bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–08–10
48 papers selected by
Christian Frezza, Universität zu Köln
  1. Macrophages say NO to nucleotide synthesis and salvage instead.
  2. Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
  3. Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
  4. Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
  5. Stromal senescence contributes to age-related increases in cancer.
  6. Somatic cells compartmentalise their metabolism to sustain germ cell survival.
  7. Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.
  8. Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
  9. The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
  10. Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
  11. A breathless brake on ferroptosis.
  12. Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
  13. Unlocking spatial metabolomics with isotopically labelled internal standards.
  14. NADH reductive stress drives metabolic reprogramming.
  15. Integrated Respirometry and Metabolomics Unveil Circadian Metabolic Dynamics in Drosophila.
  16. Lysosomal membrane homeostasis and its importance in physiology and disease.
  17. KAT8-mediated MDH2 lactylation promotes renal cancer progression by enhancing mitochondrial function and stress resistance.
  18. Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.
  19. Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
  20. EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
  21. Glycogen shepherd guides the hidden trail of pentose phosphate pathway.
  22. Multiplexed quantum sensing reveals coordinated thermomagnetic regulation of mitochondria.
  23. TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis.
  24. NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers.
  25. Inferring Metabolic Flux from Gene Expression Data Using METAFlux.
  26. Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.
  27. The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
  28. Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis.
  29. Mitochondrial metabolism and cancer therapeutic innovation.
  30. Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo.
  31. OPPORTUNITIES AND CHALLENGES FOR TARGETING CANCER METABOLISM.
  32. Analysis of individual patient pathway coordination in a cross-species single-cell kidney atlas.
  33. Rag GTPases Suppress Renal Cystic Disease by Inhibiting TFEB Independently of mTORC1.
  34. A cholesterol-dependent switch controls organ-specific metastasis in pancreatic cancer.
  35. Clonal lineage tracing of innate immune cells in human cancer.
  36. Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
  37. Baseline expression of c-Myc defines the tissue specificity of oncogenic K-Ras.
  38. Brain amino acid sensing for organismal amino acid homeostasis.
  39. Nucleus-translocated glucokinase functions as a protein kinase to phosphorylate TAZ and promote tumour growth.
  40. Intracrine FFA4 signaling controls lipolysis at lipid droplets.
  41. Spatial quantitative metabolomics enables identification of remote and sustained ipsilateral cortical metabolic reprogramming after stroke.
  42. Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
  43. What do we know of human fuel use during aerobic exercise and how do we know it?
  44. Mechanistic Insight into Serine Flux Regulation through Nanoscale Organization of Glucose and Serine Transporters by Substrate Probe-Based Direct Stochastic Optical Reconstruction Microscopy Imaging.
  45. Vagal blockade of the brain-liver axis deters cancer-associated cachexia.
  46. RNA N-glycosylation enables immune evasion and homeostatic efferocytosis.
  47. The intricate link between circadian rhythms and aging: can resetting our circadian clock hold the key to longevity?
  48. MR1-ligand cross-linking identifies vitamin B6 metabolites as TCR-reactive antigens.
  1. Nat Metab. 2025 Aug 04.
    Macrophages say NO to nucleotide synthesis and salvage instead.
    Eloïse Marques, Dylan G Ryan.
      
    DOI:  https://doi.org/10.1038/s42255-025-01322-w
  2. Cell Metab. 2025 Jul 30. pii: S1550-4131(25)00333-X. [Epub ahead of print]
    Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
    Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Nicole M Foy, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.
      Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8+ T cell responses in vivo.
    Keywords:  CD8(+) T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.006
  3. bioRxiv. 2025 Aug 02. pii: 2025.08.01.668168. [Epub ahead of print]
    Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
    Sherry X Zhou, Benjamin Madden, Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis J Maher.
       BACKGROUND: The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. While loss of components in these pathways typically impairs cell survival, such defects can paradoxically promote tumorigenesis in certain cell types. One such example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Deleterious mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia, respectively. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells.
    METHODS: We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition.
    RESULTS: SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
    CONCLUSIONS: SDH loss differentially impacts the proteomes and acylproteomes of imCCs and iMEFs, with compartment-specific effects. These findings reveal cell type-specific adaptations to SDH loss. The plasticity of the response of imCCs may underlie the tissue-specific susceptibility to tumorigenesis and could illuminate therapeutic vulnerabilities of SDH-loss tumors.
    DOI:  https://doi.org/10.1101/2025.08.01.668168
  4. bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]
    Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
    Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.
      Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
    Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.
    DOI:  https://doi.org/10.1101/2025.07.28.667051
  5. Nat Rev Cancer. 2025 Aug 04.
    Stromal senescence contributes to age-related increases in cancer.
    Jiayu Ye, Anupama Melam, Sheila A Stewart.
      Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.
    DOI:  https://doi.org/10.1038/s41568-025-00840-9
  6. bioRxiv. 2025 Jul 24. pii: 2025.07.22.666113. [Epub ahead of print]
    Somatic cells compartmentalise their metabolism to sustain germ cell survival.
    Diego Sainz de la Maza, Holly Jefferson, Celine I Brucker, Sonia Paoli, Marc Amoyel.
      To ensure success in reproduction, organisms dedicate substantial resources to supporting the germline. In testes, somatic gonadal cells form a barrier that isolates germ cells from circulating nutrients, raising the question of how germ cell metabolism is sustained and how somatic cells ensure sufficient resources are directed to the germline. We use lineage-specific manipulations and metabolite reporters to show in vivo that somatic gonadal cells break down circulating sugars to produce and shuttle lactate to the germline, sustaining germ cell survival. We show that somatic cells ensure that carbohydrate metabolism is allocated specifically to germ cell support and that increasing autonomous consumption of carbohydrates in the soma increases germ cell death. Thus, germ cell survival depends on correct metabolic compartmentalisation within gonadal somatic support cells.
    DOI:  https://doi.org/10.1101/2025.07.22.666113
  7. Nat Metab. 2025 Aug 04.
    Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.
    Steven V John, Gretchen L Seim, Billy J Erazo-Flores, James A Votava, Uzziah S Urquiza, Nicholas L Arp, John Steill, Jack Freeman, Lauren N Carnevale, Isaiah Roberts, Xin Qing, Stuart A Lipton, Ron Stewart, Laura J Knoll, Jing Fan.
      During an immune response, macrophages specifically reprogramme their metabolism to support functional changes. Here, we revealed that nucleotide metabolism is one of the most significantly reprogrammed pathways upon classical activation. Specifically, de novo synthesis of pyrimidines is maintained up to uridine monophosphate, but blocked at cytidine triphosphate and deoxythymidine monophosphate synthesis; de novo synthesis of purines is shut off at the last step (catalysed by AICAR transformylase/IMP cyclohydrolase, ATIC), and cells switch to increased purine salvage. Nucleotide degradation to nitrogenous bases is upregulated but complete oxidation of purine bases (catalysed by xanthine oxidoreductase, XOR) is inhibited, diverting flux into salvage. Mechanistically, nitric oxide was identified as a major regulator of nucleotide metabolism, simultaneously driving multiple key changes, including the transcriptional downregulation of Tyms and profound inhibition of ATIC and XOR. Inhibiting purine salvage using Hgprt knockout or inhibition alters the expression of many stimulation-induced genes, suppresses macrophage migration and phagocytosis, and increases the proliferation of the intracellular parasite Toxoplasma gondii. Together, these results thoroughly uncover the dynamic reprogramming of macrophage nucleotide metabolism upon classical activation and elucidate the regulatory mechanisms and functional significance of such reprogramming.
    DOI:  https://doi.org/10.1038/s42255-025-01337-3
  8. Sci Adv. 2025 Aug 08. 11(32): eadw4954
    Allele frequency selection and no age-related increase in human oocyte mitochondrial mutations.
    Barbara Arbeithuber, Kate Anthony, Bonnie Higgins, Peter Oppelt, Omar Shebl, Irene Tiemann-Boege, Francesca Chiaromonte, Thomas Ebner, Kateryna D Makova.
      Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.
    DOI:  https://doi.org/10.1126/sciadv.adw4954
  9. Annu Rev Cell Dev Biol. 2025 Aug 06.
    The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
    Nazma Malik, Reuben J Shaw.
      Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-094431
  10. bioRxiv. 2025 Aug 01. pii: 2025.07.29.667471. [Epub ahead of print]
    Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
    Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.
      Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYC's ability to reprogram cancer cell metabolism, and the liver's role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.
    DOI:  https://doi.org/10.1101/2025.07.29.667471
  11. Mol Cell. 2025 Aug 07. pii: S1097-2765(25)00609-4. [Epub ahead of print]85(15): 2815-2817
    A breathless brake on ferroptosis.
    Mingchuang Sun, Li Zhuang, Boyi Gan.
      In this issue of Molecular Cell, Minikes et al.1 reveal that hypoxia suppresses ferroptosis independently of HIF signaling via inhibition of the oxygen-sensitive histone demethylase KDM6A, linking hypoxia-mediated chromatin regulation to phospholipid metabolism and ferroptosis resistance in cancer.
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.008
  12. bioRxiv. 2025 Jul 24. pii: 2025.07.23.666448. [Epub ahead of print]
    Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
    Milan R Savani, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Bingbing Li, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Tracey Shipman, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.
      Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism. Therefore, we created a platform to simultaneously trace 30 nitrogen isotope-labeled metabolites. This platform revealed that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine despite expressing de novo pathway enzymes. This link between cell state and pyrimidine synthesis routes persisted in physiological contexts, including primary murine and human tissues and tumor xenografts. Mechanistically, we found that Ser1900 phosphorylation of CAD, the first enzyme of the de novo pathway, was enriched in primitive cells and that mimicking this modification in differentiated cells abrogated their preference for pyrimidine salvage. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.
    DOI:  https://doi.org/10.1101/2025.07.23.666448
  13. Nat Metab. 2025 Aug 05.
    Unlocking spatial metabolomics with isotopically labelled internal standards.
      
    DOI:  https://doi.org/10.1038/s42255-025-01341-7
  14. Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]
    NADH reductive stress drives metabolic reprogramming.
    Ronghui Yang, Zihao Guo, Binghui Li.
      Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.
    Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
  15. bioRxiv. 2025 Jul 25. pii: 2025.07.22.665580. [Epub ahead of print]
    Integrated Respirometry and Metabolomics Unveil Circadian Metabolic Dynamics in Drosophila.
    Farheen Akhtar, Dania Malik, Arjun Sengupta, Paula Haynes, Jaco Klok, Amita Sehgal, Aalim M Weljie.
      Precise temporal regulation of metabolism by sleep and circadian rhythms is essential for dynamic energy homeostasis, yet the link between systemic metabolism and respiratory demands remains poorly defined. We combined high-resolution respirometry with LC-MS-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster to uncover genotype-specific impacts of sleep and circadian disruption. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. In contrast, short-sleep mutants ( fmn , sss ) exhibited elevated metabolic rates and reactive shifts of fuel preferences toward lipid and amino acid catabolism and displayed signs of mitochondrial stress. Circadian-clock disrupted flies ( per 01 , WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems are essential for aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.
    DOI:  https://doi.org/10.1101/2025.07.22.665580
  16. Nat Rev Mol Cell Biol. 2025 Aug 04.
    Lysosomal membrane homeostasis and its importance in physiology and disease.
    Maja Radulovic, Chonglin Yang, Harald Stenmark.
      Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization.
    DOI:  https://doi.org/10.1038/s41580-025-00873-w
  17. Int J Biol Macromol. 2025 Aug 04. pii: S0141-8130(25)07128-4. [Epub ahead of print] 146571
    KAT8-mediated MDH2 lactylation promotes renal cancer progression by enhancing mitochondrial function and stress resistance.
    Yuangui Tang, Chenyun Dai, Huihui Yang, Xian Yang, Ziyu Chen, Jinxiu Dou, Liuxu Zhang, Tao Bai, Junfang Zheng.
      Non-histone proteins localized in membrane, cytosol and nucleus are lactylated to promote tumor progression. However, whether mitochondrial proteins undergo lactylation and contribute to tumor progression remains unexplored. Here, we identified multiple lactylated mitochondrial proteins in human renal cell carcinoma (RCC) cells using lactylome profiling. Among these, malate dehydrogenase 2 (MDH2)-the only lactylated protein in the tricarboxylic acid (TCA) cycle-emerged as a key target, with K239 as its lactylation site. MDH2K239la levels are regulated by KAT8 and SIRT3. Under low-glucose, high-lactate conditions mimicking the tumor microenvironment, MDH2K239la elevated the NADH/NAD+ ratio to drive ATP production and boosted NADPH generation to reduce ROS. This enables cells to alleviate oxidative stress, sustain mitochondrial function, and promote RCC malignancy in vitro and in vivo. Mechanistically, MDH2K239la enhances MDH2 enzymatic activity and strengthens its interaction with the citrate transporter SLC25A1. This facilitates citrate efflux, fueling IDH1-dependent NADPH production when lactate serves as an energy source. Collectively, we unveil a lactylation-dependent mechanism that reprograms mitochondrial metabolism to confer oxidative stress resistance and drive RCC progression. Targeting mitochondrial proteins lactylation, exemplified by MDH2K239la, represents a promising therapeutic strategy for RCC.
    Keywords:  Lactylation; MDH2; RCC
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146571
  18. Nat Cell Biol. 2025 Aug 08.
    Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.
    Xian Du, Wenyan Li, Guiying Li, Chenyue Guo, Xuyi Tang, Rujuan Bao, Runchang Li, Haiyan Huang, Shuiyu Xu, Xiaoyan Yu, Qiaoqiao Han, Jie Wan, Song Li, Jiayuan Sun, Ren Zhao, Youqiong Ye, Qiang Gao, Zhi-Yu Ni, Xingang Cui, Qiang Zou.
      Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.
    DOI:  https://doi.org/10.1038/s41556-025-01716-8
  19. Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00321-0. [Epub ahead of print]86 103808
    Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
    Jose Adan Arevalo, Dianna Xing, Roberto Garcia Leija, Max A Thorwald, Diana Daniela Moreno-Santillán, Kaitlin N Allen, Giovanna Selleghin-Veiga, Heidi C Avalos, Eva Utke, Justin L Conner, George A Brooks, José Pablo Vázquez-Medina.
      An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A2 activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.
    DOI:  https://doi.org/10.1016/j.redox.2025.103808
  20. Geroscience. 2025 Aug 06.
    EnsembleAge: enhancing epigenetic age assessment with a multi-clock framework.
    Amin Haghani, Ake T Lu, Qi Yan, Juan Carlos Izpisua Belmonte, Pradeep Reddy, Victor Cheng, X William Yang, Nan Wang, Khyobeni Mozhui, Kevin Murach, Alejandro Ocampo, Robert W Williams, Mathias Jucker, Carina Bergmann, Jesse R Poganik, Bohan Zhang, Vadim N Gladyshev, Steve Horvath.
      Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
    Keywords:  Aging biomarkers; Biological age; DNA methylation; EnsembleAge; Epigenetic clocks; Healthspan; Lifespan interventions; MethylGauge dataset; Mouse models; Rejuvenation; Stress response
    DOI:  https://doi.org/10.1007/s11357-025-01808-1
  21. Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00329-8. [Epub ahead of print]37(8): 1633-1635
    Glycogen shepherd guides the hidden trail of pentose phosphate pathway.
    Lin Wang, Kaili Ma, Lianjun Zhang, Ping-Chih Ho.
      In a recent Molecular Cell study,1 Zhou et al. elucidated how glycogenolysis-derived glucose-1-phosphate mediates source-specific routing of glucose-6-phosphate into the pentose phosphate pathway through allosteric activation of glucose-6-phosphate dehydrogenase and liquid-liquid phase separation-mediated metabolic compartments. This compartmentalized distribution enables efficient reduced nicotinamide adenine dinucleotide phosphate (NADPH) generation from glycogenolytic flux, promoting Tm cell persistence by maintaining redox homeostasis.
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.002
  22. bioRxiv. 2025 Aug 01. pii: 2025.07.30.666664. [Epub ahead of print]
    Multiplexed quantum sensing reveals coordinated thermomagnetic regulation of mitochondria.
    Md Shakil Bin Kashem, Stella Varnum, Olivia Lazorik, Rocky Giwa, Shiva Iyer, Changyu Yao, David W Piston, Chong Zu, Jonathan R Brestoff, Shankar Mukherji.
      Mitochondria are multifunctional organelles that convert the potential energy stored in nutrients and intermediary metabolites into both heat and an electrochemical proton-motive force. However, how these outputs are synchronized in cells remains an enduring question. In this work, leveraging multiplexed nanodiamond quantum sensors to monitor both changes in temperature and magnetic field fluctuations in single primary cells obtained from diverse tissues in adult mice, we identified thermomagnetic correlation profiles uncovering a regulatory feedback loop in which the cell draws upon available intracellular iron to maintain the mitochondrial electrochemical gradient. These profiles reverse in cells derived from a mouse model of Leigh syndrome and raise the intriguing possibility that primary mitochondrial diseases can be understood as disorders of thermomagnetic homeostasis.
    DOI:  https://doi.org/10.1101/2025.07.30.666664
  23. bioRxiv. 2025 Jul 24. pii: 2025.07.23.666333. [Epub ahead of print]
    TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis.
    Fei Li, Niv Vigder, David R Ziehr, Mari Kamiya, Hung N Nguyen, Matthew L Steinhauser, Edy Y Kim, William M Oldham.
      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease marked by aberrant fibroblast-to-myofibroblast differentiation, a process that requires metabolic reprogramming. We identify alanine as a critical metabolite that confers metabolic flexibility to support differentiation. TGF-β increases alanine by activating both its synthesis and import in normal and IPF lung fibroblasts. Alanine is synthesized primarily by GPT2, which is regulated by a glutamine-glutamate-α-ketoglutarate axis. Inhibiting GPT2 depletes alanine and suppresses TGF-β-induced expression of α-SMA and COL1A1, an effect reversed by alanine supplementation. We also identify SLC38A2 as a key transporter of both alanine and glutamine that is upregulated by TGF-β and alanine deprivation. Together, SLC38A2 and GPT2 activities converge to maintain intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency suppresses glycolysis and depletes tricarboxylic acid cycle intermediates, while supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly in the absence of glutamine. Combined inhibition of GPT2 and SLC38A2 suppresses fibrogenic responses in fibroblasts and in human precision-cut lung slices, highlighting a potential therapeutic strategy for fibrotic lung disease.
    DOI:  https://doi.org/10.1101/2025.07.23.666333
  24. Nature. 2025 Aug 06.
    NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers.
    Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski, Natasha M Flores, Andy Garcia Gonzalez, Liyang Shi, Xiaoyin Lu, Joanna Lempiäinen, Moritz Jakab, Liyong Zeng, Tourkian Chasan, Eric Bareke, Rui Dong, Emma Carlson, Reinnier Padilla, Dylan Husmann, Julia Thompson, Gerry A Shipman, Emily Zahn, Courtney A Barnes, Laiba F Khan, Liz Marie Albertorio-Sáez, Eva Brill, Vishnu Udayakumar Sunita Kumary, Matthew R Marunde, Danielle N Maryanski, Cheryl C Szany, Bryan J Venters, Carolina Lin Windham, Michal Eligiusz Nowakowski, Iwona Czaban, Mariusz Jaremko, Michael-Christopher Keogh, Kang Le, Michael J Soth, Benjamin A Garcia, Łukasz Jaremko, Jacek Majewski, Pawel K Mazur, Or Gozani.
      NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3-5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in difficult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.
    DOI:  https://doi.org/10.1038/s41586-025-09299-y
  25. Methods Mol Biol. 2025 ;2932 187-202
    Inferring Metabolic Flux from Gene Expression Data Using METAFlux.
    Yuchen Pan, Yuefan Huang, Vakul Mohanty, Ken Chen.
      Metabolic dysregulation is a hallmark of malignant cells, which contributes significantly to tumor proliferation, persistence, and therapeutic resistance. Further, metabolic interplay between malignant cells and cells in the tumor microenvironment (TME) has a significant impact on tumor phenotype. Examining the reconfiguration of metabolic pathways within tumors and TME is therefore critical to understand cancer biology and improve patient care. Current limitations of metabolomic techniques, however, restrict broad and deep characterization of tumor metabolome. To address this gap, we developed METAFlux (METAbolic Flux balance analysis), a computational technique that uses flux balance analysis (FBA) to infer activity or flux of metabolic reactions from bulk and single-cell RNA sequencing data (scRNA-seq). Here, we describe the workflow along with a detailed step-by-step explanation for calculating metabolic fluxes using METAFlux from bulk RNA-seq and scRNA-seq data and the extension to characterize metabolic heterogeneity and metabolic interaction among cell types.
    Keywords:  Bulk RNA-seq; Flux balance analysis; Metabolism; Single-cell RNA-seq; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-4566-6_10
  26. J Biol Chem. 2025 Jul 31. pii: S0021-9258(25)02406-8. [Epub ahead of print] 110555
    Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.
    Runtai Chen, Seyed Amirhossein Tabatabaei Dakhili, Rokas Geruskis, Yuan Yuan Zhao, Steven Lockhart, Lusine Tonoyan, Arno Siraki, Guocheng Huang, Adam Kinnaird, Darren H Freed, Shelley Minteer, Evangelos D Michelakis, John R Ussher, Gopinath Sutendra.
      The mitochondrial Electron Transport Chain (ETC) is a four complex unit that could be considered the most essential infrastructure within the mitochondria, as it primarily functions to generate the mitochondrial membrane potential (ΔΨm, the cells equivalent to battery capacity), which can then be utilized for ATP synthesis or heat production. Another important aspect of ETC function is the generation of mitochondrial reactive oxygen species (mtROS), which are essential physiologic signaling mediators that can be toxic to the cell if their levels become too high. Currently, it remains unresolved how a highly utilized and functioning ETC can sense excessive mtROS generation and adapt, to enhance ΔΨm. Here we identified a redox hub consisting of cysteine (Cys) residues 64, 75, 78 and 92 within Ndufs1 of complex I of the ETC. Oxidation of these Cys residues promotes the incorporation of complex I into the respirasome supercomplex. Mechanistically, oxidation of the redox hub increased the distance between Fe-S clusters N5 and N6a in complex I, compromising complex I activity. This impairment was rescued by integration with complex III2 and IV into the respirasome supercomplex. Compared to parental cells or Ndufs1-KO cells, C92D (an oxidation mimetic) Ndufs1-knockin A549 cells had higher levels of ETC supercomplexes, ΔΨm and oxygen consumption rates, while isolated mitochondrial membranes generated more electrical current when integrated onto a biobattery platform. Knockdown of complex III2 significantly reduced complex I activity (within the respirasome) from C92D Ndufs1-knockin cells, but not parental A549 cells. Finally, disruption of ETC supercomplexes with the small molecule drug MitoTam increased the therapeutic efficacy of mtROS inducing chemotherapeutics in both C92D Ndufs1-knockin or metastatic lung cancer cells. These findings provide new insights into how the ETC can initiate supercomplex transformation.
    Keywords:  Cancer Resistance; Cysteine Oxidation; Electron Transport Chain; Mitochondria; Reactive Oxygen Species; Supercomplex
    DOI:  https://doi.org/10.1016/j.jbc.2025.110555
  27. Nat Cell Biol. 2025 Aug 04.
    The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.
    Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari.
      Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors' IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors' IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.
    DOI:  https://doi.org/10.1038/s41556-025-01728-4
  28. Nat Commun. 2025 Aug 02. 16(1): 7110
    Decompartmentalization of the yeast mitochondrial metabolism to improve chemical production in Issatchenkia orientalis.
    Vinh G Tran, Shih-I Tan, Hao Xu, Daniel R Weilandt, Xi Li, Sarang S Bhagwat, Zhixin Zhu, Jeremy S Guest, Joshua D Rabinowitz, Huimin Zhao.
      Microbial production of chemicals may suffer from inadequate cofactor provision, a challenge further exacerbated in yeasts due to compartmentalized cofactor metabolism. Here, we perform cofactor engineering through the decompartmentalization of mitochondrial metabolism to improve succinic acid (SA) production in Issatchenkia orientalis. We localize the reducing equivalents of mitochondrial NADH to the cytosol through cytosolic expression of its pyruvate dehydrogenase (PDH) complex and couple a reductive tricarboxylic acid pathway with a glyoxylate shunt, partially bypassing an NADH-dependent malate dehydrogenase to conserve NADH. Cytosolic SA production reaches a titer of 104 g/L and a yield of 0.85 g/g glucose, surpassing the yield of 0.66 g/g glucose constrained by cytosolic NADH availability. Additionally, expressing cytosolic PDH, we expand our I. orientalis platform to enhance acetyl-CoA-derived citramalic acid and triacetic acid lactone production by 1.22- and 4.35-fold, respectively. Our work establishes I. orientalis as a versatile platform to produce markedly reduced and acetyl-CoA-derived chemicals.
    DOI:  https://doi.org/10.1038/s41467-025-62304-w
  29. Signal Transduct Target Ther. 2025 Aug 04. 10(1): 245
    Mitochondrial metabolism and cancer therapeutic innovation.
    Hongxiang Du, Tianhan Xu, Sihui Yu, Sufang Wu, Jiawen Zhang.
      Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.
    DOI:  https://doi.org/10.1038/s41392-025-02311-x
  30. Cell Rep. 2025 Aug 05. pii: S2211-1247(25)00868-X. [Epub ahead of print]44(8): 116097
    Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo.
    Mamoru Oyabu, Tomoki Sato, Runa Kawaguchi, Kiyoshi Yoshioka, Naoki Ito, Takahiro Eguchi, Hitoshi Gotoh, Tatsuya Yoshizawa, Yoshihiro Ogawa, Yusuke Ono, Shinji Miura, Yasutomi Kamei.
      Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.
    Keywords:  Amd; CE-TOFMS; CP: Metabolism; FoxO triple knockout; atrometabolite; cancer cachexia; metabolic elasticity; metabolomic analysis; muscle atrophy; polyamine; sarcopenia
    DOI:  https://doi.org/10.1016/j.celrep.2025.116097
  31. Trans Am Clin Climatol Assoc. 2025 ;135 196-205
    OPPORTUNITIES AND CHALLENGES FOR TARGETING CANCER METABOLISM.
    Chi V Dang.
      Otto Warburg sparked the field of cancer metabolism in the 1920s through his observations that human and animal cancer tissues converted significant amounts of glucose to lactate with an elusive underlying mechanism. The discovery of oncogenes led to the notion that neoplasia results from deregulated cell division control with metabolism at the margin, standing by to support cell growth. Studies over the past several decades have linked oncogenes to the direct regulation of metabolism, such as the myelocytomatosis (MYC) oncogene, driving glycolysis and other central metabolic pathways, necessary for cell growth and proliferation. Deregulated oncogenic drive of metabolism renders tumor cells addicted to glucose and other nutrients, such that nutrient deprivation can trigger cancer cell death. The revelation of this addiction stimulated pharmaceutical companies to target metabolism for cancer therapy, but due to several failed clinical studies, this exuberance fizzled commercially. However, the transformative impact of cancer immunotherapy ushered in an interest in understanding the hostile metabolic tumor microenvironment that limits the function of anti-tumor T cells and clinical responses to immunotherapy. This interest drives the convergence of immunometabolism and cancer cell metabolism research to provide a richer understanding of tumor metabolic vulnerability. Herein, I discuss the historical and current context of opportunities and challenges to targeting cancer metabolism.
  32. Nat Genet. 2025 Aug 07.
    Analysis of individual patient pathway coordination in a cross-species single-cell kidney atlas.
    Konstantin A Klötzer, Amin Abedini, Shen Li, Michael S Balzer, Xiujie Liang, Jonathan Levinsohn, Eunji Ha, Bernhard Dumoulin, Jonathan J Hogan, Ghazal Quinn, Roy D Bloom, Max Schuller, Kathrin Eller, Balazs Halmos, Nancy R Zhang, Katalin Susztak.
      The use of single-cell RNA sequencing in clinical and translational research is limited by the challenge of identifying cell-type-specific, targetable molecular changes in individual patients and cross-species differences. Here we created an integrated single-cell kidney atlas including over 1 million cells from 140 samples, defining more than 70 conserved cell states in human and rodent models. We developed CellSpectra, a computational tool that quantifies changes in gene expression coordination across cellular functions, which we applied to kidney and lung cancer data. This tool powers our patient-level single-cell functional profiling report, which highlights cell-type-specific changes in the coordination of pathway gene expression in individuals. Our cross-species atlas facilitates the selection of a rodent model that closely reflects the cellular and pathway-level signatures observed in patient samples, advancing the application of single-cell methodologies in clinical precision medicine. Finally, using experimental models, we demonstrate how our informatics approach can be applied for the potential selection of suitable therapeutics.
    DOI:  https://doi.org/10.1038/s41588-025-02285-0
  33. bioRxiv. 2025 Jul 31. pii: 2025.07.24.664930. [Epub ahead of print]
    Rag GTPases Suppress Renal Cystic Disease by Inhibiting TFEB Independently of mTORC1.
    Flaviane de Fatima Silva, Alexander R Boucher, Huawei Li, Qingbo Chen, Maria Gaughan, Ekaterina D Korobkina, Marie Sophie Isidor, Abigail O Smith, Kuang Shen, Derek B Allison, Pamela V Tran, Gregory J Pazour, David A Guertin.
      Aberrant mTORC1 activation in renal tubular epithelial cells (rTECs) is implicated as a critical driver of renal cystic diseases (RCDs), including autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis (TSC), yet its precise role remains unclear. Rag GTPases recruit mTORC1 to lysosomes, its intracellular activation site. Unexpectedly, we found that deleting RagA/B in rTECs, despite inhibiting mTORC1, triggers renal cystogenesis and kidney failure. We identify TFEB as the key driver of cystogenesis downstream of RagA/B loss and show that Rag GTPases, rather than mTORC1, are the primary suppressors of TFEB in vivo . We further highlight increased nuclear TFEB as a shared feature of several RCD models, whereas differences in mTORC1 activity may explain the variable efficacy of mTORC1 inhibitors. Finally, we provide evidence that nuclear TFEB, rather than mTORC1 activation, is a more consistent biomarker of cyst-lining epithelial cells in ADPKD. Overall, these findings challenge the prevailing view that mTORC1 hyperactivation is required for renal cystogenesis, which has important translational implications.
    Teaser: A serendipitous finding uncovers the Rag GTPases as strong suppressors of renal cystogenesis with important disease implications.
    DOI:  https://doi.org/10.1101/2025.07.24.664930
  34. Dev Cell. 2025 Aug 04. pii: S1534-5807(25)00439-3. [Epub ahead of print]60(15): 2029-2031
    A cholesterol-dependent switch controls organ-specific metastasis in pancreatic cancer.
    Julie Haenlin, Almut Schulze.
      As different organs offer distinct chemical microenvironments, cancer cells require unique metabolic adaptation to colonize distant sites. In a recent issue of Nature, Rademaker et al. identify PCSK9 as a predictive factor for metastatic colonization of different organs, showing adaptation of cancer cells to different environments by regulating cholesterol metabolism.
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.001
  35. bioRxiv. 2025 Jul 21. pii: 2025.07.16.665245. [Epub ahead of print]
    Clonal lineage tracing of innate immune cells in human cancer.
    Vincent Liu, Katalin Sandor, Patrick K Yan, Max Miao, Yajie Yin, Robert R Stickels, Andy Y Chen, Kamir Hiam-Galvez, Jacob Gutierrez, Wenxi Zhang, Sairaj M Sajjath, Raeline Valbuena, Steven Wang, Bence Dániel, Leif S Ludwig, Brooke E Howitt, Caleb Lareau, Ansuman T Satpathy.
      Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n =124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n =93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.
    DOI:  https://doi.org/10.1101/2025.07.16.665245
  36. Nat Commun. 2025 Aug 07. 16(1): 7304
    Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.
    Shengnan Li, Zhaoliang Shan, Guochun Zhao, Yuwei Li, Minghui Du, Xiuxiu Ti, Yuxue Gao, Wenting Li, Hui Zuo, Yan Wang, Qing Zhang.
      Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.
    DOI:  https://doi.org/10.1038/s41467-025-62147-5
  37. bioRxiv. 2025 Jul 25. pii: 2025.07.21.665965. [Epub ahead of print]
    Baseline expression of c-Myc defines the tissue specificity of oncogenic K-Ras.
    Olesja Popow, Qing Yu, Clarance Yapp, Shannon Hull, João A Paulo, Benjamin Hanna, Shidong Xu, Yanan Kuang, Carlie Sigel, Cloud P Paweletz, Steven P Gygi, Kevin M Haigis.
      KRAS is among the most frequently mutated oncogenes in cancer. Yet, mutations in KRAS are common only in tumors originating from a subset of tissues. It is critical to understand the molecular mechanisms underlying this oncogene tissue specificity. Utilizing genetically engineered mouse models carrying a conditional oncogenic allele of Kras , we expressed activated K-Ras in adult tissues to investigate its specificity. We discovered that the ability of K-Ras G12D to influence the fitness of cells in a given tissue is not determined by its canonical signaling through MAPK. Instead, low baseline expression of c-Myc renders tissues non-permissive to oncogenic K-Ras, a context that can be reversed in the liver by ectopically expressing c-Myc. This functions independently of the proliferative index of the tissue or the induction of cell cycle arrest or apoptosis. Our findings reveal the importance of the basal state of the tissue-inherent signaling network for determining oncogene specificity.
    DOI:  https://doi.org/10.1101/2025.07.21.665965
  38. Open Biol. 2025 Aug;15(8): 250092
    Brain amino acid sensing for organismal amino acid homeostasis.
    Anthony H Tsang, Liubou Samson, Clemence Blouet.
      Amino acids are essential for normal physiological functions, and disruptions in their circulating concentrations are implicated in the pathophysiology of various diseases. Therefore, understanding the mechanisms that regulate circulating amino acid levels in normal physiology is of critical importance. Evidence indicates that in healthy mammals, post-absorptive circulating levels of essential amino acids are maintained within a range that varies little from day to day or following bidirectional changes in dietary protein intake. This suggests the presence of homeostatic control mechanisms. Here, we propose a conceptual framework for the homeostatic regulation of essential amino acid availability, emphasizing the role of the brain in generating feedback controls to restore baseline levels acutely after a meal and during chronic changes in dietary protein intake. We review current evidence supporting brain amino acid sensing as a component of this regulatory system, integrating peripheral and central signals to modulate dietary protein intake and peripheral amino acid metabolism. We highlight major knowledge gaps regarding the specific neural circuits, molecular mechanisms and physiological outcomes of brain amino acid sensing. Future inquiry using the proposed framework and addressing these gaps will significantly enhance our understanding of the pathways involved in the maintenance of circulating amino acid availability and the regulation of lean mass in health, disease states or in response to therapeutic strategies for metabolic diseases.
    Keywords:  amino acid; dietary protein; food intake; homeostasis; hypothalamus; metabolism; physiology
    DOI:  https://doi.org/10.1098/rsob.250092
  39. Nat Commun. 2025 Aug 04. 16(1): 7156
    Nucleus-translocated glucokinase functions as a protein kinase to phosphorylate TAZ and promote tumour growth.
    Gaoxiang Zhao, Shudi Luo, Hong Zhao, Qingxia Ma, Hongfei Jiang, Lin Wang, Juanjuan Liu, Dong Guo, Runze Wang, Qianqian Xu, Jie Lun, Ranran Xie, Yixin Duan, Leina Ma, Wensheng Qiu, Jing Fang, Zhimin Lu.
      Hypoxia frequently occurs during rapid tumour growth. However, how tumour cells adapt to hypoxic stress by remodeling central cellular pathways remains largely unclear. Here, we show that hypoxia induces casein kinase 2 (CK2)-mediated glucokinase (GCK) S398 phosphorylation, which exposes its nuclear localization signal (NLS) for importin α1 binding and nuclear translocation. Importantly, nuclear GCK interacts with the transcriptional coactivator with PDZ-binding motif (TAZ) and functions as a protein kinase that phosphorylates TAZ T346. Phosphorylated TAZ recruits peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) for cis-trans isomerization of TAZ, which inhibits the binding of β-TrCP to TAZ and β-TrCP-mediated TAZ degradation. Activated TAZ-TEAD induces the expression of downstream target genes to promote tumour growth. These findings reveal an instrumental mechanism by which a glycolytic enzyme regulates the Hippo pathway under hypoxic conditions and highlight the moonlighting function of GCK as a protein kinase in modulating TAZ activity and tumour growth.
    DOI:  https://doi.org/10.1038/s41467-025-62566-4
  40. Nat Chem Biol. 2025 Aug 05.
    Intracrine FFA4 signaling controls lipolysis at lipid droplets.
    Shannon L O'Brien, Emma Tripp, Natasja Barki, Elodie Blondel-Tepaz, Gabrielle Smith, Adam Boufersaoui, Jennie Roberts, Jeremy A Pike, Joao Correia, Tamara Miljus, Michel Bouvier, Daniel A Tennant, Brian D Hudson, Zachary Gerhart-Hines, Graeme Milligan, Thue W Schwartz, Davide Calebiro.
      G-protein-coupled receptors (GPCRs) can signal from intracellular compartments but the occurrence and relevance of this phenomenon for metabolite-sensing GPCRs is largely unknown. Here, we investigate free fatty acid receptor 4 (FFA4), a metabolite-sensing GPCR activated by medium-chain and long-chain fatty acids. Using live-cell imaging, bioluminescence resonance energy transfer, super-resolution microscopy and cell fractionation, we show that FFA4 localizes to intracellular membranes, particularly endoplasmic reticulum subdomains surrounding lipid droplets, in both immortalized adipocytes and mouse adipose tissue. Upon lipolysis, locally released fatty acids appear to rapidly activate this intracellular FFA4 pool, leading to Gi/o protein signaling and preferential reduction of cyclic adenosine monophosphate levels near lipid droplets. These mechanisms are required for efficient FFA4-mediated lipolysis regulation, as shown using tethered mini-Gαi/o proteins to locally inhibit Gi/o signaling. These findings reveal an unexpected 'intracrine' GPCR signaling modality involved in the local regulation of cell metabolism, with biological and pharmacological implications.
    DOI:  https://doi.org/10.1038/s41589-025-01982-5
  41. Nat Metab. 2025 Aug 05.
    Spatial quantitative metabolomics enables identification of remote and sustained ipsilateral cortical metabolic reprogramming after stroke.
    Gangqi Wang, Bernard M van den Berg, Sarantos Kostidis, Kelsey Pinkham, Marleen E Jacobs, Arthur Liesz, Martin Giera, Ton J Rabelink.
      Mass spectrometry imaging (MSI) has become a cornerstone of spatial biology research. However, various factors that are intrinsic to the technology limit the quantitative capacity of MSI-based spatial metabolomics and thus reliable interpretation. Here we developed an improved quantitative MSI workflow, based on isotopically 13C-labelled yeast extract as internal standards, to overcome these pitfalls. Using brain and kidney tissue, we demonstrate that this approach allows for quantification of more than 200 metabolic features. Applying our workflow to a stroke model allowed us to not only map metabolic remodelling of the infarct and peri-infarct area over time, but also discover hitherto unnoted remote metabolic remodelling in the histologically unaffected ipsilateral sensorimotor cortex. At day 7 post-stroke, increased levels of neuroprotective lysine and reduced excitatory glutamate levels were found when compared with the contralateral cortex. By day 28 post-stroke, lysine and glutamate levels appeared normal, while decreased precursor pools of uridine diphosphate N-acetylglucosamine and linoleate persisted that were previously linked to vulnerability. Importantly, traditional normalization strategies not using internal standards were unable to visualize these differences. Using 13C-labelled yeast extracts as a normalization strategy establishes a paradigm in quantitative MSI-based spatial metabolomics that greatly enhances reliability and interpretive strength.
    DOI:  https://doi.org/10.1038/s42255-025-01340-8
  42. Nat Commun. 2025 Aug 04. 16(1): 7174
    Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
    Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.
      The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.
    DOI:  https://doi.org/10.1038/s41467-025-62484-5
  43. Physiology (Bethesda). 2025 Aug 05.
    What do we know of human fuel use during aerobic exercise and how do we know it?
    Jessie Axsom, Zolt Arany.
      Aerobic exercise is arguably the most metabolically demanding challenge imposed on the human body. The metabolic adaptations to exercise are complex, involving most tissues, and differing substantially depending on the type, severity, and duration of exercise, as well as extent of prior training. Studies of these metabolic responses have been ongoing for decades, including the active NIH-supported consortium MotrPAC. Most studies have been carried out in model organisms, generally rodents or dogs. However, the metabolism of these model organisms substantially differs from humans. We therefore review here what is known specifically of human metabolism during exercise. For the sake of brevity, we focus on aerobic exercise, without extensive prior training. We review methods used to reach conclusions, highlight the many remaining unknowns, and discuss questions requiring future experimental attention.
    Keywords:  exercise; human; metabolism
    DOI:  https://doi.org/10.1152/physiol.00002.2025
  44. Research (Wash D C). 2025 ;8 0805
    Mechanistic Insight into Serine Flux Regulation through Nanoscale Organization of Glucose and Serine Transporters by Substrate Probe-Based Direct Stochastic Optical Reconstruction Microscopy Imaging.
    Pengwei Jiang, Hao Hou, Jiaqi Wang, Xumin Wang, Yaqi Wang, Simin Liu, Junling Chen, Hongda Wang, Feng Liang.
      Serine serves as a metabolic nexus in tumors, coordinating one-carbon metabolism, nucleotide synthesis, and redox regulation. While serine transporters (SerTs) are known to be dysregulated in cancer, their functional nanoscale organization remains unresolved due to the limitation of resolution imaging and available probes. Here, we developed a substrate-based fluorescent probe (Ser-probe) enabling direct stochastic optical reconstruction microscopy of SerTs, revealing malignancy-associated clustering assembly of SerTs that correlates with transport capacity. Compared to MDA-MB-231 cells, MCF7 cells with higher endogenous serine biosynthetic capacity exhibited more pronounced SerT/glucose transporter (GluT) co-clustering, suggesting that their spatial assemblies closely correlate with serine transport and biosynthetic functions in maintaining serine homeostasis. Their cluster morphology and co-assembly were revealed to depend critically on lipid rafts and glycan cross-linking, identifying the key determinants of spatial distribution to enable mechanistic understanding and potential regulation. Glucose deprivation weakened SerT/GluT clustering and their colocalization, which may be caused by their attenuated functional cooperativity in serine homeostasis maintenance under glucose-dependent suppression of serine synthesis. Pharmacological inhibition of phosphoglycerate dehydrogenase (PHGDH) initially enhanced SerT/GluT aggregation and colocalization, but this effect gradually attenuated as doses increased. The strategic combination of a PHGDH inhibitor with glucose restriction or free sialic acid synergistically disrupted SerT/GluT nanoscale organization, amplifying the anti-tumor efficacy of the PHGDH inhibitor and establishing the metabolic plasticity of transporter assemblies as a targetable vulnerability. This work establishes a fundamental link between transporter spatial assembly and tumor serine metabolic reprogramming, providing a new perspective to better understand SerT dysfunction in tumor metabolic reprogramming, offering novel therapeutic avenues for targeting serine metabolism in cancer.
    DOI:  https://doi.org/10.34133/research.0805
  45. Cell. 2025 Jul 29. pii: S0092-8674(25)00805-0. [Epub ahead of print]
    Vagal blockade of the brain-liver axis deters cancer-associated cachexia.
    Aliesha Garrett, Naama Darzi, Ashlesha Deshmukh, Nataly Rosenfeld, Omer Goldman, Lital Adler, Elizabeta Bab-Dinitz, Oded Singer, Alireza Hassani Najafabadi, Chi Wut Wong, Shree Bose, Peggy M Randon, Francisco Bustamante, Rene Larios, Alexander Brandis, Tevie Mehlman, Brandon Smaglo, Ping Chang, Jacqueline Oliva, Cara Haymaker, Laukik Nagawekar, Sophie R Wu, Yixuan Huang, Aidan Shen, Ahana Vora, Jon Floyd Padilla, Alissa Pfeffer, Gary Sutherland, Mark Starr, Teresa Zimmers, Yangzhi Zhu, James Morizio, Ayelet Erez, Xiling Shen.
      Cancer-associated cachexia (CAC) is a multifactorial and currently incurable syndrome responsible for nearly one-third of cancer-related deaths. It contributes to therapy resistance and increases mortality among affected patients. In this study, we show that cancer-induced systemic inflammation alters vagal tone in CAC mouse models. This vagal dysregulation disrupts the brain-liver vagal axis, leading to a reprogramming of hepatic protein metabolism through the depletion of HNF4α, a key transcriptional regulator of liver function. The loss of HNF4α disrupts hepatic metabolism and promotes systemic inflammation, resulting in cachectic phenotypes. Interventions targeting the right cervical vagus nerve surgically, chemically, electrically, or through a non-invasive transcutaneous device attenuate CAC progression, alleviate its clinical manifestations, and synergize with chemotherapy to improve overall health and survival in mice.
    Keywords:  HNF4α; cancer-associated cachexia; liver; metabolism; neuromodulation; vagus nerve
    DOI:  https://doi.org/10.1016/j.cell.2025.07.016
  46. Nature. 2025 Aug 06.
    RNA N-glycosylation enables immune evasion and homeostatic efferocytosis.
    Vincent R Graziano, Jennifer Porat, Marie Dominique Ah Kioon, Ivana Mejdrová, Alyssa J Matz, Charlotta G Lebedenko, Peiyuan Chai, John V Pluvinage, Rafael Ricci-Azevedo, Andrew G Harrison, Skylar S Wright, Xinzheng Wang, Madison S Strine, Penghua Wang, Michael R Wilson, Sivapriya Kailasan Vanaja, Beiyan Zhou, Franck J Barrat, Thomas Carell, Ryan A Flynn, Vijay A Rathinam.
      Glycosylation is central to the localization and function of biomolecules1. We recently discovered that small RNAs undergo N-glycosylation2 at the modified RNA base 3-(3-amino-3-carboxypropyl) uridine (acp3U)3. However, the functional significance of N-glycosylation of RNAs is unknown. Here we show that the N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs. We found that de-N-glycosylation of cell-culture-derived and circulating human and mouse glycoRNA elicited potent inflammatory responses including the production of type I interferons in a Toll-like receptor 3- and Toll-like receptor 7-dependent manner. Furthermore, we show that N-glycans on cell surface RNAs prevent apoptotic cells from triggering endosomal RNA sensors in efferocytes, thus facilitating the non-inflammatory clearance of dead cells. Mechanistically, N-glycans conceal the hypermodified uracil base acp3U, which we identified as immunostimulatory when exposed in RNA. Consistent with this, genetic deletion of an enzyme (DTWD2) that synthesizes acp3U abrogated innate immune activation by de-N-glycosylated small RNAs and apoptotic cells. Furthermore, synthetic acp3U-containing RNAs are sufficient to trigger innate immune responses. Thus, our study has uncovered a natural mechanism by which N-glycans block RNAs from inducing acp3U-dependent innate immune activation, demonstrating how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.
    DOI:  https://doi.org/10.1038/s41586-025-09310-6
  47. Biogerontology. 2025 Aug 06. 26(4): 156
    The intricate link between circadian rhythms and aging: can resetting our circadian clock hold the key to longevity?
    Najm Ul Hassan, William Kojo Smith, Hafiza Ayesha Nawaz, Han Wang.
      The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.
    Keywords:  Aging; Circadian clocks; Healthspan; Lifespan; Longevity; Suprachiasmatic nuclei
    DOI:  https://doi.org/10.1007/s10522-025-10299-8
  48. Cell Rep Methods. 2025 Jul 29. pii: S2667-2375(25)00156-0. [Epub ahead of print] 101120
    MR1-ligand cross-linking identifies vitamin B6 metabolites as TCR-reactive antigens.
    Thierry Schmidlin, Enas Behiry, Hannah Thomas, Garry Dolton, Fabio Marino, Samiul Hasan, Magdalena von Essen, Rose M Gathungu, Barbara A Steigenberger, Hayden Selvadurai, Joseph Dukes, Paul E Brennan, Owen B Spiller, Jonathan D Silk, Andrew K Sewell, Nicola Ternette.
      Major histocompatibility complex class I-related protein 1 (MR1) plays a central role in the immune recognition of infected cells and can mediate T cell detection of cancer. Knowledge of the nature of the ligands presented by MR1 is still sparse and has been limited by a lack of efficient approaches for MR1 ligand discovery. Here, we present a cross-linking strategy to investigate Schiff base-bound MR1 ligands. Our methodology employs reductive amination to stabilize the labile Schiff base bond between MR1 and its ligand, allowing for the detection of ligands as covalent MR1 adducts by mass spectrometry-based proteomics. We apply our approach to identifying vitamin B6 vitamers pyridoxal and pyridoxal 5'-phosphate (PLP) as MR1 ligands and show that both compounds are recognized by T cells expressing either A-F7, a mucosal-associated invariant T (MAIT) cell T cell receptor (TCR), or MC.7.G5, an MR1-restricted TCR reported to recognize cancer cells, highlighting them as immunogenic MR1 ligands.
    Keywords:  CP: Immunology; MAIT; MR1; T cell; TCR; antigen presentation; cross-linking; mass spectrometry; metabolite antigens; pyridoxal; vitamin B6
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101120
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