat Rev Mol Cell Biol. 2025 May 14.
    Molecular machineries shaping the mitochondrial inner membrane.
    Oliver Daumke, Martin van der Laan.
      Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.
    DOI:  https://doi.org/10.1038/s41580-025-00854-z
  4. J Cell Sci. 2025 May 01. pii: jcs263895. [Epub ahead of print]138(9):
    Mitochondria-membranous organelle contacts at a glance.
    Antigoni Diokmetzidou, Luca Scorrano.
      Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.
    Keywords:  Contact sites; Mitochondria; Organelles
    DOI:  https://doi.org/10.1242/jcs.263895
  5. Nat Cell Biol. 2025 May;27(5): 847-862
    ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
    Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin.
      MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.
    DOI:  https://doi.org/10.1038/s41556-025-01651-8
  6. PLoS Biol. 2024 Aug;22(8): e3002754
    To transfer mitochondria or not to transfer mitochondria: ADP does the trick.
    Jaromir Novak, Jiri Neuzil.
      Horizontal mitochondrial transfer (HMT) has emerged as a novel phenomenon in cell biology, but it is unclear how this process of intercellular movement of mitochondria is regulated. A new study in PLOS Biology reports that ADP released by stressed cells is a signal that triggers HMT.
    DOI:  https://doi.org/10.1371/journal.pbio.3002754
  7. Nat Rev Cancer. 2025 May 14.
    How cancer reduces motivation.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-025-00834-7
  8. J Cell Sci. 2025 May 15. pii: jcs.263850. [Epub ahead of print]
    A data-driven model for mitochondrial inner membrane remodeling as a driving force of organelle shaping.
    Noga Preminger, Ben Zucker, Sarah Hassdenteufel, Till Stephan, Stefan Jakobs, Michael M Kozlov, Maya Schuldiner.
      Mitochondria are dynamic organelles exhibiting diverse shapes. While the variation of shapes, ranging from spheres to elongated tubules, and the transition between them, are clearly seen in many cell types, the molecular mechanisms governing this morphological variability remain poorly understood. Here, we propose a biophysical model for the shape transition between spheres and tubules based on the interplay between the inner and outer mitochondrial membranes. Our model suggests that the difference in surface area, arising from the folding of the inner membrane into cristae, correlates with mitochondrial elongation. Analysis of live cell super-resolution microscopy data supports this correlation, linking elongated shapes to the extent of cristae in the inner membrane. Knocking down cristae shaping proteins further confirms the impact on mitochondrial shape, demonstrating that defects in cristae formation correlate with mitochondrial sphericity. Our results suggest that the dynamics of the inner mitochondrial membrane are important not only for simply creating surface area required for respiratory capacity, but go beyond that to affect the whole organelle morphology. This work explores the biophysical foundations of individual mitochondrial shape, suggesting potential links between mitochondrial structure and function. This should be of profound significance, particularly in the context of disrupted cristae shaping proteins and their implications in mitochondrial diseases.
    Keywords:  Biophysical model; Cristae; Membrane remodeling; Mitochondrial membranes; Mitochondrial shape; Organelle shape
    DOI:  https://doi.org/10.1242/jcs.263850
  9. Cell Rep. 2025 May 14. pii: S2211-1247(25)00475-9. [Epub ahead of print]44(5): 115704
    Adipocyte metabolic state regulates glial phagocytic function.
    Mroj Alassaf, Aditi Madan, Sunidhi Ranganathan, Shannon Marschall, Jordan J Wong, Zachary H Goldberg, Ava E Brent, Akhila Rajan.
      Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.
    Keywords:  ApoB; CP: Metabolism; CP: Neuroscience; Drosophila; OxPhos; adipokine; glycolysis; high-sugar diet; injury-response; ketogenesis; lipid metabolism; mitochondria; neurodegeneration; pyronic sensor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115704
  10. Cell Metab. 2025 May 08. pii: S1550-4131(25)00253-0. [Epub ahead of print]
    Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
    Jessica W Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Monther Abu-Remaileh, Judith A Simcox.
      Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
    Keywords:  BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.015
  11. Nat Genet. 2025 May;57(5): 1189-1200
    Three-dimensional genome landscape of primary human cancers.
    Cancer Genome Atlas Analysis Network
      Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy.
    DOI:  https://doi.org/10.1038/s41588-025-02188-0
  12. Nat Metab. 2025 May 13.
    Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
    Anne Loft, Margo P Emont, Ada Weinstock, Adeline Divoux, Adhideb Ghosh, Allon Wagner, Ann V Hertzel, Babukrishna Maniyadath, Bart Deplancke, Boxiang Liu, Camilla Scheele, Carey Lumeng, Changhai Ding, Chenkai Ma, Christian Wolfrum, Clarissa Strieder-Barboza, Congru Li, Danh D Truong, David A Bernlohr, Elisabet Stener-Victorin, Erin E Kershaw, Esti Yeger-Lotem, Farnaz Shamsi, Hannah X Hui, Henrique Camara, Jiawei Zhong, Joanna Kalucka, Joseph A Ludwig, Julie A Semon, Jutta Jalkanen, Katie L Whytock, Kyle D Dumont, Lauren M Sparks, Lindsey A Muir, Lingzhao Fang, Lucas Massier, Luis R Saraiva, Marc D Beyer, Marc G Jeschke, Marcelo A Mori, Mariana Boroni, Martin J Walsh, Mary-Elizabeth Patti, Matthew D Lynes, Matthias Blüher, Mikael Rydén, Natnael Hamda, Nicole L Solimini, Niklas Mejhert, Peng Gao, Rana K Gupta, Rinki Murphy, Saeed Pirouzpanah, Silvia Corvera, Su'an Tang, Swapan K Das, Søren F Schmidt, Tao Zhang, Theodore M Nelson, Timothy E O'Sullivan, Vissarion Efthymiou, Wenjing Wang, Yihan Tong, Yu-Hua Tseng, Susanne Mandrup, Evan D Rosen.
      Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.
    DOI:  https://doi.org/10.1038/s42255-025-01296-9
  13. Life Sci Alliance. 2025 Aug;pii: e202403076. [Epub ahead of print]8(8):
    A fluorescent sensor for real-time monitoring of DPP8/9 reveals crucial roles in immunity and cancer.
    Konstantin Weiss, Yelizaveta Agarkova, Alexandra Zwosta, Sarah Hoevel, Ann-Kathrin Himmelreich, Magdalena Shumanska, Julia Etich, Gereon Poschmann, Bent Brachvogel, Ivan Bogeski, Dirk Mielenz, Jan Riemer.
      Dipeptidyl peptidases 8 and 9 (DPP8/9) are critical for the quality control of mitochondrial and endoplasmic reticulum protein import, immune regulation, cell adhesion, and cell migration. Dysregulation of DPP8/9 is associated with pathologies including tumorigenesis and inflammation. Commonly, DPP8/9 activity is analysed by in vitro assays using artificial substrates, which allow neither continuously monitoring DPP8/9 activity in individual, living cells nor detecting effects from endogenous interactors and posttranslational modifications. Here, we developed DiPAK (for DPP8/9 activity sensor based on AK2), a ratiometric genetically encoded fluorescent sensor, which enables studying DPP8/9 activity in living cells. Using DiPAK, we determined the dynamic range of DPP8/9 activity in cells overexpressing or lacking DPP9. We identified distinct activity levels among melanoma cell lines and found that LPS-induced primary B-cell activation depends on DPP8/9 as the absence of DPP8/9 activity results in apoptotic but not pyroptotic cell death. Consistently, we observed increasing DPP8/9 activity during B-cell maturation. Overall, DiPAK is a versatile tool for real-time single-cell monitoring of DPP8/9 activity in a broad range of cells and organisms.
    DOI:  https://doi.org/10.26508/lsa.202403076
  14. Nat Aging. 2025 May 12.
    Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
    Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco Paneni, Jürg H Beer.
      Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H2O2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.
    DOI:  https://doi.org/10.1038/s43587-025-00864-8
  15. Cell Rep. 2025 May 09. pii: S2211-1247(25)00418-8. [Epub ahead of print]44(5): 115647
    Beta cells intrinsically sense and limit their secretory activity via mTORC1-RhoA signaling.
    Saar Krell, Amit Hamburg, Ofer Gover, Kfir Molakandov, Gil Leibowitz, Kfir Sharabi, Michael D Walker, Aharon Helman.
      Precise regulation of insulin secretion by pancreatic β cells is essential to prevent excessive insulin release. Here, we show that the nutrient sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) is rapidly activated by glucose in β cells via the insulin secretion machinery, positioning mTORC1 as a sensor of β cell activity. Acute pharmacological inhibition of mTORC1 during glucose stimulation enhances insulin release, suggesting that mTORC1 acts as an intrinsic feedback regulator that restrains insulin secretion. Phosphoproteomic profiling reveals that mTORC1 modulates the phosphorylation of proteins involved in actin remodeling and vesicle trafficking, with a prominent role in the RhoA-GTPase pathway. Mechanistically, mTORC1 promotes RhoA activation and F-actin polymerization, limiting vesicle movement and dampening the second phase of insulin secretion. These findings identify a glucose-mTORC1-RhoA signaling axis that forms an autonomous feedback loop to constrain insulin exocytosis, providing insight into how β cells prevent excessive insulin release and maintain metabolic balance.
    Keywords:  CP: Metabolism; CP: Molecular biology; RhoA-GTPase; Torin-1; actin remodeling; activity sensor; autonomous regulation; insulin secretion; mTORC1; negative feedback loop; pancreatic β cell; rapamycin
    DOI:  https://doi.org/10.1016/j.celrep.2025.115647
  16. J Cell Sci. 2025 May 01. pii: jcs263757. [Epub ahead of print]138(9):
    Quality control of un-imported mitochondrial proteins at a glance.
    Megan Balzarini, John Kim, Hilla Weidberg.
      Mitochondria are metabolic hubs that are essential for cellular homeostasis. Most mitochondrial proteins are translated in the cytosol and imported into the organelle. However, import machineries can become overwhelmed or disrupted by physiological demands, mitochondrial damage or diseases, such as metabolic and neurodegenerative disorders. Impaired import affects mitochondrial function and causes un-imported pre-proteins to accumulate not only in the cytosol but also in other compartments, including the endoplasmic reticulum and nucleus. Quality control pathways have evolved to mitigate the accumulation of these mistargeted proteins and prevent proteotoxicity. In this Cell Science at a Glance article and the accompanying poster, we summarize the fate of un-imported mitochondrial proteins and the compartment-specific quality control pathways that regulate them.
    Keywords:  Mitochondrial protein import; Mitochondrial stress; Protein quality control
    DOI:  https://doi.org/10.1242/jcs.263757
  17. Semin Cancer Biol. 2025 May 08. pii: S1044-579X(25)00063-X. [Epub ahead of print]113 9-24
    Metabolic pathway analysis of tumors using stable isotopes.
    Qiufen Bi, Junzhang Zhao, Jun Nie, Fang Huang.
      Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.
    Keywords:  Cancer metabolism; Metabolic flux analysis; Stable-isotope tracing
    DOI:  https://doi.org/10.1016/j.semcancer.2025.05.002
  18. Nat Rev Cancer. 2025 May 15.
    Ageing lipids map melanoma's journey.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-025-00833-8
  19. Cell Death Differ. 2025 May 15.
    Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis.
    Komal Pekhale, Vinod Tiwari, Mansoor Hussain, Christy C Bridges, Deborah L Croteau, Moshe Levi, Avi Z Rosenberg, Briana Santo, Xiaoping Yang, Tomasz Kulikowicz, Xiaoxin X Wang, Jong-Hyuk Lee, Vilhelm A Bohr.
      Cockayne Syndrome (CS) is a premature aging disorder caused by mutations in the CSA and CSB genes involved in DNA metabolism and other cellular processes. CS patients display many features including premature aging, neurodegeneration, and kidney abnormalities. Nicotinamide dinucleotide (NAD+) deprivation has been observed in CS patient-derived cells. NAD+ has essential roles in regulating cellular health, stress responses, and renal homeostasis. While kidney dysfunction is a common feature in CS patients, its molecular pathogenesis is not understood. Here, we report that severe kidney pathology is present in CS A and B mice. We find that the NAD+ biosynthetic pathways are impaired in kidneys from these mice. Using human renal tubular epithelial cells, we show that CSA/B downregulation causes persistent activation of the ATF3 transcription factor on the quinolinate phosphoribosyl transferase gene locus, a rate-limiting enzyme in de novo NAD+ biosynthesis in the kidney, causing impaired transcription and deficient NAD+ homeostasis.
    DOI:  https://doi.org/10.1038/s41418-025-01522-7
  20. Cell Rep. 2025 May 12. pii: S2211-1247(25)00470-X. [Epub ahead of print]44(5): 115699
    Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones.
    Long V Nguyen, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Sarah Kronheim, Suet-Feung Chin, Raquel Manzano Garcia, Stephen-John Sammut, Giulia Lerda, Allan J W Lui, Helen A Bardwell, Wendy Greenwood, Hee Jin Shin, Riccardo Masina, Katarzyna Kania, Alejandra Bruna, Elham Esmaeilishirazifard, Emily A Kolyvas, Samuel Aparicio, Oscar M Rueda, Carlos Caldas.
      Clonal fitness and plasticity drive cancer heterogeneity. We used expressed lentiviral-based cellular barcodes combined with single-cell RNA sequencing to associate single-cell profiles with in vivo clonal growth. This generated a significant resource of growth measurements from over 20,000 single-cell-derived clones in 110 xenografts from 26 patient-derived breast cancer xenograft models. 167,375 single-cell RNA profiles were obtained from 5 models and revealed that rare propagating clones display a highly conserved model-specific differentiation program with reproducible regeneration of the entire transcriptomic landscape of the original xenograft. In 2 models of basal breast cancer, propagating clones demonstrated remarkable transcriptional plasticity at single-cell resolution. Dichotomous cell populations with different clonal growth properties, signaling pathways, and metabolic programs were characterized. By directly linking clonal growth with single-cell transcriptomes, these findings provide a profound understanding of clonal fitness and plasticity with implications for cancer biology and therapy.
    Keywords:  CP: Cancer; breast cancer; cancer stem cells; cellular barcoding; clonal heterogeneity; clonal tracking; patient-derived tumor xenografts; plasticity; single-cell sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2025.115699
  21. J Cell Physiol. 2025 May;240(5): e70044
    Lysosomal Repair in Health and Disease.
    Jinrui Xun, Jay Xiaojun Tan.
      Lysosomes are essential organelles degrading a wide range of substrates, maintaining cellular homeostasis, and regulating cell growth through nutrient and metabolic signaling. A key vulnerability of lysosomes is their membrane permeabilization (LMP), a process tightly linked to diseases including aging, neurodegeneration, lysosomal storage disorders, and cardiovascular disease. Research progress in the past few years has greatly improved our understanding of lysosomal repair mechanisms. Upon LMP, cells activate multiple membrane remodeling processes to restore lysosomal integrity, such as membrane invagination, tubulation, lipid patching, and membrane stabilization. These repair pathways are critical in preserving cellular stress tolerance and preventing deleterious inflammation and cell death triggered by lysosomal damage. This review focuses on the expanding mechanistic insights of lysosomal repair, highlighting its crucial role in maintaining cellular health and the implications for disease pathogenesis and therapeutic strategies.
    Keywords:  Atg8ylation; CASM; ESCRT; Lysosomal repair; PITT; annexins; lysosomal membrane permeabilization; microlysophagy; stress granules
    DOI:  https://doi.org/10.1002/jcp.70044
  22. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2418525122
    Mitochondria regulate MR1 protein expression and produce self-metabolites that activate MR1-restricted T cells.
    Gennaro Prota, Giuliano Berloffa, Wael Awad, Alessandro Vacchini, Andrew Chancellor, Verena Schaefer, Daniel Constantin, Dene R Littler, Rodrigo Colombo, Vladimir Nosi, Lucia Mori, Jamie Rossjohn, Gennaro De Libero.
      Mitochondria coordinate several metabolic pathways, producing metabolites that influence the immune response in various ways. It remains unclear whether mitochondria impact antigen presentation by the MHC-class-I-related antigen-presenting molecule, MR1, which presents small molecules to MR1-restricted T-lymphocytes. Here, we demonstrate that mitochondrial complex III and the enzyme dihydroorotate dehydrogenase are essential for the cell-surface expression of MR1 and for generating uridine- and thymidine-related compounds that bind to MR1 and are produced upon oxidation by reactive oxygen species. One mitochondria-derived immunogenic formylated metabolite we identified is 5-formyl-deoxyuridine (5-FdU). Structural studies indicate that 5-FdU binds in the A'-antigen-binding pocket of MR1, positioning the deoxyribose toward the surface of MR1 for TCR interaction. 5-FdU stimulates specific T cells and detects circulating T cells when loaded onto MR1-tetramers. 5-FdU-reactive cells resemble adaptive T cells and express the phenotypes of naïve, memory, and effector cells, indicating prior in vivo stimulation. These findings suggest that mitochondria may play a role in MR1-mediated immune surveillance.
    Keywords:  MR1; T cells; antigen presentation; formylated metabolite; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2418525122
  23. PLoS Genet. 2025 May;21(5): e1011685
    Incomplete paralog compensation generates selective dependency on TRA2A in cancer.
    Amanda R Lee, Anna Tangiyan, Isha Singh, Peter S Choi.
      Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other's loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A. We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B, we discover that a subset of cancer cell lines are highly TRA2A-dependent. Upon TRA2A depletion, these cell lines exhibit a lack of paralog buffering specifically on shared splicing targets, leading to defects in mitosis and cell death. Notably, TRA2B overexpression rescues both the aberrant splicing and lethality associated with TRA2A loss, indicating that paralog compensation is dosage-sensitive. Together, these findings reveal a complex dosage-dependent relationship between paralogous splicing factors, and highlight how dysfunctional paralog buffering can create a selective dependency in cancer.
    DOI:  https://doi.org/10.1371/journal.pgen.1011685
  24. Nature. 2025 May 14.
    Interferon-γ orchestrates leptomeningeal anti-tumour response.
    Jan Remsik, Xinran Tong, Russell Z Kunes, Min Jun Li, Rachel Estrera, Jenna Snyder, Clark Thomson, Ahmed M Osman, Kiana Chabot, Ugur T Sener, Jessica A Wilcox, Danielle Isakov, Helen Wang, Tejus A Bale, Ronan Chaligné, Joseph C Sun, Chrysothemis Brown, Dana Pe'er, Adrienne Boire.
      Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space.
    DOI:  https://doi.org/10.1038/s41586-025-09012-z
  25. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122
    Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
    Weiwei Fan, Tae Gyu Oh, Hui J Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan L Truitt, Christopher Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.
    Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle
    DOI:  https://doi.org/10.1073/pnas.2426179122
  26. Cell Rep. 2025 May 12. pii: S2211-1247(25)00454-1. [Epub ahead of print]44(5): 115683
    TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.
    Raffaele Nicastro, Marie-Pierre Péli-Gulli, Marco Caligaris, Malika Jaquenoud, Ladislav Dokládal, Josephine Alba, Farida Tripodi, Benjamin Pillet, Melanie Brunner, Michael Stumpe, Kenji Muneshige, Riko Hatakeyama, Jörn Dengjel, Claudio De Virgilio.
      The eukaryotic target of rapamycin complex 1 (TORC1) kinase is a homeostatic regulator of growth, integrating nutritional cues at the endolysosomal compartment. Amino acids activate mammalian TORC1 (mTORC1) through the Rag GTPases that recruit it to lysosomes via a short domain within the mTORC1 subunit Raptor. Intriguingly, this "Raptor claw" domain is absent in Kog1, the Raptor ortholog in yeast. Instead, as we show here, yeast utilizes the fungal-specific Tco89 to tether TORC1 to active Rag GTPases. This interaction enables TORC1 to precisely calibrate the activity of the S6K1-related effector kinase Sch9 in response to amino acid availability. TORC1 stabilizes Tco89 by phosphorylation, and its inactivation causes swift Tco89 proteolysis, provoking a redistribution of TORC1 from the vacuole to signaling endosomes and its spatial separation from Sch9. Thus, TORC1 not only operates in spatially distinct subcellular pools but also controls its own quantitative distribution between these pools to economize energy resources under fluctuating nutrient conditions.
    Keywords:  CP: Cell biology; CP: Molecular biology; Rag GTPases; TORC1; Tco89; amino acid signaling; growth control; target of rapamycin complex 1
    DOI:  https://doi.org/10.1016/j.celrep.2025.115683
  27. Cell Metab. 2025 May 08. pii: S1550-4131(25)00252-9. [Epub ahead of print]
    FGF21 reverses MASH through coordinated actions on the CNS and liver.
    Jesse P Rose, Donald A Morgan, Andrew I Sullivan, Xiaorong Fu, Melissa Inigo-Vollmer, Shawn C Burgess, David K Meyerholz, Kamal Rahmouni, Matthew J Potthoff.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.
    Keywords:  FGF21; MASH; MASLD; betaklotho; brain; hepatic innervation; hepatokine; liver; sympathetic nerve activity
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.014
  28. Mol Syst Biol. 2025 May 12.
    Metabolic mapping of the human solute carrier superfamily.
    Tabea Wiedmer, Shao Thing Teoh, Eirini Christodoulaki, Gernot Wolf, Chengzhe Tian, Vitaly Sedlyarov, Abigail Jarret, Philipp Leippe, Fabian Frommelt, Alvaro Ingles-Prieto, Sabrina Lindinger, Barbara M G Barbosa, Svenja Onstein, Christoph Klimek, Julio Garcia, Iciar Serrano, Daniela Reil, Diana Santacruz, Mary Piotrowski, Stephen Noell, Christoph Bueschl, Huanyu Li, Gamma Chi, Stefan Mereiter, Tiago Oliveira, Josef M Penninger, David B Sauer, Claire M Steppan, Coralie Viollet, Kristaps Klavins, J Thomas Hannich, Ulrich Goldmann, Giulio Superti-Furga.
      Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked to cellular function and identity. Despite their key role, individual functions of the SLC superfamily members were not evaluated systematically. We determined the metabolic and transcriptional profiles upon SLC overexpression in knock-out or wild-type isogenic cell backgrounds for 378 SLCs and 441 SLCs, respectively. Targeted metabolomics provided a fingerprint of 189 intracellular metabolites, while transcriptomics offered insights into cellular programs modulated by SLC expression. Beyond the metabolic profiles of 102 SLCs directly related to their known substrates, we identified putative substrates or metabolic pathway connections for 71 SLCs without previously annotated bona fide substrates, including SLC45A4 as a new polyamine transporter. By comparing the molecular profiles, we identified functionally related SLC groups, including some with distinct impacts on osmolyte balancing and glycosylation. The assessment of functionally related human genes presented here may serve as a blueprint for other systematic studies and supports future investigations into the functional roles of SLCs.
    Keywords:  Membrane Transporters; Metabolism; Metabolomics; Solute Carriers; Transcriptomics
    DOI:  https://doi.org/10.1038/s44320-025-00106-4
  29. bioRxiv. 2025 Apr 29. pii: 2025.04.13.647987. [Epub ahead of print]
    Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion.
    Sara Zirpoli, Noah Copperman, Shrey Patel, Alexander Forrest, Zhanjun Hou, Larry H Matherly, David M Loeb, Antonio Di Cristofano.
      Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish the upregulation of the one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.
    Statement of Significance: Using both genetic and pharmacologic approaches, this study identifies Ewing sarcoma's dependence on the mitochondrial arm, but not the cytoplasmic arm, of one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.
    DOI:  https://doi.org/10.1101/2025.04.13.647987
  30. NPJ Syst Biol Appl. 2025 May 10. 11(1): 46
    Computational modeling of cancer cell metabolism along the catabolic-anabolic axes.
    Javier Villela-Castrejon, Herbert Levine, Benny A Kaipparettu, José N Onuchic, Jason T George, Dongya Jia.
      Abnormal metabolism is a hallmark of cancer, this was initially recognized nearly a century ago through the observation of aerobic glycolysis in cancer cells. Mitochondrial respiration can also drive tumor progression and metastasis. However, it remains largely unclear the mechanisms by which cancer cells mix and match different metabolic modalities (oxidative/reductive) and leverage various metabolic ingredients (glucose, fatty acids, glutamine) to meet their bioenergetic and biosynthetic needs. Here, we formulate a phenotypic model for cancer metabolism by coupling master gene regulators (AMPK, HIF-1, MYC) with key metabolic substrates (glucose, fatty acids, and glutamine). The model predicts that cancer cells can acquire four metabolic phenotypes: a catabolic phenotype characterized by vigorous oxidative processes-O, an anabolic phenotype characterized by pronounced reductive activities-W, and two complementary hybrid metabolic states-one exhibiting both high catabolic and high anabolic activity-W/O, and the other relying mainly on glutamine oxidation-Q. Using this framework, we quantified gene and metabolic pathway activity by developing scoring metrics based on gene expression. We validated the model-predicted gene-metabolic pathway association and the characterization of the four metabolic phenotypes by analyzing RNA-seq data of tumor samples from TCGA. Strikingly, carcinoma samples exhibiting hybrid metabolic phenotypes are often associated with the worst survival outcomes relative to other metabolic phenotypes. Our mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations, which ultimately could facilitate an effective treatment targeting cancer metabolic plasticity.
    DOI:  https://doi.org/10.1038/s41540-025-00525-x
  31. Cell Rep. 2025 May 10. pii: S2211-1247(25)00460-7. [Epub ahead of print]44(5): 115689
    Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.
    Jeremy B Ducharme, Daria Neyroud, Martin M Schonk, Miguel A Gutierrez-Monreal, Zhiguang Huo, Haley O Tucker, Karyn A Esser, Sarah M Judge, Andrew R Judge.
      Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.
    Keywords:  CP: Cancer; ChIP-seq; RNA-seq; cancer cachexia; circadian rhythm; inflammation; metabolism; muscle atrophy; muscle clock; pancreatic cancer; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.115689
  32. Int J Mol Sci. 2025 Apr 23. pii: 3978. [Epub ahead of print]26(9):
    Tryptophan Hydroxylase 1 Regulates Tryptophan and Its Metabolites.
    Katsunori Nonogaki, Takao Kaji.
      Tryptophan hydroxylase (Tph), the rate-limiting enzyme of serotonin (5-hydroxytryptophan; 5-HT) synthesis, exists in two isoforms, Tph1 and Tph2. Tph1 upregulates peripheral 5-HT synthesis and blood 5-HT levels, whereas Tph2 upregulates brain 5-HT synthesis. Here, we show that plasma and brain levels of tryptophan and its metabolites, including 5-HT, 5-hydroxy indoleacetic acid, indolepropionic acid, indole-3-acetic acid, kynurenine, and xanthurenic acid, are decreased in young (8-week-old) Tph1-mutant mice compared with age-matched wild-type mice. In older (7-month-old) Tph1-mutants, the decreases in tryptophan and its metabolites outside the 5-HT pathway were diminished. Although single-housed Tph1 mutants displayed age-related alterations in food intake, body weight, and plasma FGF21 levels, blood glucose levels were lower in both young and older Tph1 mutants compared with age-matched wild-type mice. These findings suggest that Tph1 regulates tryptophan and its metabolites in the plasma and brain, as well as blood glucose homeostasis.
    Keywords:  FGF21; Tph1; blood glucose; brain; food intake; indolepropionic acid; kynurenine; serotonin; tryptophan
    DOI:  https://doi.org/10.3390/ijms26093978
  33. J Cell Sci. 2025 May 16. pii: jcs.263679. [Epub ahead of print]
    Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.
    Gabriel P Faber, Gilad Gross, Oz Mualem, Matan Y Avivi, Hiba Waldman Ben-Asher, Orly Yaron, Orit Shefi, Rakefet Ben-Yishay, Dana Ishay-Ronen, Yaron Shav-Tal.
      Cytoplasmic stress granules (SGs) induced by various stresses have been linked to cancer and other disorders. Which active energy pathways are required for SG formation remains unclear. We used nutrient deprivation to show that glutamine is the sole amino acid source governing whether cancer cells form SGs. Metabolic profiling revealed the essential functions of glutamine and glucose in SG formation under limiting metabolic conditions. Providing glutamine during metabolic stress restored ATP levels in cancer cells and revived many essential gene expression patterns. Myc, a known regulator of the shift between glucose and glutamine metabolism, showed increased expression as cells moved to glutamine uptake. Inhibition of MYC prevented SG formation even with glutamine present and increased cell death after arsenite exposure. The RNA-binding proteins G3BP1/2 were required for glutamine utilization, with G3BP1/2 knockout cells displaying a heavier reliance on glucose, yielding reduced cell survival and inability to properly utilize glutamine. Altogether, we show that cancer cells require glutamine for SG formation under nutrient deprivation, and its absence reduces cell survival, lowering ATP levels below an energy threshold required for SG formation.
    Keywords:  Glutamine; Myc; RNA FISH; Stress granules
    DOI:  https://doi.org/10.1242/jcs.263679
  34. Nat Metab. 2025 May 13.
    Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions.
    Yu-San Kao, Mario Lauterbach, Aleksandra Lopez Krol, Ute Distler, Gloria Janet Godoy, Matthias Klein, Rafael Jose Argüello, Fatima Boukhallouk, Sara Vallejo Fuente, Kathrin Luise Braband, Assel Nurbekova, Monica Romero, Panagiota Mamareli, Luana Silva, Luis Eduardo Alves Damasceno, Francesca Rampoldi, Luciana Berod, Lydia Lynch, Karsten Hiller, Tim Sparwasser.
      Metabolic reprogramming determines γδ T cell fate during thymic development; however, the metabolic requirements of interleukin (IL)-17A-producing γδ T cells (γδT17 cells) under psoriatic conditions are unclear. Combining high-throughput techniques, including RNA sequencing, SCENITH, proteomics and stable isotope tracing, we demonstrated that psoriatic inflammation caused γδT17 cells to switch toward aerobic glycolysis. Under psoriatic conditions, γδT17 cells upregulated ATP-citrate synthase to convert citrate to acetyl-CoA, linking carbohydrate metabolism and fatty acid synthesis (FAS). Accordingly, we used a pharmacological inhibitor, Soraphen A, which blocks acetyl-CoA carboxylase (ACC), to impair FAS in γδT17 cells, reducing their intracellular lipid stores and ability to produce IL-17A under psoriatic conditions in vitro. We pinpointed the pathogenic role of ACC1 in γδT17 cells in vivo by genetic ablation, ameliorating inflammation in a psoriatic mouse model. Furthermore, ACC inhibition limited human IL-17A-producing γδT17 cells. Targeting ACC1 to attenuate pathogenic γδT17 cell function has important implications for psoriasis management.
    DOI:  https://doi.org/10.1038/s42255-025-01276-z
  35. Nat Commun. 2025 May 10. 16(1): 4349
    RNA transcripts serve as a template for double-strand break repair in human cells.
    Manisha Jalan, Alessandra Brambati, Hina Shah, Niamh McDermott, Juber Patel, Yingjie Zhu, Ahmet Doymaz, Julius Wu, Kyrie S Anderson, Andrea Gazzo, Fresia Pareja, Takafumi N Yamaguchi, Theodore Vougiouklakis, Sana Ahmed-Seghir, Philippa Steinberg, Anna Neiman-Golden, Benura Azeroglu, Joan Gomez-Aguilar, Edaise M da Silva, Suleman Hussain, Daniel Higginson, Paul C Boutros, Nadeem Riaz, Jorge S Reis-Filho, Simon N Powell, Agnel Sfeir.
      Double-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, growing evidence suggests that RNA:DNA hybrids and nearby transcripts can influence repair outcomes. However, whether transcript RNA can directly serve as a template for DSB repair in human cells remains unclear. In this study, we develop fluorescence and sequencing-based assays to show that RNA-containing oligonucleotides and messenger RNA can serve as templates during DSB repair. We conduct a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR). Of the candidate polymerases, we identify DNA polymerase zeta (Polζ) as a potential reverse transcriptase that facilitates RT-DSBR. Furthermore, analysis of cancer genome sequencing data reveals whole intron deletions - a distinct genomic signature of RT-DSBR that occurs when spliced mRNA guides repair. Altogether, our findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.
    DOI:  https://doi.org/10.1038/s41467-025-59510-x
  36. Nat Immunol. 2025 May 12.
    Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.
    Theodore J Sanders, Christopher S Nabel, Margreet Brouwer, Annelise L Hermant, Lucas Chaible, Jean-Philippe Deglasse, Nicolas Rosewick, Angélique Pabois, Wilfried Cathou, Aurore Smets, Michael Deligny, João Marchante, Quentin Dubray, Marie-Claire Letellier, Chiara Martinoli, Reece Marillier, Olivier De Henau, Yvonne McGrath, Matthew G Vander Heiden, Erica Houthuys.
      The benefit of immune checkpoint blockade for cancer therapy is limited to subsets of patients because of factors including the accumulation of immunosuppressive metabolites, such as adenosine, within tumors. Pharmacological inhibition of adenosine generation and signaling is an active area of clinical investigation, but only limited clinical benefit has been reported. Here, we show that adenosine suppresses anti-cancer T cell responses following uptake into activated T cells by equilibrative nucleoside transporter 1 (ENT1) and inhibition of de novo pyrimidine nucleotide synthesis. We identify EOS301984 as a potent ENT1 antagonist that restores pyrimidine levels in activated T cells in adenosine-rich environments, resulting in enhanced tumor cell killing by memory T cells and increased ex vivo expansion of functional human tumor-infiltrating lymphocytes. A combination of EOS301984 with anti-PD-1 led to synergistic control of tumor growth in a humanized mouse model of triple-negative breast cancer. ENT1 inhibition, therefore, augments anti-cancer immune responses through the restoration of pyrimidine nucleotide synthesis in T cells suppressed by adenosine.
    DOI:  https://doi.org/10.1038/s41590-025-02153-3
  37. Mol Metab. 2025 May 08. pii: S2212-8778(25)00072-9. [Epub ahead of print] 102165
    Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.
    Caitlyn E Bowman, Michael D Neinast, Ryo Kawakami, Nicholas Forelli, Cholsoon Jang, Jiten Patel, Megan C Blair, Michael C Noji, Emily T Mirek, William O Jonsson, Qingwei Chu, Lauren Merlo, Laura Mandik-Nayak, Tracy G Anthony, Joshua D Rabinowitz, Zolt Arany.
      The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Bckdk-/- animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprisingly, however, BT2 strongly reduced plasma tryptophan levels and promoted catabolism of tryptophan to kynurenine in both control and Bckdk-/- mice. Mechanistic studies revealed that none of the principal tryptophan catabolic or kynurenine-producing/consuming enzymes (TDO, IDO1, IDO2, or KATs) were required for BT2-mediated lowering of plasma tryptophan. Instead, using equilibrium dialysis assays and mice lacking albumin, we show that BT2 avidly binds plasma albumin and displaces tryptophan, releasing it for catabolism. These data confirm that BT2 activates BCAA oxidation via inhibition of BCKDK but also reveal a robust off-target effect on tryptophan metabolism via displacement from serum albumin. The data highlight a potential confounding effect for pharmaceutical compounds that compete for binding with albumin-bound tryptophan.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102165
  38. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2415779122
    Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
    Takashi Sakamoto, Julie Leca, Xin Zhang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Liam D Hendrikse, Wenjing Zhou, Thorsten Berger, Jerome Fortin, Steven M Chan, Ming-Feng Chiang, Satoshi Inoue, Wanda Y Li, Mandy F Chu, Gordon S Duncan, Andrew Wakeham, François Lemonnier, Chantal Tobin, Ryan Mcwilliam, Isabelle Colonna, Christophe Bontoux, Soode Moghadas Jafari, Robert L Bowman, Brandon Nicolay, Sebastien Ronseaux, Rohini Narayanaswamy, Ross L Levine, Ari M Melnick, Christopher E Mason, Mark D Minden, Tak W Mak.
      In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (IDH1) often co-occur with NPM1 mutations, and less frequently with FLT3 mutations. To investigate whether the effects of IDH1 mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. Idh1R132H combined with Npm1c induced overt AML, whereas Idh1R132H plus Flt3ITD resulted in Flt3ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1R132H;Npm1c cells and Idh1R132H;Flt3ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1R132H;Npm1c cells corresponded to that of human IDH-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of Idh1R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1R132H with Npm1c vs. Flt3ITD may have implications for the devising of subtype-specific treatments for human AML.
    Keywords:  FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model
    DOI:  https://doi.org/10.1073/pnas.2415779122
  39. Nat Methods. 2025 May;22(5): 886-889
    Unlocking in vivo metabolic insights with vibrational microscopy.
    Tao Chen, Marzia Savini, Meng C Wang.
      
    DOI:  https://doi.org/10.1038/s41592-025-02616-3
  40. Nat Commun. 2025 May 12. 16(1): 4373
    Spatial mapping of the brain metabolome lipidome and glycome.
    Harrison A Clarke, Xin Ma, Cameron J Shedlock, Terrymar Medina, Tara R Hawkinson, Lei Wu, Roberto A Ribas, Shannon Keohane, Sakthivel Ravi, Jennifer L Bizon, Sara N Burke, Jose Francisco Abisambra, Matthew E Merritt, Boone M Prentice, Craig W Vander Kooi, Matthew S Gentry, Li Chen, Ramon C Sun.
      Metabolites, lipids, and glycans are fundamental but interconnected classes of biomolecules that form the basis of the metabolic network. These molecules are dynamically channeled through multiple pathways that govern cellular physiology and pathology. Here, we present a framework for the simultaneous spatial analysis of the metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. This workflow integrates a computational platform, the Spatial Augmented Multiomics Interface (Sami), which enables multiomics integration, high-dimensional clustering, spatial anatomical mapping of matched molecular features, and metabolic pathway enrichment. To demonstrate the utility of this approach, we applied Sami to evaluate metabolic diversity across distinct brain regions and to compare wild-type and Ps19 Alzheimer's disease (AD) mouse models. Our findings reveal region-specific metabolic demands in the normal brain and highlight metabolic dysregulation in the Ps19 model, providing insights into the biochemical alterations associated with neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-025-59487-7
  41. EMBO Rep. 2025 May 14.
    NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis.
    Ryan J Conrad, James A Mondo, Mike Lingjue Wang, Peter S Liu, Zijuan Lai, Feroza K Choudhury, Qingling Li, Weng Ruh Wong, James Lee, Frances Shanahan, Eva Lin, Scott Martin, Joachim Rudolph, John G Moffat, Dewakar Sangaraju, Wendy Sandoval, Timothy Sterne-Weiler, Scott A Foster.
      Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers (NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in cancer cell lines, and observed that a significant portion of these genes is devoid of promoter-proximal NRF2 occupancy. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent cancer cell growth does not require this enhanced glutathione production.
    Keywords:  CBP/p300; Glutathione; NRF2; Non-small Cell Lung Cancer; ROS
    DOI:  https://doi.org/10.1038/s44319-025-00463-z
  42. Elife. 2025 May 15. pii: RP99670. [Epub ahead of print]13
    AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism.
    Zongwang Zhang, Lixia Zheng, Yang Chen, Yuanyuan Chen, Junjie Hou, Chenglu Xiao, Xiaojun Zhu, Shi-Min Zhao, Jing-Wei Xiong.
      AARS2, an alanyl-tRNA synthase, is essential for protein translation, but its function in mouse hearts is not fully addressed. Here, we found that cardiomyocyte-specific deletion of mouse AARS2 exhibited evident cardiomyopathy with impaired cardiac function, notable cardiac fibrosis, and cardiomyocyte apoptosis. Cardiomyocyte-specific AARS2 overexpression in mice improved cardiac function and reduced cardiac fibrosis after myocardial infarction (MI), without affecting cardiomyocyte proliferation and coronary angiogenesis. Mechanistically, AARS2 overexpression suppressed cardiomyocyte apoptosis and mitochondrial reactive oxide species production, and changed cellular metabolism from oxidative phosphorylation toward glycolysis in cardiomyocytes, thus leading to cardiomyocyte survival from ischemia and hypoxia stress. Ribo-Seq revealed that Aars2 overexpression increased pyruvate kinase M2 (PKM2) protein translation and the ratio of PKM2 dimers to tetramers that promote glycolysis. Additionally, PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency. Thus, this study demonstrates that AARS2 plays an essential role in protecting cardiomyocytes from ischemic pressure via fine-tuning PKM2-mediated energy metabolism, and presents a novel cardiac protective AARS2-PKM2 signaling during the pathogenesis of MI.
    Keywords:  AARS2; PKM2; cardiac remodeling; cardiomyocytes; cell biology; glycolysis; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.99670
  43. Mol Syst Biol. 2025 May 12.
    Data- and knowledge-derived functional landscape of human solute carriers.
    Ulrich Goldmann, Tabea Wiedmer, Andrea Garofoli, Vitaly Sedlyarov, Manuel Bichler, Ben Haladik, Gernot Wolf, Eirini Christodoulaki, Alvaro Ingles-Prieto, Evandro Ferrada, Fabian Frommelt, Shao Thing Teoh, Philipp Leippe, Gabriel Onea, Martin Pfeifer, Mariah Kohlbrenner, Lena Chang, Paul Selzer, Jürgen Reinhardt, Daniela Digles, Gerhard F Ecker, Tanja Osthushenrich, Aidan MacNamara, Anders Malarstig, David Hepworth, Giulio Superti-Furga.
      The human solute carrier (SLC) superfamily of ~460 membrane transporters remains the largest understudied protein family despite its therapeutic potential. To advance SLC research, we developed a comprehensive knowledgebase that integrates systematic multi-omics data sets with selected curated information from public sources. We annotated SLC substrates through literature curation, compiled SLC disease associations using data mining techniques, and determined the subcellular localization of SLCs by combining annotations from public databases with an immunofluorescence imaging approach. This SLC-centric knowledge is made accessible to the scientific community via a web portal featuring interactive dashboards and visualization tools. Utilizing this systematically collected and curated resource, we computationally derived an integrated functional landscape for the entire human SLC superfamily. We identified clusters with distinct properties and established functional distances between transporters. Based on all available data sets and their integration, we assigned biochemical/biological functions to each SLC, making this study one of the largest systematic annotations of human gene function and a potential blueprint for future research endeavors.
    Keywords:  Human Gene Function; Knowledgebase; Membrane Transporters; Multimodal Data Integration; Solute Carriers
    DOI:  https://doi.org/10.1038/s44320-025-00108-2
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