bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–03–23
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.
  2. The tumor microenvironment is an ecosystem sustained by metabolic interactions.
  3. VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
  4. Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
  5. The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research.
  6. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  7. AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.
  8. How extreme lethargy can promote healthy ageing.
  9. Mitochondrial fission - changing perspectives for future progress.
  10. A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.
  11. SIRT5 slows skeletal muscle ageing by alleviating inflammation.
  12. CLYBL averts vitamin B12 depletion by repairing malyl-CoA.
  13. The somatic mutation landscape of normal gastric epithelium.
  14. Developmental mitochondrial complex I activity determines lifespan.
  15. The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
  16. Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
  17. Quantitative characterization of cell niches in spatially resolved omics data.
  18. Blocking lactate: kick T cells when they are down.
  19. Untargeted pixel-by-pixel metabolite ratio imaging as a novel tool for biomedical discovery in mass spectrometry imaging.
  20. Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
  21. The end of the genetic paradigm of cancer.
  22. β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
  23. PPDPF: Preventing kidney disease through NAD+ regulation.
  24. Integrative single-cell metabolomics and phenotypic profiling reveals metabolic heterogeneity of cellular oxidation and senescence.
  25. Mutations that accrue through life set the stage for stomach cancer.
  26. Moonlighting Enzymes at the Interface Between Metabolism and Epigenetics.
  27. Adsl-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.
  28. Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.
  29. Advances in mitophagy initiation mechanisms.
  30. GLP-2 attenuates antipsychotics' adverse metabolic effects.
  31. HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA.
  32. Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.
  33. DNA methylation entropy is a biomarker for aging.
  34. Recycling for a cleaner metabolism.
  35. Of HIFs and hERVs: Neoantigen generation in kidney cancer.
  36. Age-dependent cytokine surge in blood precedes cancer diagnosis.
  37. Nutrients shape T cell exhaustion.
  38. Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.
  39. Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.
  40. Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression.
  41. In-cell architecture of the mitochondrial respiratory chain.
  42. Deciphering the dark cancer phosphoproteome using machine-learned co-regulation of phosphosites.
  43. Emerging Approaches for Studying Lipid Dynamics, Metabolism, and Interactions in Cells.
  44. The cyclic metabolic switching theory of intermittent fasting.
  45. The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy.
  46. Genetically encoding ε-N-methacryllysine into proteins in live cells.
  47. Why humans have puzzle-shaped cells.
  48. An unexpected player in organ tropism: aspartate functions as signalling molecule to drive lung metastasis.
  49. A genetically encoded fluorescent sensor enables sensitive and specific detection of IDH mutant associated oncometabolite D-2-hydroxyglutarate.
  50. Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
  51. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
  52. Growth of the maternal intestine during reproduction.
  53. AI-driven framework to map the brain metabolome in three dimensions.
  54. Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
  55. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  56. CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.
  57. Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions.
  58. Activated T cells break tumor immunosuppression by macrophage re-education.
  59. PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases.
  1. Sci Adv. 2025 Mar 21. 11(12): eads9182
    A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells.
    Mariana Bustamante Eduardo, Gannon Cottone, Curtis W McCloskey, Shiyu Liu, Flavio R Palma, Maria Paula Zappia, Abul B M M K Islam, Peng Gao, Joel Setya, Saya Dennis, Hongyu Gao, Qian Zhang, Xiaoling Xuei, Yuan Luo, Jason Locasale, Marcelo G Bonini, Rama Khokha, Maxim V Frolov, Elizaveta V Benevolenskaya, Navdeep S Chandel, Seema A Khan, Susan E Clare.
      Lipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer.
    DOI:  https://doi.org/10.1126/sciadv.ads9182
  2. Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00203-7. [Epub ahead of print]44(3): 115432
    The tumor microenvironment is an ecosystem sustained by metabolic interactions.
    Emily Jane Kay, Sara Zanivan.
      Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.
    Keywords:  CAFs; CP: Cancer; CP: Metabolism; immune cells; metabolism; stroma immune; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115432
  3. Nature. 2025 Mar 19.
    VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.
    Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk, Hongbo Chi.
      Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-08732-6
  4. Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430
    Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
    Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.
      Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.
    Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.celrep.2025.115430
  5. Nat Metab. 2025 Mar 17.
    The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research.
    Shaunak Deota, Julie S Pendergast, Ullas Kolthur-Seetharam, Karyn A Esser, Frédéric Gachon, Gad Asher, Charna Dibner, Salvador Aznar Benitah, Carolina Escobar, Deborah M Muoio, Eric Erquan Zhang, Gökhan S Hotamışlıgil, Joseph Bass, Joseph S Takahashi, Joshua D Rabinowitz, Katja A Lamia, Rafael de Cabo, Shingo Kajimura, Valter D Longo, Ying Xu, Mitchell A Lazar, Eric Verdin, Juleen R Zierath, Johan Auwerx, Daniel J Drucker, Satchidananda Panda.
      The constant expansion of the field of metabolic research has led to more nuanced and sophisticated understanding of the complex mechanisms that underlie metabolic functions and diseases. Collaborations with scientists of various fields such as neuroscience, immunology and drug discovery have further enhanced the ability to probe the role of metabolism in physiological processes. However, many behaviours, endocrine and biochemical processes, and the expression of genes, proteins and metabolites have daily ~24-h biological rhythms and thus peak only at specific times of the day. This daily variation can lead to incorrect interpretations, lack of reproducibility across laboratories and challenges in translating preclinical studies to humans. In this Review, we discuss the biological, environmental and experimental factors affecting circadian rhythms in rodents, which can in turn alter their metabolic pathways and the outcomes of experiments. We recommend that these variables be duly considered and suggest best practices for designing, analysing and reporting metabolic experiments in a circadian context.
    DOI:  https://doi.org/10.1038/s42255-025-01237-6
  6. Nat Commun. 2025 Mar 19. 16(1): 2685
    Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
    Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.
      Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-57439-9
  7. J Clin Invest. 2025 Mar 18. pii: e179572. [Epub ahead of print]
    AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia.
    Manuel A Torres Acosta, Jonathan K Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A Helmin, Anthony M Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E Weinberg, Benjamin D Singer.
      CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
    Keywords:  Immunology; Intermediary metabolism; Mitochondria; Oncology; Pulmonology; T cells
    DOI:  https://doi.org/10.1172/JCI179572
  8. Nature. 2025 Mar;639(8055): 549
    How extreme lethargy can promote healthy ageing.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00707-x
  9. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  10. Bioact Mater. 2025 Jun;48 493-509
    A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.
    Jeong Min Oh, Tianze Guo, Hydari Masuma Begum, Saci-Elodie Marty, Liang Sha, Cem Kilic, Hao Zhou, Yali Dou, Keyue Shen.
      Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors.
    Keywords:  Hypoxia; Metabolic rewiring; Metabolism-targeting therapy; Tumor heterogeneity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.030
  11. Nat Metab. 2025 Mar 14.
    SIRT5 slows skeletal muscle ageing by alleviating inflammation.
    Vera Gorbunova, Andrei Seluanov.
      
    DOI:  https://doi.org/10.1038/s42255-025-01228-7
  12. Nat Chem Biol. 2025 Mar 19.
    CLYBL averts vitamin B12 depletion by repairing malyl-CoA.
    Corey M Griffith, Jean-François Conrotte, Parisa Paydar, Xinqiang Xie, Ursula Heins-Marroquin, Floriane Gavotto, Christian Jäger, Kenneth W Ellens, Carole L Linster.
      Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of CLYBL loss of function with reduced circulating vitamin B12 levels was proposed to result from inhibition of the B12-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of CLYBL across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that CLYBL knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B12 deficiency observed in individuals with CLYBL loss of function.
    DOI:  https://doi.org/10.1038/s41589-025-01857-9
  13. Nature. 2025 Mar 19.
    The somatic mutation landscape of normal gastric epithelium.
    Tim H H Coorens, Grace Collord, Hyungchul Jung, Yichen Wang, Luiza Moore, Yvette Hooks, Krishnaa Mahbubani, Simon Y K Law, Helen H N Yan, Siu Tsan Yuen, Kourosh Saeb-Parsy, Peter J Campbell, Iñigo Martincorena, Suet Yi Leung, Michael R Stratton.
      The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development1. Here, by whole-genome sequencing of 238 microdissections2 from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, metaplastic glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying 829 polyclonal gastric microbiopsies by targeted sequencing, we find somatic 'driver' mutations in a distinctive repertoire of known cancer genes, including ARID1A, ARID1B, ARID2, CTNNB1 and KDM6A. The prevalence of mutant clones increases with age to occupy roughly 8% of the gastric epithelial lining by age 60 years and is significantly increased by the presence of severe chronic inflammation. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states.
    DOI:  https://doi.org/10.1038/s41586-025-08708-6
  14. EMBO Rep. 2025 Mar 17.
    Developmental mitochondrial complex I activity determines lifespan.
    Rhoda Stefanatos, Fiona Robertson, Beatriz Castejon-Vega, Yizhou Yu, Alejandro Huerta Uribe, Kevin Myers, Tetsushi Kataura, Viktor I Korolchuk, Oliver D K Maddocks, L Miguel Martins, Alberto Sanz.
      Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
    Keywords:  Ageing; Complex I; Drosophila; Mitochondria; Mitochondrial Disease
    DOI:  https://doi.org/10.1038/s44319-025-00416-6
  15. J Cell Sci. 2025 Mar 17. pii: jcs.263661. [Epub ahead of print]
    The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
    Moritz Resch, Johanna S Frickel, Korbinian Dischinger, Rachel Choo Shen Wen, Kai Hell, Max E Harner.
      Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.
    Keywords:  CHCHD10; Mia40; Mic14; Mix17; Protein import; Tom40
    DOI:  https://doi.org/10.1242/jcs.263661
  16. Cancer Cell. 2025 Mar 18. pii: S1535-6108(25)00081-9. [Epub ahead of print]
    Horizontal mitochondrial transfer in cancer biology: Potential clinical relevance.
    Michael V Berridge, Renata Zobalova, Stepana Boukalova, Andrés Caicedo, Stuart A Rushworth, Jiri Neuzil.
      Recent research highlights horizontal mitochondrial transfer as a key biological phenomenon linked to cancer onset and progression. The transfer of mitochondria and their genomes between cancer and non-cancer cells shifts our understanding of intercellular gene trafficking, increasing the metabolic fitness of cancer cells and modulating antitumor immune responses. This process not only facilitates tumor progression but also presents potential therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.002
  17. Nat Genet. 2025 Mar 18.
    Quantitative characterization of cell niches in spatially resolved omics data.
    Sebastian Birk, Irene Bonafonte-Pardàs, Adib Miraki Feriz, Adam Boxall, Eneritz Agirre, Fani Memi, Anna Maguza, Anamika Yadav, Erick Armingol, Rong Fan, Gonçalo Castelo-Branco, Fabian J Theis, Omer Ali Bayraktar, Carlos Talavera-López, Mohammad Lotfollahi.
      Spatial omics enable the characterization of colocalized cell communities that coordinate specific functions within tissues. These communities, or niches, are shaped by interactions between neighboring cells, yet existing computational methods rarely leverage such interactions for their identification and characterization. To address this gap, here we introduce NicheCompass, a graph deep-learning method that models cellular communication to learn interpretable cell embeddings that encode signaling events, enabling the identification of niches and their underlying processes. Unlike existing methods, NicheCompass quantitatively characterizes niches based on communication pathways and consistently outperforms alternatives. We show its versatility by mapping tissue architecture during mouse embryonic development and delineating tumor niches in human cancers, including a spatial reference mapping application. Finally, we extend its capabilities to spatial multi-omics, demonstrate cross-technology integration with datasets from different sequencing platforms and construct a whole mouse brain spatial atlas comprising 8.4 million cells, highlighting NicheCompass' scalability. Overall, NicheCompass provides a scalable framework for identifying and analyzing niches through signaling events.
    DOI:  https://doi.org/10.1038/s41588-025-02120-6
  18. Immunometabolism (Cobham). 2025 Apr;7(2): e00059
    Blocking lactate: kick T cells when they are down.
    Veronika Horkova, Bart Everts, Dirk Brenner.
      In the last couple of decades, cancer research has been shifting its focus to the immune system. Cancer cells, with their ability to adapt and evade immune responses, seem to accelerate the evolutionary pressure that has been put on our immune system during evolution. We thus try to aid these natural selection processes and assist our immune system to combat cancer. Here, we are discussing a study by Greg Delgoffe and colleagues that was published in Nature Immunology in December 2024, exploring a new approach to bring the dysfunctional immune cells back to life by blocking their lactate uptake.
    Keywords:  MCT11; T cell exhaustion; anti-tumor immunity; hypoxia; immune checkpoint blockade; lactate; metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000059
  19. Elife. 2025 Mar 18. pii: RP96892. [Epub ahead of print]13
    Untargeted pixel-by-pixel metabolite ratio imaging as a novel tool for biomedical discovery in mass spectrometry imaging.
    Huiyong Cheng, Dawson Miller, Nneka Southwell, Paola Porcari, Joshua L Fischer, Isobel Taylor, J Michael Salbaum, Claudia Kappen, Fenghua Hu, Cha Yang, Kayvan R Keshari, Steven S Gross, Marilena D'Aurelio, Qiuying Chen.
      Mass spectrometry imaging (MSI) is a powerful technology used to define the spatial distribution and relative abundance of metabolites across tissue cryosections. While software packages exist for pixel-by-pixel individual metabolite and limited target pairs of ratio imaging, the research community lacks an easy computing and application tool that images any metabolite abundance ratio pairs. Importantly, recognition of correlated metabolite pairs may contribute to the discovery of unanticipated molecules in shared metabolic pathways. Here, we describe the development and implementation of an untargeted R package workflow for pixel-by-pixel ratio imaging of all metabolites detected in an MSI experiment. Considering untargeted MSI studies of murine brain and embryogenesis, we demonstrate that ratio imaging minimizes systematic data variation introduced by sample handling, markedly enhances spatial image contrast, and reveals previously unrecognized metabotype-distinct tissue regions. Furthermore, ratio imaging facilitates identification of novel regional biomarkers and provides anatomical information regarding spatial distribution of metabolite-linked biochemical pathways. The algorithm described herein is applicable to any MSI dataset containing spatial information for metabolites, peptides or proteins, offering a potent hypothesis generation tool to enhance knowledge obtained from current spatial metabolite profiling technologies.
    Keywords:  adipose; brain; computational biology; embryo; mouse; systems biology
    DOI:  https://doi.org/10.7554/eLife.96892
  20. bioRxiv. 2025 Mar 07. pii: 2025.03.03.641255. [Epub ahead of print]
    Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
    Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.
      Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.
    DOI:  https://doi.org/10.1101/2025.03.03.641255
  21. PLoS Biol. 2025 Mar;23(3): e3003052
    The end of the genetic paradigm of cancer.
    Sui Huang, Ana M Soto, Carlos Sonnenschein.
      Genome sequencing of cancer and normal tissues, alongside single-cell transcriptomics, continues to produce findings that challenge the idea that cancer is a 'genetic disease', as posited by the somatic mutation theory (SMT). In this prevailing paradigm, tumorigenesis is caused by cancer-driving somatic mutations and clonal expansion. However, results from tumor sequencing, motivated by the genetic paradigm itself, create apparent 'paradoxes' that are not conducive to a pure SMT. But beyond genetic causation, the new results lend credence to old ideas from organismal biology. To resolve inconsistencies between the genetic paradigm of cancer and biological reality, we must complement deep sequencing with deep thinking: embrace formal theory and historicity of biological entities, and (re)consider non-genetic plasticity of cells and tissues. In this Essay, we discuss the concepts of cell state dynamics and tissue fields that emerge from the collective action of genes and of cells in their morphogenetic context, respectively, and how they help explain inconsistencies in the data in the context of SMT.
    DOI:  https://doi.org/10.1371/journal.pbio.3003052
  22. Mol Cell. 2025 Mar 14. pii: S1097-2765(25)00183-2. [Epub ahead of print]
    β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
    Min Tang, Yingfeng Tu, Yanqiu Gong, Qin Yang, Jinrui Wang, Zhenzhen Zhang, Junhong Qin, Shenghui Niu, Jiamin Yi, Zehua Shang, Hongyu Chen, Yingying Tang, Qian Huang, Yanmei Liu, Daniel D Billadeau, Xingguo Liu, Lunzhi Dai, Da Jia.
      Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.
    Keywords:  MDV; PTMs; metabolite; mitochondrial functions
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.022
  23. Sci Adv. 2025 Mar 21. 11(12): eadw6815
    PPDPF: Preventing kidney disease through NAD+ regulation.
    Shin-Ichiro Imai.
      Researchers have discovered PPDPF, a critical cellular factor that controls NAD+ biosynthesis, whose function is important to prevent kidney diseases.
    DOI:  https://doi.org/10.1126/sciadv.adw6815
  24. Nat Commun. 2025 Mar 20. 16(1): 2740
    Integrative single-cell metabolomics and phenotypic profiling reveals metabolic heterogeneity of cellular oxidation and senescence.
    Ziyi Wang, Siyuan Ge, Tiepeng Liao, Man Yuan, Wenwei Qian, Qi Chen, Wei Liang, Xiawei Cheng, Qinghua Zhou, Zhenyu Ju, Hongying Zhu, Wei Xiong.
      Emerging evidence has unveiled heterogeneity in phenotypic and transcriptional alterations at the single-cell level during oxidative stress and senescence. Despite the pivotal roles of cellular metabolism, a comprehensive elucidation of metabolomic heterogeneity in cells and its connection with cellular oxidative and senescent status remains elusive. By integrating single-cell live imaging with mass spectrometry (SCLIMS), we establish a cross-modality technique capturing both metabolome and oxidative level in individual cells. The SCLIMS demonstrates substantial metabolomic heterogeneity among cells with diverse oxidative levels. Furthermore, the single-cell metabolome predicted heterogeneous states of cells. Remarkably, the pre-existing metabolomic heterogeneity determines the divergent cellular fate upon oxidative insult. Supplementation of key metabolites screened by SCLIMS resulted in a reduction in cellular oxidative levels and an extension of C. elegans lifespan. Altogether, SCLIMS represents a potent tool for integrative metabolomics and phenotypic profiling at the single-cell level, offering innovative approaches to investigate metabolic heterogeneity in cellular processes.
    DOI:  https://doi.org/10.1038/s41467-025-57992-3
  25. Nature. 2025 Mar 19.
    Mutations that accrue through life set the stage for stomach cancer.
    Callum Oddy, Marnix Jansen.
      
    Keywords:  Cancer; DNA sequencing; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-00803-y
  26. Annu Rev Biochem. 2025 Mar 17.
    Moonlighting Enzymes at the Interface Between Metabolism and Epigenetics.
    Jan A van der Knaap, C Peter Verrijzer.
      Metabolism and gene regulation are vital processes that need to be tightly coordinated to maintain homeostasis or to enable growth and development. Recent research has begun to reveal the surprisingly interlaced relationship between metabolism and gene expression control. Because key metabolites are cofactors or cosubstrates of chromatin-modifying enzymes, changes in their concentrations can modulate chromatin states and gene expression. Additionally, an increasing number of key metabolic enzymes are found to directly regulate chromatin and transcription in response to changes in metabolic state. These include enzymes that fuel chromatin-associated metabolism and moonlighting enzymes that function as transcription factors, independent of their enzymatic activity. Conversely, accumulating evidence suggests that chromatin itself serves key metabolic functions, independent of transcriptional regulation. Here, we discuss the bidirectional interface between metabolism and chromatin and its corruption in cancer cells.
    DOI:  https://doi.org/10.1146/annurev-biochem-030122-044718
  27. Autophagy. 2025 Mar 18.
    Adsl-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.
    Lei Wang, Guimei Ji, Yuran Duan, Peixiang Zheng, Zhiqiang Hu, Zheng Wang, Daqian Xu.
      Cancer cells depend on the reprogramming of cell metabolism to constantly adapt metabolically to the tumor microenvironment. ADSL (adenylosuccinate lyase), a rate-limiting enzyme in de novo purine synthesis, is overexpressed in various cancer cells. However, whether ADSL functions in other oncogenic signaling is largely unknown. Here, our recent study shows that ADSL interacts with BECN1 (beclin 1) to regulate macroautophagy/autophagy upon lipid deprivation. Mechanistically, ADSL is phosphorylated at S140 by EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) in response to lipid deprivation, which enhances the association between ADSL and BECN1. ADSL-produced fumarate reduces the BECN1-associated KDM8 activity, leading to increased BECN1 K117 dimethylation. BECN1 K117 dimethylation inhibits its interaction with BCL2 to initiate autophagy. Targeting the ADSL-BECN1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy and blunts liver tumor growth in mice. These findings broaden the physiological significance of ADSL in autophagy and liver tumor development.
    Keywords:  ADSL; Beclin1; autophagy; fumarate
    DOI:  https://doi.org/10.1080/15548627.2025.2481125
  28. Cell Metab. 2025 Mar 13. pii: S1550-4131(25)00066-X. [Epub ahead of print]
    Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.
    Ning Wang, Sijia Lu, Ziyi Cao, Huimin Li, Junting Xu, Qian Zhou, Hanrui Yin, Qiqi Qian, Xianjing Zhang, Mijia Tao, Quanxin Jiang, Peihui Zhou, Liaoyuan Zheng, Liu Han, Hongtao Li, Limin Yin, Yunqing Gu, Xuefeng Dou, Haipeng Sun, Wei Wang, Hai-Long Piao, Fuming Li, Yingjie Xu, Weiwei Yang, Suzhen Chen, Junli Liu.
      Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.
    Keywords:  DLAT; LNP-mRNA; acetylation; hepatocellular carcinoma; leucine catabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.008
  29. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00031-6. [Epub ahead of print]94 102493
    Advances in mitophagy initiation mechanisms.
    Catharina Küng, Michael Lazarou, Thanh Ngoc Nguyen.
      Mitophagy is an important lysosomal degradative pathway that removes damaged or unwanted mitochondria to maintain cellular and organismal homeostasis. The mechanisms behind how mitophagy is initiated to form autophagosomes around mitochondria have gained a lot of interest since they can be potentially targeted by mitophagy-inducing therapeutics. Mitophagy initiation can be driven by various autophagy receptors or adaptors that respond to different cellular and mitochondrial stimuli, ranging from mitochondrial damage to metabolic rewiring. This review will cover recent advances in our understanding of how mitophagy is initiated, and by doing so reveal the mechanistic plasticity of how autophagosome formation can begin.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102493
  30. Nat Metab. 2025 Mar 20.
    GLP-2 attenuates antipsychotics' adverse metabolic effects.
    Sandra Pereira, Margaret K Hahn.
      
    DOI:  https://doi.org/10.1038/s42255-025-01248-3
  31. Nat Commun. 2025 Mar 18. 16(1): 2663
    HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA.
    Ji-Eun Bae, Soyoung Jang, Joon Bum Kim, Na Yeon Park, Doo Sin Jo, Hyejin Hyung, Pansoo Kim, Min-Seon Kim, Hong-Yeoul Ryu, Hyun-Shik Lee, Dong-Seok Lee, Myriam Baes, Zae Young Ryoo, Dong-Hyung Cho.
      Primary cilia are dynamic sensory organelles orchestrating key signaling pathways, and disruption of primary ciliogenesis is implicated in a spectrum of genetic disorders. The peroxisomal bifunctional enzyme HSD17B4 is pivotal for peroxisomal β-oxidation and acetyl-CoA synthesis, and its deficiency profoundly impairs peroxisomal metabolism. While patients with HSD17B4 deficiency exhibit ciliopathy-like symptoms due to dysfunctional primary cilia, the molecular connection between HSD17B4 and ciliopathy remains poorly understood. Here, we demonstrate that HSD17B4 deficiency impairs primary ciliogenesis and alters cilia-mediated signaling, suggesting a potential link between peroxisomal metabolism and ciliary function. Notably, elevation of acetyl-CoA rescues ciliary defects via HDAC6-mediated ciliogenesis in HSD17B4-deficient cells. Strikingly, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer in Hsd17B4-knockout mice. These findings provide insights into the functional link between HSD17B4 and primary cilia, highlighting acetyl-CoA as a potential therapeutic target for HSD17B4 deficiency and ciliopathy.
    DOI:  https://doi.org/10.1038/s41467-025-57793-8
  32. J Clin Invest. 2025 Mar 18. pii: e186478. [Epub ahead of print]
    Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.
    Yinkun Fu, Xin Peng, Hongyong Song, Xiaoyun Li, Yang Zhi, Jieting Tang, Yifan Liu, Ding Chen, Wenyan Li, Jing Zhang, Jing Ma, Ming He, Yimin Mao, Xu-Yun Zhao.
      Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
    Keywords:  Amino acid metabolism; Fibrosis; Hepatology; Metabolism; RNA processing
    DOI:  https://doi.org/10.1172/JCI186478
  33. Aging (Albany NY). 2025 Mar 12. 17
    DNA methylation entropy is a biomarker for aging.
    Jonathan Chan, Liudmilla Rubbi, Matteo Pellegrini.
      The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual's age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon's entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.
    Keywords:  DNA methylation; aging; entropy; epigenetic clocks; epigenetics
    DOI:  https://doi.org/10.18632/aging.206220
  34. Nat Chem Biol. 2025 Mar 19.
    Recycling for a cleaner metabolism.
    Adam Chatoff, Nathaniel W Snyder.
      
    DOI:  https://doi.org/10.1038/s41589-025-01852-0
  35. Cancer Cell. 2025 Mar 13. pii: S1535-6108(25)00080-7. [Epub ahead of print]
    Of HIFs and hERVs: Neoantigen generation in kidney cancer.
    Nicholas J Salgia, Nazli Dizman, Sumanta K Pal.
      New evidence published in Cell provides insight into the interplay between hypoxia-inducible factor activity and downstream neoantigen production in clear cell renal cell carcinoma (ccRCC). Jiang et al. show that HIF2α regulates expression of immunogenic human endogenous retroelements, with implications for antitumor immunity and immunotherapy responsiveness in ccRCC.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.001
  36. Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2420502122
    Age-dependent cytokine surge in blood precedes cancer diagnosis.
    Guangbo Chen, Azam Mohsin, Hong Zheng, Yael Rosenberg-Hasson, Cindy Padilla, Kavita Y Sarin, Cornelia L Dekker, Philip Grant, Holden T Maecker, Ying Lu, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M Davis.
      Aging is associated with increased variability and dysregulation of the immune system. We performed a system-level analysis of serum cytokines in a longitudinal cohort of 133 healthy individuals over 9 y. We found that cancer incidence is a major contributor to increased cytokine abundance variability. Circulating cytokines increase up to 4 y before a cancer diagnosis in subjects with age over 80 y. We also analyzed cytokine expression in 10 types of early-stage cancers from The Cancer Genome Atlas. We found that a similar set of cytokines is upregulated in tumor tissues, specifically after the age of 80 y. Similarly, cellular senescence activity and CDKN1A/p21 expression increase with age in cancer tissues. Finally, we demonstrated that the cytokine levels in serum can be used to predict cancers among subjects age at 80+ y. Our results suggest that latent senescent cancers contribute to age-related chronic inflammation.
    Keywords:  aging; cancer; cytokine surge; immunology
    DOI:  https://doi.org/10.1073/pnas.2420502122
  37. Nat Cell Biol. 2025 Mar;27(3): 371
    Nutrients shape T cell exhaustion.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s41556-025-01644-7
  38. J Cell Sci. 2025 Mar 19. pii: jcs.263576. [Epub ahead of print]
    Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.
    Metin Özdemir, Silke Oeljeklaus, Schendzielorz Alexander, Marcel Morgenstern, Anusha Valpadashi, Roya Yousefi, Bettina Warscheid, Sven Dennerlein.
      The mitochondrial proteome arises from dual genetic origin. Nuclear-encoded proteins need to be transported across or inserted into two distinguished membranes, and the TOM complex represents the main translocase in the outer mitochondrial membrane. Its composition and regulations have been extensively investigated within yeast cells. However, we have little knowledge of the TOM complex composition within human cells. Here, we have defined the TOM interactome in a comprehensive manner using biochemical approaches to isolate the TOM complex in combination with quantitative mass spectrometry analyses. Within these studies, we defined the pleiotropic nature of the human TOM complex, including new interactors, such as TRABD. Our studies provide a framework to understand the various biogenesis pathways that merge at the TOM complex within human cells.
    Keywords:  Mitochondria; Mitochondrial Biogenesis; Mitochondrial protein import; Mitochondrial quality control; Protein transport; TOM complex
    DOI:  https://doi.org/10.1242/jcs.263576
  39. Acta Neuropathol Commun. 2025 Mar 15. 13(1): 61
    Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.
    Vladislav O Sviderskiy, Varshini Vasudevaraja, Luiz Gustavo Dubois, James Stafford, Elisa K Liu, Jonathan Serrano, Richard Possemato, Matija Snuderl.
      Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.
    Keywords:  Adult glioma; Fatty acid oxidation; Glucose; H3 mutant; Metabolic profiling; Pediatric glioma
    DOI:  https://doi.org/10.1186/s40478-025-01961-w
  40. Immunity. 2025 Mar 19. pii: S1074-7613(25)00090-1. [Epub ahead of print]
    Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression.
    Isidoro Cobo, Jessica Murillo, Mohnish Alishala, Stephen Calderon, Roxana Coras, Benjamin Hemming, Faith Inkum, Fiorella Rosas, Riku Takei, Nathan Spann, Thomas A Prohaska, Paulo V G Alabarse, Se-Jin Jeong, Christian K Nickl, Anyan Cheng, Benjamin Li, Andrea Vogel, Thomas Weichhart, José J Fuster, Thomas Le, Tara R Bradstreet, Ashlee M Webber, Brian T Edelson, Babak Razani, Benjamin L Ebert, Reshma Taneja, Robert Terkeltaub, Ru Liu Bryan, Monica Guma, Christopher K Glass.
      Exposure to particles is a driver of several inflammatory diseases. Here, we investigated macrophage responses to monosodium urate crystals, calcium pyrophosphate crystals, aluminum salts, and silica nanoparticles. While each particle induced a distinct gene expression pattern, we identified a common inflammatory signature and acute activation of lysosomal acidification genes. Using monosodium urate crystals as a model, we demonstrated that this lysosomal gene program is regulated by a 5'-prime-AMP-activated protein kinase (AMPK)-dependent transcriptional network, including TFEB, TFE3, and the epigenetic regulators DNA methyl transferase 3a (DNMT3A) and DOT1L. This lysosomal acidification program operates in parallel with, but largely independently of, a JNK-AP-1-dependent network driving crystal-induced chemokine and cytokine expression. These findings reveal a bifurcation in pathways governing inflammatory and lysosomal responses, offering insights for treating particle-associated diseases.
    Keywords:  AMPK; JNK; epigenetic regulation; lysosome; macrophages; particles; transcription
    DOI:  https://doi.org/10.1016/j.immuni.2025.02.023
  41. Science. 2025 Mar 21. 387(6740): 1296-1301
    In-cell architecture of the mitochondrial respiratory chain.
    Florent Waltz, Ricardo D Righetto, Lorenz Lamm, Thalia Salinas-Giegé, Ron Kelley, Xianjun Zhang, Martin Obr, Sagar Khavnekar, Abhay Kotecha, Benjamin D Engel.
      Mitochondria regenerate adenosine triphosphate (ATP) through oxidative phosphorylation. This process is carried out by five membrane-bound complexes collectively known as the respiratory chain, working in concert to transfer electrons and pump protons. The precise organization of these complexes in native cells is debated. We used in situ cryo-electron tomography to visualize the native structures and organization of several major mitochondrial complexes in Chlamydomonas reinhardtii cells. ATP synthases and respiratory complexes segregate into curved and flat crista membrane domains, respectively. Respiratory complexes I, III, and IV assemble into a respirasome supercomplex, from which we determined a native 5-angstrom (Å) resolution structure showing binding of electron carrier cytochrome c. Combined with single-particle cryo-electron microscopy at 2.4-Å resolution, we model how the respiratory complexes organize inside native mitochondria.
    DOI:  https://doi.org/10.1126/science.ads8738
  42. Nat Commun. 2025 Mar 20. 16(1): 2766
    Deciphering the dark cancer phosphoproteome using machine-learned co-regulation of phosphosites.
    Wen Jiang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Tomer M Yaron-Barir, Jared L Johnson, Lewis C Cantley, Bing Zhang.
      Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, yet our limited knowledge about the regulation and function of most phosphosites hampers the extraction of meaningful biological insights. To address this challenge, we integrate machine learning with phosphoproteomic data from 1195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network that maps the co-regulation of 26,280 phosphosites. By incorporating network features from CoPheeMap into a second machine learning model, namely CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA uncovers 24,015 associations between 9399 phosphosites and 104 serine/threonine kinases, shedding light on many unannotated phosphosites and understudied kinases. We validate the accuracy of these predictions using experimentally determined kinase-substrate specificities. Through the application of CoPheeMap and CoPheeKSA to phosphosites with high computationally predicted functional significance and those associated with cancer, we demonstrate their effectiveness in systematically elucidating phosphosites of interest. These analyses unveil dysregulated signaling processes in human cancer and identify understudied kinases as potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-025-57993-2
  43. Annu Rev Biochem. 2025 Mar 18.
    Emerging Approaches for Studying Lipid Dynamics, Metabolism, and Interactions in Cells.
    Lin Luan, Nathan P Frederick, Jeremy M Baskin.
      Lipids are a major class of biological molecules, the primary components of cellular membranes, and critical signaling molecules that regulate cell biology and physiology. Due to their dynamic behavior within membranes, rapid transport between organelles, and complex and often redundant metabolic pathways, lipids have traditionally been considered among the most challenging biological molecules to study. In recent years, a plethora of tools bridging the chemistry-biology interface has emerged for studying different aspects of lipid biology. Here, we provide an overview of these approaches. We discuss methods for lipid detection, including genetically encoded biosensors, synthetic lipid analogs, and metabolic labeling probes. For targeted manipulation of lipids, we describe pharmacological agents and controllable enzymes, termed membrane editors, that harness optogenetics and chemogenetics. To conclude, we survey techniques for elucidating lipid-protein interactions, including photoaffinity labeling and proximity labeling. Collectively, these strategies are revealing new insights into the regulation, dynamics, and functions of lipids in cell biology.
    DOI:  https://doi.org/10.1146/annurev-biochem-083024-110827
  44. Nat Metab. 2025 Mar 14.
    The cyclic metabolic switching theory of intermittent fasting.
    Mark P Mattson.
      Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.
    DOI:  https://doi.org/10.1038/s42255-025-01254-5
  45. Nat Commun. 2025 Mar 18. 16(1): 2682
    The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy.
    G Kefalas, A Priya, A Astori, A Persaud, L Jing, A M Sydor, H H Y Yao, N Warner, Y Zhang, J H Brumell, A M Muise, S Sari, H C Su, M J Lenardo, W H A Kahr, B Raught, D Rotin.
      The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW(n)-HECT domains, regulates protein trafficking. We recently described a primate-specific Nedd4-1 splice isoform with an extended N-terminus replacing the C2 domain, called Nedd4-1(NE). Here, we show that while canonical Nedd4-1 is primarily localized to the cytosol, Nedd4-1(NE) localizes to late endosomes. This localization is mediated by the NE region, is dependent on amino acid availability, is independent of mTORC1, and is inhibited by the autophagy inducer IKKβ. We further demonstrate that VPS16B, which regulates late endosome to lysosome maturation, is a unique Nedd4-1(NE) substrate that co-localizes with Nedd4-1(NE) in the presence of nutrients. Importantly, a potentially pathogenic homozygous variant identified in the NE region (E70Q) of a patient with lymphangiectasia and protein-losing enteropathy leads to reduced VPS16B ubiquitination by Nedd4-1(NE). Finally, we report that Nedd4-1(NE) inhibits autophagy, likely by disrupting late endosome to autophagosome maturation. This work identified an mTORC1-independent, IKK-driven mechanism to regulate Nedd4-1(NE) localization to late endosomes in primates in response to nutrient availability, and uncovered suppression of autophagy by this ubiquitin ligase.
    DOI:  https://doi.org/10.1038/s41467-025-57944-x
  46. Nat Commun. 2025 Mar 17. 16(1): 2623
    Genetically encoding ε-N-methacryllysine into proteins in live cells.
    Tian-Yi Zhu, Shi-Yi Chen, Mengdi Zhang, Heyu Li, Ting Wu, Emmanuel Ajiboye, Jia Wen Wang, Bi-Kun Jin, Dan-Dan Liu, Xintong Zhou, He Huang, Xiaobo Wan, Ke Sun, Peilong Lu, Yaxin Fu, Ying Yuan, Hai Song, Anna A Sablina, Chao Tong, Long Zhang, Ming Wu, Haifan Wu, Bing Yang.
      Lysine acylation is a ubiquitous post-translational modification (PTM) that plays pivotal roles in various cellular processes, such as transcription, metabolism, protein localization and folding. Thousands of lysine acylation sites have been identified based on advances in antibody enrichment strategies, highly sensitive analysis by mass spectrometry (MS), and bioinformatics. However, only 27 lysine methacrylation (Kmea) sites have been identified exclusively in histone proteins. It is hard to separate, purify and differentiate the Kmea modification from its structural isomer lysine crotonylation (Kcr) using general biochemical approaches. Here, we identify Kmea sites on a non-histone protein, Cyclophillin A (CypA). To investigate the functions of Kmea in CypA, we develop a general genetic code expansion approach to incorporate a non-canonical amino acid (ncAA) ε-N-Methacryllysine (MeaK) into target proteins and identify interacting proteins of methacrylated CypA using affinity-purification MS. We find that Kmea at CypA site 125 regulates cellular redox homeostasis, and HDAC1 is the regulator of Kmea on CypA. Moreover, we discover that genetically encode Kmea can be further methylated to ε-N-methyl-ε-N-methacrylation (Kmemea) in live cells.
    DOI:  https://doi.org/10.1038/s41467-025-57969-2
  47. Nature. 2025 Mar 19.
    Why humans have puzzle-shaped cells.
    Shamini Bundell.
      
    Keywords:  Cell biology; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-00846-1
  48. Signal Transduct Target Ther. 2025 Mar 21. 10(1): 95
    An unexpected player in organ tropism: aspartate functions as signalling molecule to drive lung metastasis.
    Felix C E Vogel, Almut Schulze.
      
    DOI:  https://doi.org/10.1038/s41392-025-02189-9
  49. BMC Cancer. 2025 Mar 14. 25(1): 473
    A genetically encoded fluorescent sensor enables sensitive and specific detection of IDH mutant associated oncometabolite D-2-hydroxyglutarate.
    Kristian A Choate, Wren W L Konickson, Zoe L Moreno, Olivia S Brill, Brett C Cromell, Bella M Detienne, Matthew J Jennings, Paul B Mann, Robert J Winn, David O Kamson, Evan P S Pratt.
      D-2-hydroxyglutarate (D-2-HG) is an oncometabolite that accumulates due to mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2). D-2-HG may be used as a surrogate marker for IDH1/2 mutant cancers, yet simple and specific methods for D-2-HG detection are limited. Here, we present the development and characterization of a genetically encoded fluorescent sensor of D-2-HG (D2HGlo). D2HGlo responds to clinically relevant concentrations of D-2-HG, demonstrates exceptional selectivity and can quantify D-2-HG in various body fluids and glioma tumor supernatants. Additionally, analysis of tumor lysates using D2HGlo accurately predicted the IDH mutational status of gliomas. The successful quantification of D-2-HG within contrived samples suggests that D2HGlo may facilitate the detection and monitoring of IDH mutant cancers through liquid biopsies following further validation. In addition to D2HGlo's potential clinical utility, we also present findings for its adaptation to the cellular environment. To assess D-2-HG production in living immortalized glioma cells, we engineered D2HGlo sensors that localize to subcellular compartments, which yielded findings of elevated D-2-HG in the cytosol, mitochondria, and nucleus of IDH1 mutant cells. D2HGlo was used to perform a side-by-side comparison of cytosolic and secreted D-2-HG to reveal that glycolysis, but not glutamine catabolism, drives D-2-HG production in IDH1 mutant cells.
    Keywords:  D-2-hydroxyglutarate; Diagnostic; Fluorescent biosensor; Glioma; Isocitrate dehydrogenase
    DOI:  https://doi.org/10.1186/s12885-025-13877-8
  50. Nat Commun. 2025 Mar 16. 16(1): 2597
    Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
    Haibin Deng, Liang Zhao, Huixiang Ge, Yanyun Gao, Yan Fu, Yantang Lin, Mojgan Masoodi, Tereza Losmanova, Michaela Medová, Julien Ott, Min Su, Wenxiang Wang, Ren-Wang Peng, Patrick Dorn, Thomas Michael Marti.
      Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB's role in countering mitochondria-associated ferroptosis independently of lactate's function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.
    DOI:  https://doi.org/10.1038/s41467-025-57906-3
  51. Cell Rep. 2025 Mar 18. pii: S2211-1247(25)00212-8. [Epub ahead of print]44(4): 115441
    Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth.
    Keqiang Rao, Xinchao Zhang, Yi Luo, Qiang Xia, Yuting Jin, Jing He.
      Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.
    Keywords:  CP: Cancer; PIK3CB; PSMA4; ULK1; cGAS; innate immune system; lactylation; tumor growth; ubiquitin-independent degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115441
  52. Cell. 2025 Mar 14. pii: S0092-8674(25)00200-4. [Epub ahead of print]
    Growth of the maternal intestine during reproduction.
    Tomotsune Ameku, Anna Laddach, Hannah Beckwith, Alexandra Milona, Loranzie S Rogers, Cornelia Schwayer, Emma Nye, Iain R Tough, Jean-Louis Thoumas, Umesh Kumar Gautam, Yi-Fang Wang, Shreya Jha, Alvaro Castano-Medina, Christopher Amourda, Patric M Vaelli, Sira Gevers, Elaine E Irvine, Leah Meyer, Ivan Andrew, Ka Lok Choi, Bhavik Patel, Alice J Francis, Chris Studd, Laurence Game, George Young, Kevin G Murphy, Bryn Owen, Dominic J Withers, Maria Rodriguez-Colman, Helen M Cox, Prisca Liberali, Martin Schwarzer, François Leulier, Vassilis Pachnis, Nicholas W Bellono, Irene Miguel-Aliaga.
      The organs of many female animals are remodeled by reproduction. Using the mouse intestine, a striking and tractable model of organ resizing, we find that reproductive remodeling is anticipatory and distinct from diet- or microbiota-induced resizing. Reproductive remodeling involves partially irreversible elongation of the small intestine and fully reversible growth of its epithelial villi, associated with an expansion of isthmus progenitors and accelerated enterocyte migration. We identify induction of the SGLT3a transporter in a subset of enterocytes as an early reproductive hallmark. Electrophysiological and genetic interrogations indicate that SGLT3a does not sustain digestive functions or enterocyte health; rather, it detects protons and sodium to extrinsically support the expansion of adjacent Fgfbp1-positive isthmus progenitors, promoting villus growth. Our findings reveal unanticipated specificity to physiological organ remodeling. We suggest that organ- and state-specific growth programs could be leveraged to improve pregnancy outcomes or prevent maladaptive consequences of such growth.
    Keywords:  Fgfbp1; SGLT3a; adult organ remodeling; intestinal epithelium; isthmus progenitor; lactation; plasticity; pregnancy; reproduction; small intestine
    DOI:  https://doi.org/10.1016/j.cell.2025.02.015
  53. Nat Metab. 2025 Mar 18.
    AI-driven framework to map the brain metabolome in three dimensions.
    Xin Ma, Cameron J Shedlock, Terrymar Medina, Roberto A Ribas, Harrison A Clarke, Tara R Hawkinson, Praveen K Dande, Hari K R Golamari, Lei Wu, Borhane Ec Ziani, Sara N Burke, Matthew E Merritt, Craig W Vander Kooi, Matthew S Gentry, Nirbhay N Yadav, Li Chen, Ramon C Sun.
      High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional (2D) space and is poised to be extended into the three-dimensional (3D) world of biology. Here we introduce MetaVision3D, a pipeline driven by computer vision, a branch of artificial intelligence focusing on image workflow, for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework uses advanced algorithms for image registration, normalization and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at submesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas of normal and diseased animals (available at https://metavision3d.rc.ufl.edu ) as an interactive online database and web server to further advance brain metabolism and related research.
    DOI:  https://doi.org/10.1038/s42255-025-01242-9
  54. J Clin Invest. 2025 Mar 17. pii: e185340. [Epub ahead of print]135(6):
    Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
    Yu-Sheng Yeh, Trent D Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J Schopfer, Adam C Straub, Jaehyung Cho, Irfan J Lodhi, Babak Razani.
      Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
    Keywords:  Adipose tissue; Endocrinology; Lysosomes; Metabolism; Obesity; Therapeutics
    DOI:  https://doi.org/10.1172/JCI185340
  55. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  56. Sci Adv. 2025 Mar 21. 11(12): eadt2117
    CD38-mediated metabolic reprogramming promotes the stability and suppressive function of regulatory T cells in tumor.
    Ishita Sarkar, Debashree Basak, Puspendu Ghosh, Anupam Gautam, Arpita Bhoumik, Praveen Singh, Anwesha Kar, Shaun Mahanti, Snehanshu Chowdhury, Lagnajita Chakraborty, Soumya Mondal, Ramanuj Mukherjee, Shikhar Mehrotra, Saikat Majumder, Shantanu Sengupta, Sandip Paul, Shilpak Chatterjee.
      In the tumor microenvironment (TME), regulatory T cells (Tregs) adapt their metabolism to thrive in low-glucose, high-lactate conditions, but the mechanisms remain unclear. Our study identifies CD38 as a key regulator of this adaptation by depleting nicotinamide adenine dinucleotide (oxidized form) (NAD+), redirecting lactate-derived pyruvate toward phosphoenolpyruvate and bypassing the tricarboxylic acid (TCA) cycle. This prevents accumulation of α-ketoglutarate, which destabilizes Tregs by inducing hypermethylation at the Foxp3 locus. Restoring NAD+ with nicotinamide mononucleotide reverses this adaptation, pushing Tregs back to the TCA cycle and reducing their suppressive function. In YUMM1.7 melanoma-bearing mice, small-molecule CD38 inhibition selectively destabilizes intratumoral Tregs, sparking robust antitumor immunity. These findings reveal that targeting the CD38-NAD+ axis disrupts Tregs metabolic adaptation and offers a strategy to enhance antitumor responses.
    DOI:  https://doi.org/10.1126/sciadv.adt2117
  57. Cell. 2025 Mar 14. pii: S0092-8674(25)00209-0. [Epub ahead of print]
    Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions.
    Wenxue Li, Abhijit Dasgupta, Ka Yang, Shisheng Wang, Nisha Hemandhar-Kumar, Surendhar R Chepyala, Jay M Yarbro, Zhenyi Hu, Barbora Salovska, Eugenio F Fornasiero, Junmin Peng, Yansheng Liu.
      Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications such as phosphorylation are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood. Here, we present Turnover-PPT, a comprehensive resource mapping the abundance and lifetime of 11,000 proteins and 40,000 phosphosites in eight mouse tissues and various brain regions using advanced proteomics and stable isotope labeling. We reveal tissue-specific short- and long-lived proteins, strong correlations between interacting protein lifetimes, and distinct impacts of phosphorylation on protein turnover. Notably, we discover a remarkable pattern of turnover changes for peroxisome proteins in specific tissues and that phosphorylation regulates the stability of neurodegeneration-related proteins, such as Tau and α-synuclein. Thus, Turnover-PPT provides fundamental insights into protein stability, tissue dynamic proteotypes, and functional protein phosphorylation and is accessible via an interactive web-based portal at https://yslproteomics.shinyapps.io/tissuePPT.
    Keywords:  DIA-MS; TMT; brain regions; mouse tissues; protein lifetime; protein phosphorylation; protein turnover; proteomics; pulse SILAC
    DOI:  https://doi.org/10.1016/j.cell.2025.02.021
  58. Cancer Discov. 2025 Mar 18.
    Activated T cells break tumor immunosuppression by macrophage re-education.
    Rosa Trotta, Silvia Rivis, Shikang Zhao, Marie-Pauline Orban, Sarah Trusso Cafarello, Iris Charatsidou, Joanna Pozniak, Jonas Dehairs, Lotte Vanheer, Carlos A Pulido Vicuna, Veerle Boecxstaens, Oliver Bechter, Francesca M Bosisio, Johannes V Swinnen, Jean-Christophe Marine, Massimiliano Mazzone.
      Here, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAMs) through TNFα signaling. Mechanistically, HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces anti-tumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a pro-tumoral environment and αPD1-resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0415
  59. Sci Adv. 2025 Mar 21. 11(12): eadr8648
    PPDPF preserves integrity of proximal tubule by modulating NMNAT activity in chronic kidney diseases.
    Xiaoliang Fang, Yi Zhong, Rui Zheng, Qihui Wu, Yu Liu, Dexin Zhang, Yuwei Wang, Wubing Ding, Kaiyuan Wang, Fengbo Zhong, Kai Lin, Xiaohui Yao, Qingxun Hu, Xiaofei Li, Guofeng Xu, Na Liu, Jing Nie, Dali Li, Hongquan Geng, Yuting Guan.
      Genome-wide association studies (GWAS) have identified loci associated with kidney diseases, but the causal variants, genes, and pathways involved remain elusive. Here, we identified a kidney disease gene called pancreatic progenitor cell differentiation and proliferation factor (PPDPF) through integrating GWAS on kidney function and multiomic analysis. PPDPF was predominantly expressed in healthy proximal tubules of human and mouse kidneys via single-cell analysis. Further investigations revealed that PPDPF functioned as a thiol-disulfide oxidoreductase to maintain cellular NAD+ levels. Deficiency in PPDPF disrupted NAD+ and mitochondrial homeostasis by impairing the activities of nicotinamide mononucleotide adenylyl transferases (NMNATs), thereby compromising the function of proximal tubules during injuries. Consequently, knockout of PPDPF notably accelerated the progression of chronic kidney disease (CKD) in mouse models induced by aging, chemical exposure, and obstruction. These findings strongly support targeting PPDPF as a potential therapy for kidney fibrosis, offering possibilities for future CKD interventions.
    DOI:  https://doi.org/10.1126/sciadv.adr8648
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