bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–11–16
57 papers selected by
Christian Frezza, Universität zu Köln
  1. Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
  2. Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.
  3. Sphingolipid and methionine metabolism in aging.
  4. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  5. The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
  6. Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
  7. PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
  8. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  9. Reawakening cAMP signalling in cancer cachexia.
  10. Molecular grammars of predicted intrinsically disordered regions that span the human proteome.
  11. Spatial Immunometabolism: Integrating Technologies to Decode Cellular Metabolism in Tissues.
  12. A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.
  13. Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
  14. Metabolite maps reveal spatial gradients in liver and intestinal tissue.
  15. Alternative start codon selection shapes mitochondrial function and rare human diseases.
  16. The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
  17. Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
  18. Firewater, fructose and appetite.
  19. Somatic mutations at scale.
  20. Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.
  21. The tumor microenvironment of 14,837 breast cancers is associated with clinical outcome independently of genomic subtypes.
  22. Single-cell imaging of liver metabolic dynamics using fluorescent biosensors.
  23. An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels.
  24. TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.
  25. Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
  26. qMaLioffG: a genetically encoded green fluorescence lifetime-based indicator enabling quantitative imaging of intracellular ATP.
  27. iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
  28. Calcium Regulation of Mitochondrial Metabolism.
  29. Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.
  30. Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
  31. Is ageing a disease? The debate that could reshape medicine.
  32. Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction.
  33. An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma.
  34. Therapeutic remodeling of the ceramide backbone prevents kidney injury.
  35. Strength through diversity: how cancers thrive when clones cooperate.
  36. A century of theories of balancing selection.
  37. Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
  38. Spatially organized cellular communities shape functional tissue architecture in the pancreas.
  39. Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway.
  40. Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.
  41. Lead induces cell-autonomous proliferation and metabolic reprogramming of hepatocytes.
  42. Bridging single cells to organs: Mesoscale modules as fundamental units of tissue function.
  43. Chemical modulation of gut bacterial metabolism induces colanic acid and extends the lifespan of nematode and mammalian hosts.
  44. Evolving life-history traits promote biodiversity via eco-evolutionary feedback mechanisms.
  45. Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
  46. Neuron-tumor crosstalk fuels small cell lung cancer.
  47. Time, space, memory and brain-body rhythms.
  48. Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.
  49. From microbiome to metabolism: Bridging a two-decade translational gap.
  50. Aging and immunity.
  51. Inferring pathway activity from single-cell and spatial transcriptomics data with PaaSc.
  52. β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy.
  53. Uniform dynamics of cohesin-mediated loop extrusion in living human cells.
  54. Serine tRNAs compete to regulate the mRNA translation of serine-sensitive codons.
  55. Understanding end-of-life cancer biology.
  56. Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells.
  57. Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
  1. Nat Metab. 2025 Nov 13.
    Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
    Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.
      Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01419-2
  2. Nat Commun. 2025 Nov 10. 16(1): 9896
    Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.
    Cissy Yong, Christina Schmidt, Ming Yang, Alexander Von Kriegsheim, Anne Y Warren, Shubha Anand, James N Armitage, Antony C P Riddick, Thomas J Mitchell, Vishal Patil, Kourosh Saeb-Parsy, Sakari Vanharanta, Grant D Stewart, Christian Frezza.
      Human isotopic tracer studies are key for in vivo studies of cancer metabolism. Yet, the effects of sampling conditions on the tissue metabolome remain understudied. Here, we perform a 13C-glucose study coupled with metabolomic, transcriptomic, and proteomic profiling in patients with clear cell renal cell carcinoma (ccRCC) to assess the impact of ischaemia on tissues sampled intraoperatively and post-surgical resection, where tissues are exposed to varying degrees of warm ischaemia. Although several metabolic features were preserved, including suppressed TCA cycle activity, ischaemia masked other metabolic phenotypes of ccRCC, such as suppressed gluconeogenesis. Notably, normal kidneys were more metabolically susceptible to ischaemia than the ccRCC tumours. Despite their overall stability, ischaemia caused subtle changes in the proteome and transcriptome. Using orthotopic ccRCC-derived xenografts, we evidenced that prolonged ischaemia disrupted the tissue metabolome stability. Overall, minimising tissue ischaemia is pivotal in accurately profiling cancer metabolism in patient studies.
    DOI:  https://doi.org/10.1038/s41467-025-65676-1
  3. J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):
    Sphingolipid and methionine metabolism in aging.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.
      Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.
    Keywords:  Aging; Metabolism; Methionine; Sphingolipids
    DOI:  https://doi.org/10.1242/jcs.264026
  4. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  5. Nat Commun. 2025 Nov 14. 16(1): 10012
    The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
    Treg Grubb, Pooneh Koochaki, Sayed Matar, Fatme Ghandour, Marc Machaalani, Eddy Saad, Cerise Tang, Eduard Reznik, Jesminara Khatun, Carleigh Salem, Noah Dubasik, David A Orlando, Matthew G Guenther, Gyanu Parajuli, Raghvendra M Srivastava, Steven R Martinez, Jesse A Coker, Ritesh R Kotecha, A Ari Hakimi, John M Asara, Timothy A Chan, Sakari Vanharanta, Shaun R Stauffer, William G Kaelin, Sabina Signoretti, Toni K Choueiri, Abhishek A Chakraborty.
      Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.
    DOI:  https://doi.org/10.1038/s41467-025-64983-x
  6. Nat Metab. 2025 Nov 14.
    Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
    Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner.
      Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD.
    DOI:  https://doi.org/10.1038/s42255-025-01399-3
  7. J Am Heart Assoc. 2025 Nov 11. e043921
    PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.
       BACKGROUND: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here, we examined how cardiac mitochondrial flexibility and the posttranslational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
    METHODS: cKO and litter-matched controls were euthanized in the fed or fasted (12 hours) states, with or without a 20-minute stimulant stress of caffeine and epinephrine. Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
    RESULTS: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and carnitine palmitoyl transferase 1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
    CONCLUSIONS: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.
    Keywords:  O‐GlcNAc; O‐GlcNAcylation; PFK‐2; glycolysis; metabolic flexibility
    DOI:  https://doi.org/10.1161/JAHA.125.043921
  8. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
  9. Nat Metab. 2025 Nov 12.
    Reawakening cAMP signalling in cancer cachexia.
    Honglei Ji, Maria Rohm.
      
    DOI:  https://doi.org/10.1038/s42255-025-01417-4
  10. Cell. 2025 Nov 12. pii: S0092-8674(25)01191-2. [Epub ahead of print]
    Molecular grammars of predicted intrinsically disordered regions that span the human proteome.
    Kiersten M Ruff, Matthew R King, Alexander W Ying, Vicky Liu, Avnika Pant, Whitney E Lieberman, Min Kyung Shinn, Xiaolei Su, Cigall Kadoch, Rohit V Pappu.
      Intrinsically disordered regions (IDRs) of proteins are defined by molecular grammars. This refers to IDR-specific non-random amino acid compositions and non-random patterning of distinct pairs of amino acid types. Here, we introduce grammars inferred using NARDINI+ (GIN) as a resource that uncovers IDR-specific and IDRome-spanning grammars. Using GIN-enabled analyses, we find that specific IDR features and GIN clusters are associated with distinct biological processes, intra-cellular localization preferences, specialized molecular functions, and functionalization as assessed by cellular fitness correlations. IDRs with exceptional grammars, defined as sequences with high-scoring non-random features, are harbored in proteins and complexes that enable spatial and temporal sorting of biochemical activities within the nucleus. Overall, GIN can be used to extract sequence-function relationships of individual IDRs or clusters of IDRs, to redesign extant IDRs or design de novo IDRs, to perform evolutionary analyses through the lens of molecular grammars and GIN clusters, and to make sense of IDR-specific disease-associated mutations.
    Keywords:  RNA polymerase; biomolecular condensates; cancer; intrinsically disordered regions; molecular grammars; subcellular localization; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.cell.2025.10.019
  11. Eur J Immunol. 2025 Nov;55(11): e70094
    Spatial Immunometabolism: Integrating Technologies to Decode Cellular Metabolism in Tissues.
    Felix J Hartmann.
      The metabolic programs of immune cells influence their activation, differentiation, and effector functions. While much of immunometabolism has focused on cell-intrinsic regulation, it is now clear that metabolic activity is profoundly influenced by the surrounding tissue environment. In tumors and other inflammatory settings, immune cells are shaped by nutrient gradients, hypoxia, and immunoregulatory metabolites, factors that are spatially heterogeneous and often poorly captured by traditional methods. This review highlights recent technological advances that enable spatially resolved analysis of immune metabolism, with an emphasis on multimodal integration and cancer as a model system. Mass spectrometry imaging (MALDI, DESI), high-resolution platforms like SIMS, and vibrational imaging approaches such as Raman microscopy enable direct visualization of metabolites in tissue. Transcriptomic and proteomic data can be used to infer metabolic states, and computational models are being developed to integrate these diverse data layers. Together, these technologies are transforming the study of immunometabolism from dissociated cells to the intact tissue context. Key challenges remain in resolution, annotation, and data integration, but spatial immunometabolism holds particular promise for illuminating mechanisms of immune regulation in health and disease.
    Keywords:  antitumor immunity; cellular metabolism; immunometabolism; multiplexed imaging; spatial biology; systems immunology; tumor microenvironment
    DOI:  https://doi.org/10.1002/eji.70094
  12. Cell Rep. 2025 Nov 07. pii: S2211-1247(25)01293-8. [Epub ahead of print]44(11): 116522
    A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.
    Megumi Mori, Grant Kauwe, Ammar Aly, Edward H Liao, Gary Scott, A Pejmun Haghighi.
      Neuronal response to changes in nutrient availability is critical for maintaining metabolic homeostasis and organismal survival. Nevertheless, we know little about the molecular players that regulate and maintain neurotransmission under nutritional stress. We demonstrate that, under acute amino acid restriction, the maintenance of normal synaptic strength at the Drosophila larval neuromuscular junction critically depends on the integrated stress response (ISR) machinery. Our findings indicate that amino acid restriction triggers a non-canonical ISR cascade in muscle via GCN2 and eIF2α phosphorylation but independently of ATF4. We have identified Still life (Sif), an ortholog of human TIAM1, as a translational target of the ISR and show that it is required in muscle for mediating the action of the ISR. Our results reveal an intricate non-canonical ISR signaling cascade at the synapse and offer a new framework to separate the role of the ISR in proteostasis from its synaptic actions.
    Keywords:  CP: metabolism; CP: neuroscience; GCN2; amino acid sensing; eIF2alpha; integrated stress response; presynaptic release; regulation of translation; retrograde signaling; synaptic set point
    DOI:  https://doi.org/10.1016/j.celrep.2025.116522
  13. Autophagy. 2025 Nov 13.
    Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
    Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.
      Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.
    Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2589909
  14. Nature. 2025 Nov 12.
    Metabolite maps reveal spatial gradients in liver and intestinal tissue.
      
    Keywords:  Imaging; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-03457-y
  15. Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]
    Alternative start codon selection shapes mitochondrial function and rare human diseases.
    Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.
      Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.
    Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
  16. Sci Adv. 2025 Nov 14. 11(46): eadx7809
    The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis.
    Sukrut C Kamerkar, Taewook Kang, Radu V Stan, Edward J Usherwood, Henry N Higgs.
      Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.
    DOI:  https://doi.org/10.1126/sciadv.adx7809
  17. Nat Commun. 2025 Nov 10. 16(1): 9868
    Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
    Marco Scalabrin, Eloisa Turco, Ilaria Davigo, Riccardo Filadi, Leonardo Nogara, Gaia Gherardi, Lucia Barazzuol, Andrea Armani, Giulia Trani, Samuele Negro, Anais Franco-Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Paola Pizzo, Marco Sandri, Stephan Kemp, Vanina Romanello.
      Skeletal muscles, which constitute 40-50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.
    DOI:  https://doi.org/10.1038/s41467-025-64833-w
  18. Nat Metab. 2025 Nov 10.
    Firewater, fructose and appetite.
    Emma L Shepherd, Patricia F Lalor.
      
    DOI:  https://doi.org/10.1038/s42255-025-01369-9
  19. Nat Genet. 2025 Nov;57(11): 2620
    Somatic mutations at scale.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02438-1
  20. Cancers (Basel). 2025 Nov 03. pii: 3563. [Epub ahead of print]17(21):
    Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.
    Pierre Jacquet, Angélique Stéphanou.
      Background: The Warburg effect, historically regarded as a hallmark of cancer metabolism, is often interpreted as a universal metabolic feature of tumor cells. However, accumulating experimental evidence challenges this paradigm, revealing a more nuanced and context-dependent metabolic landscape. Methods: In this study, we present a hybrid multiscale model of tumor metabolism that integrates cellular and environmental dynamics to explore the emergence of metabolic phenotypes under varying conditions of stress. Our model combines a reduced yet mechanistically informed description of intracellular metabolism with an agent-based framework that captures spatial and temporal heterogeneity across tumor tissue. Each cell is represented as an autonomous agent whose behavior is shaped by local concentrations of key diffusive species-oxygen, glucose, lactate, and protons-and governed by internal metabolic states, gene expression levels, and environmental feedback. Building on our previous work, we extend existing metabolic models to include the reversible transport of lactate and the regulatory role of acidity in glycolytic flux. Results: Simulations under different environmental perturbations-such as oxygen oscillations, acidic shocks, and glucose deprivation-demonstrate that the Warburg effect is neither universal nor static. Instead, metabolic phenotypes emerge dynamically from the interplay between a cell's history and its local microenvironment, without requiring genetic alterations. Conclusions: Our findings suggest that tumor metabolic behavior is better understood as a continuum of adaptive states shaped by thermodynamic and enzymatic constraints. This systems-level perspective offers new insights into metabolic plasticity and may inform therapeutic strategies targeting the tumor microenvironment rather than intrinsic cellular properties alone.
    Keywords:  environmental stress; metabolic plasticity; systems biology; tumor metabolism
    DOI:  https://doi.org/10.3390/cancers17213563
  21. Cell Rep Med. 2025 Nov 10. pii: S2666-3791(25)00523-3. [Epub ahead of print] 102450
    The tumor microenvironment of 14,837 breast cancers is associated with clinical outcome independently of genomic subtypes.
    Kevin J Tu, Daniel Guerrero-Romero, Kate Eason, Raquel Manzano Garcia, Jia Wern, Soo-Hwang Teo, Long Nguyen, Stephen-John Sammut, Florian Markowetz, Oscar M Rueda, Carlos Caldas.
      The tumor microenvironment (TME) contributes to breast cancer heterogeneity and outcome but is rarely considered in clinical decision-making. We address this gap by systematically characterizing the TME's cellular composition to establish its independent clinical utility across intrinsic and genomic subtypes. We first compare 15 TME profiling methods in 693 samples and then apply the deconvolution algorithm InstaPrism to a meta-dataset of 14,837 expression profiles. We identify seven distinct TME patterns that associate with disease-free survival independently of intrinsic subtype. We also identify TME features that modulate chemotherapy response, relapse, and metastatic risk, with divergent patterns observed across estrogen receptor subtypes. Notably, long-term recurrence was regulated by vascular stromal cells and the innate immune response. Furthermore, the depletion of B cell lineage derivatives in metastatic lesions suggests an opportunity for therapeutic intervention. These results provide evidence for using TME characterization as a prognostic and predictive biomarker and identify potential targets for TME-based intervention.
    Keywords:  B cells; InstaPrism; TME types; breast cancer; chemotherapy response; deconvolution; metastasis; prognosis; relapse; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102450
  22. Trends Endocrinol Metab. 2025 Nov 10. pii: S1043-2760(25)00224-3. [Epub ahead of print]
    Single-cell imaging of liver metabolic dynamics using fluorescent biosensors.
    Israel Pérez-Chávez, Eduardo H Gilglioni, Daria Ezeriņa, Joris Messens, Esteban N Gurzov.
      Traditional metabolic studies rely on bulk tissue analyses, masking the cellular heterogeneity that underlies disease progression. Genetically encoded fluorescent biosensors now enable real-time, single-cell imaging of dynamic metabolic processes in the liver. These tools provide insights into the metabolic reprogramming in conditions such as chronic obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). By tracking specific metabolites involved in glycolysis, lipid oxidation, and the tricarboxylic acid (TCA) cycle, biosensors can reveal how these pathways respond to diverse stimuli. In this review we outline the core principles of fluorescent biosensors, provide specific recommendations for their usage, suggest possible applications in liver metabolism research, and discuss current technical challenges as well as emerging opportunities in this rapidly advancing field.
    Keywords:  HCC; MASLD; fluorescent genetically encoded biosensors; liver metabolism; microscopy; single-cell resolution
    DOI:  https://doi.org/10.1016/j.tem.2025.10.003
  23. Cell Chem Biol. 2025 Nov 10. pii: S2451-9456(25)00343-5. [Epub ahead of print]
    An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels.
    Rachel P M Abrams, Rebecca G Donahue, Jessica Ma, Ying Mao, Morgan E Diolaiti, Alan Ashworth.
      Dysregulation of cysteine-dependent processes is implicated in many diseases, including cancer. Despite the importance of cysteine in crucial cellular functions, including protein synthesis, redox balance, and glutathione production, a lack of efficient assays to measure cellular cysteine has limited efforts to identify agents that affect physiological cysteine levels. We employed circular permutation to engineer a fluorescent sensor that changes conformation upon cysteine binding. Biochemical experiments showed that this sensor is selective for cysteine, operating in the 10 μM-10 mM range. To demonstrate the sensor's applicability, we performed high-throughput screens for compounds that reduce cellular cysteine. Liquid chromatography of cell extracts validated the effect of two hit compounds, and mechanistic investigations showed that one was dependent on the anticancer target, xCT. Future application of this sensor in cell biology and drug discovery will advance understanding of cysteine metabolism and drive the development of therapeutics that restore cysteine homeostasis.
    Keywords:  cellular sensor; cysteine; drug discovery; ferroptosis; high-throughput screening; oxidative stress; protein engineering
    DOI:  https://doi.org/10.1016/j.chembiol.2025.10.006
  24. EMBO Rep. 2025 Nov 10.
    TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.
    Hari Shankar Sunil, Jean R Clemenceau, Anthony Grichuk, Isabel Barnfather, Sumanth R Nakkireddy, Luke Izzo, Qiang Feng, William Hartnett, Bret M Evers, Lisa Thomas, Indhumathy Subramaniyan, Li Li, William C Putnam, Steven Hepensteil, Jingfei Zhu, Barrett Updegraff, John D Minna, Ralph J DeBerardinis, Tae Hyun Hwang, Jinming Gao, Trudy G Oliver, Kathryn A O'Donnell.
      Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, particularly for lung squamous cell carcinoma (LUSC), underscoring the critical need for the identification of new therapeutic targets. We previously demonstrated that the Transmembrane Serine Protease TMPRSS11B promotes the transformation of human bronchial epithelial cells and enhances lactate export from LUSC cells. Here, we evaluate the impact of TMPRSS11B activity on the host immune system and the tumor microenvironment (TME). Tmprss11b depletion significantly reduces tumor burden in immunocompetent mice and triggers an infiltration of immune cells. RNA FISH analysis and spatial transcriptomics in the autochthonous Rosa26-Sox2-Ires-GfpLSL/LSL; Nkx2-1fl/fl; Lkb1fl/fl (SNL) model reveal an enrichment of Tmprss11b expression in LUSC tumors, specifically in Krt13+ hillock-like cells. Furthermore, utilizing ultra-pH-sensitive nanoparticle imaging and metabolite analysis, we identify regions of acidification, elevated lactate, and enrichment of immunosuppressive (M2-like) macrophages in LUSC tumors. These results demonstrate that TMPRSS11B promotes an acidified and immunosuppressive TME and nominate this enzyme as a therapeutic target in LUSC.
    Keywords:  Hillock Cells; Immune Suppression; Lactate-mediated TME Acidification; Squamous Cell Lung Cancer; Transmembrane Serine Protease TMPRSS11B
    DOI:  https://doi.org/10.1038/s44319-025-00631-1
  25. Int J Mol Sci. 2025 Oct 22. pii: 10275. [Epub ahead of print]26(21):
    Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.
    Shruti Somai, Chioma H Aloh, Dillon E King, William C Copeland.
      Mitochondria are vital for cellular energy production, as these organelles generate most of the cellular energy required for various metabolic processes. Mitochondria contain their own circular DNA, which is present in multiple copies and is exclusively maternally inherited. Cellular energy in the form of adenosine 5'-triphosphate is produced via oxidative phosphorylation and involves the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. Mitochondrial DNA itself is replicated by a dedicated set of nuclear-encoded proteins composed of the DNA polymerase gamma, the Twinkle helicase, the mitochondrial single-stranded DNA binding protein, as well as several accessory factors. Mutations in these genes, as well as in the genes involved in nucleotide metabolism, are associated with a spectrum of mitochondrial disorders that can affect individuals from infancy to old age. Additionally, mitochondrial disease can arise as a result of point mutations, deletions, or depletion in the mitochondrial DNA or in genes involved in mitochondrial transcription, replication, maintenance, and repair. Although a cure for mitochondrial diseases is currently elusive, several treatment options have been explored. In this review, we explore the molecular insights of the core mitochondrial replisome proteins that have aided our understanding of mitochondrial diseases and influenced current therapies.
    Keywords:  DNA polymerase γ; PolG; PolG2; Twinkle; mitochondria; mitochondrial diseases; mtDNA; mtDNA replication; mtSSB
    DOI:  https://doi.org/10.3390/ijms262110275
  26. Nat Commun. 2025 Nov 13. 16(1): 9972
    qMaLioffG: a genetically encoded green fluorescence lifetime-based indicator enabling quantitative imaging of intracellular ATP.
    Satoshi Arai, Hideki Itoh, Cong Quang Vu, Loan Thi Ngoc Nguyen, Mizuho Nakayama, Masanobu Oshima, Atsuya Morita, Kazuko Okamoto, Satoru Okuda, Aki Teranishi, Madori Osawa, Yoshiteru Tamura, Shigeaki Nonoyama, Megumi Takuma, Toshinori Fujie, Satya Ranjan Sarker, Thankiah Sudhaharan, Akihiro Furube, Tetsuro Katayama, Taketoshi Kiya, E Birgitte Lane, Tetsuya Kitaguchi.
      Genetically encoded indicators that can detect concentrations of metabolites and signalling molecules through fluorescence lifetime changes are gaining attention, because they expand the potential for quantitative imaging. These indicators offer advantages over conventional fluorescence intensity-based indicators by minimizing artifacts such as variations in indicator concentration, cellular morphological changes, and focus drift. However, the availability of fluorescence lifetime-based genetically encoded indicators remains limited, particularly those compatible with the widely used conventional 488 nm laser in microscopy. Here, we introduce qMaLioffG, a single green fluorescent protein-based ATP indicator that exhibits a substantial fluorescence lifetime shift (1.1 ns) within physiologically relevant ATP concentrations. This enables quantitative imaging of ATP levels in the cytoplasm and mitochondria under steady-state conditions across various cell types, providing insights into ATP distribution. We demonstrate that qMaLioffG can be used in multicellular systems, applying it to Drosophila brain and HeLa cell spheroids to reveal spatially heterogeneous ATP levels.
    DOI:  https://doi.org/10.1038/s41467-025-64946-2
  27. Sci Adv. 2025 Nov 14. 11(46): eadz3889
    iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
    Jonathan S Marvin, Philipp Mächler, Chengbo Meng, Tayfun Ates, Ronak H Patel, Raghabendra Adhikari, Monika A Makurath, Zaneta Ku, Daniel Feliciano, Deniz Atasoy, Guohong Cui, David Kleinfeld, Timothy A Brown.
      Continuous glucose monitors have proven invaluable for monitoring blood glucose levels for diabetics, but they are of limited use for observing glucose dynamics at the cellular (or subcellular) level. We have developed a second generation, genetically encoded intensity-based glucose sensing fluorescent reporter (iGlucoSnFR2). We show that when it is targeted to the cytosol, it reports intracellular glucose consumption and gluconeogenesis in cell culture, along with efflux from the endoplasmic reticulum. It outperforms the original iGlucoSnFR in vivo when observed by fiber photometry in mouse brain and reports transient increase in glucose concentration when stimulated by noradrenaline or electrical stimulation. Last, we demonstrate that membrane localized iGlucoSnFR2 can be calibrated in vivo to indicate absolute changes in extracellular glucose concentration in awake mice. We anticipate iGlucoSnFR2 facilitating previously unobservable measurements of glucose dynamics with high spatial and temporal resolution in living mammals and other experimental organisms.
    DOI:  https://doi.org/10.1126/sciadv.adz3889
  28. Annu Rev Physiol. 2025 Nov 10.
    Calcium Regulation of Mitochondrial Metabolism.
    Carmen A Mannella, Pawel Swietach, Liron Boyman.
      Mitochondrial ATP production dynamically adapts to cellular energy demands, with calcium (Ca2+) playing a crucial regulatory role. In this review, we critically evaluate the evidence for intramitochondrial Ca2+ ([Ca2+]m) sensitivity in key energy metabolic pathways, highlighting the [Ca2+]m dependence of specific mitochondrial systems. We also address the metabolic consequences of [Ca2+]m-sensitive ATP production, particularly its effects on the utilization of specific macronutrients that fuel ATP production. Next, we discuss the primary Ca2+ entry pathway into the matrix, the mitochondrial Ca2+ uniporter (MCU), its macromolecular complex structure (MCUcx), and allosteric regulation by Ca2+. Key to this regulation are specific auxiliary subunits, along with the influence of mitochondrial inner membrane architecture. While the Ca2+ signaling plays an important role, it does not fully explain the scope for regulating ATP production. Emerging evidence suggests that additional signaling systems operating alongside the Ca2+ signaling contribute to the control of mitochondrial ATP production, a topic requiring further investigation.
    DOI:  https://doi.org/10.1146/annurev-physiol-052424-082740
  29. Cancer Res. 2025 Nov 11.
    Response to Immune Checkpoint Blockade is Enhanced in the Presence of Hematopoietic TET2 Inactivation.
    Vincent Rondeau, Suraj Bansal, Marco M Buttigieg, Andy G X Zeng, Darryl Y Chan, Michelle Chan-Seng-Yue, Liqing Jin, Jessica McLeod, Meghan Kates, Elisa Donato, Patrick Stelmach, Caitlyn Vlasschaert, Yitong Yang, Aarushi Gupta, Sofia Genta, Enrique Sanz-Garcia, Liran Shlush, Mauricio Ribeiro, Marcus O Butler, Sagi Abelson, Mark D Minden, Samuel D Saibil, Steven M Chan, Michael J Rauh, Andreas Trumpp, John E Dick, Robert J Vanner.
      Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen receptor T cell function, suggesting it might also impact immunotherapy response. Here, we found that hematopoietic Tet2 mutation in mouse models enhanced the immune checkpoint blockade (ICB) response, which required the combined presence of phagocytes, CD4+, and CD8+ T cells. The effect was lost with myeloid- or T-cell restricted Tet2 inactivation or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. Clinically, tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, this work demonstrates that hematopoietic TET2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3329
  30. Nat Metab. 2025 Nov 12.
    Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
    Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D'Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani.
      Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP-PKA-CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP-PKA-CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.
    DOI:  https://doi.org/10.1038/s42255-025-01397-5
  31. Nature. 2025 Nov;647(8089): S8-S11
    Is ageing a disease? The debate that could reshape medicine.
    Rachel Nuwer.
      
    Keywords:  Ageing; Alzheimer's disease; Research data
    DOI:  https://doi.org/10.1038/d41586-025-03525-3
  32. Cell. 2025 Nov 07. pii: S0092-8674(25)01192-4. [Epub ahead of print]
    Longitudinal ultrasensitive ctDNA monitoring for high-resolution lung cancer risk prediction.
    TRACERx Consortium
      Biomarkers accurately informing prognostic assessment and therapeutic strategy are critical for improving patient outcome in oncology. Here, we apply a whole-genome, tumor-informed circulating tumor DNA (ctDNA) detection approach to address this challenge, leveraging 1,800 variants across 2,994 plasma samples from 431 patients with non-small cell lung cancer (NSCLC) from the TRACERx study. We show that ultrasensitive ctDNA detection below 80 parts per million both pre- and postoperatively is highly prognostic, and combinatorial analysis of the pre- and postoperative ctDNA status identifies an intermediate risk group, improving disease stratification. ctDNA kinetics demonstrate clinical utility during adjuvant therapy, where patients that "clear" ctDNA during adjuvant therapy experience improved outcomes. Moreover, characterization of patterns in postoperative ctDNA kinetics reveals insights into the timing, risk, and anatomical pattern of relapses. By incorporating longitudinal ultrasensitive ctDNA detection, we propose a refined schema for guiding the stratification and treatment recommendations in early stage NSCLC.
    Keywords:  circulating tumor DNA; liquid biopsy; molecular residual disease; non-small cell lung cancer; prognostic classification; therapy response prediction/monitoring
    DOI:  https://doi.org/10.1016/j.cell.2025.10.020
  33. J Exp Clin Cancer Res. 2025 Nov 14. 44(1): 306
    An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma.
    Yongrui Hai, Wenhui Wang, Renming Fan, Ye Chen, Junyan Zhuang, Shuo Fu, Guiquan Ding, Lei Liang, Junke Song, Gaofei Wei.
       BACKGROUND: Metabolic reprogramming, particularly upregulated de novo pyrimidine biosynthesis, drives cancer progression and immune evasion. Dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, is a promising therapeutic target, but its inhibitors often face resistance in immune-refractory melanoma, linked to low basal stimulator of interferon genes (STING) expression.
    METHODS: To overcome this limitation, we designed H62, a tumor-selective prodrug conjugating the DHODH inhibitor EA6 with the STING agonist MSA-2 via a cathepsin B-cleavable linker. Mechanistic studies evaluated mitochondrial disruption, pyroptosis (caspase-3/GSDME), and STING-mediated interferon signaling, alongside natural killer (NK) cell recruitment. Efficacy was tested in multiple melanoma models, including standard and neoadjuvant settings.
    RESULTS: H62 synergistically induced mitochondrial dysfunction and pyroptosis while activating STING/type I interferon responses, enhancing NK cell cytotoxicity. In melanoma models, it significantly suppressed tumor growth, reduced postoperative recurrence, and improved survival.
    CONCLUSIONS: This dual-targeting strategy overcomes DHODH inhibitor resistance by coupling metabolic interference with innate immune activation, offering translational potential for melanoma and other treatment-resistant cancers.
    Keywords:  DHODH inhibitor resistance; Immunometabolism; NK cell; Pyroptosis; STING pathway
    DOI:  https://doi.org/10.1186/s13046-025-03566-6
  34. Cell Metab. 2025 Nov 12. pii: S1550-4131(25)00440-1. [Epub ahead of print]
    Therapeutic remodeling of the ceramide backbone prevents kidney injury.
    Rebekah J Nicholson, Luis Cedeño-Rosario, J Alan Maschek, Trevor Lonergan, Jonathan G Van Vranken, Angela R S Kruse, Chris J Stubben, Liping Wang, Deborah Stuart, Queren A Alcantara, Monica P Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J Clark, Samir Parikh, Jeffrey Spraggins, Donna Romero, Jeremy T Blitzer, Steven P Gygi, Jared Rutter, William L Holland, Nirupama Ramkumar, Scott A Summers.
      Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.
    Keywords:  ETC; MICOS; acute kidney injury; ceramides; cristae; lipid metabolism; lipidomics; metabolism; mitochondria; proximal tubule; sphingolipids
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.006
  35. Mol Oncol. 2025 Nov 09.
    Strength through diversity: how cancers thrive when clones cooperate.
    Marije C Kuiken, Maartje Witsen, Emile E Voest, Krijn K Dijkstra.
      Cancer is a highly heterogeneous disease, with many cancers containing multiple distinct subclones. While subclones are often seen as competitors (survival of the fittest), intratumor heterogeneity can also offer direct benefits to the tumor through cooperation between different clones. This has important clinical implications, as interdependent populations may present therapeutic vulnerabilities. Here, we review existing evidence for clonal cooperativity to address key questions and outline future developments based on six overarching principles: (a) secreted factors are important mediators of clonal cooperation; (b) (very) small subclones can significantly affect tumor behavior; (c) both genetic and nongenetic heterogeneity are substrates for cooperation; (d) nonmalignant cells from the tumor microenvironment can act as cooperating partners; (e) clonal cooperation occurs throughout different stages of cancer, from premalignancy to metastasis; and (f) clonal cooperation can promote therapy resistance by protecting otherwise sensitive populations. Together, these principles suggest clonal cooperation as an important mechanism in cancer. Lastly, we discuss how novel technological developments could address remaining gaps to open up new therapeutic strategies that exploit clonal cooperativity by targeting the tumor's weakest link.
    Keywords:  cancer progression; clonal cooperation; intratumoral heterogeneity; secreted factors; therapy resistance
    DOI:  https://doi.org/10.1002/1878-0261.70160
  36. Biol Rev Camb Philos Soc. 2025 Nov 14.
    A century of theories of balancing selection.
    Filip Ruzicka, Martyna K Zwoinska, Debora Goedert, Hanna Kokko, Xiang-Yi Li Richter, Iain R Moodie, Sofie Nilén, Colin Olito, Erik I Svensson, Peter Czuppon, Tim Connallon.
      Traits that affect organismal fitness are often highly genetically variable. This genetic variation is vital for populations to adapt to their environments, but it is also surprising given that nature - after all - 'selects' the best genotypes at the expense of those that fall short. Explaining the extensive genetic variation of fitness-related traits is thus a longstanding puzzle in evolutionary biology, with cascading implications for ecology, conservation, and human health. Balancing selection - an umbrella term for scenarios in which natural selection maintains genetic variation - is a century-old explanation to resolve this puzzle that has gained recent momentum from genome-scale methods for detecting it. Yet evaluating whether balancing selection can, in fact, resolve the puzzle is challenging, given the logistical constraints of distinguishing balancing selection from alternative hypotheses and the daunting collection of theoretical models that formally underpin this debate. Here, we track the development of balancing selection theory over the last century and provide an accessible review of this rich collection of models. We first outline the range of biological scenarios that can generate balancing selection. We then examine how fundamental features of genetic systems - non-random mating between individuals, ploidy levels, genetic drift, linkage, and genetic architectures of traits - have been progressively incorporated into the theory. We end by linking these theoretical predictions to ongoing empirical efforts to understand the evolutionary processes that explain genetic variation.
    Keywords:  balancing selection; evolutionary theory; fitness variation; heterozygote advantage; mathematical modelling; negative frequency‐dependent selection; population genetics; trade‐offs
    DOI:  https://doi.org/10.1111/brv.70103
  37. Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]
    Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
    Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.
      Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.
    DOI:  https://doi.org/10.1182/blood.2025028933
  38. Sci Adv. 2025 Nov 14. 11(46): eadx5791
    Spatially organized cellular communities shape functional tissue architecture in the pancreas.
    Alejo Torres-Cano, Jean-Francois Darrigrand, Gabriel Herrera-Oropeza, Georgina Goss, David Willnow, Anna Salowka, Siwanart Ma, Debashish Chitnis, Morgane Rouault, Alessandra Vigilante, Francesca M Spagnoli.
      Organ function depends on the precise spatial organization of cells across multiple scales, from individual units to cellular communities that form local niches and, ultimately, higher-order structures. Although cell identities are increasingly well defined, the spatial arrangement and interactions among diverse cell types remain poorly understood. Here, we combine single-cell and spatial transcriptomics to map pancreatic cell populations across space and time, from embryonic development to adult homeostasis in mice. Using these maps, we resolve spatial heterogeneity among pancreatic cell types and uncover epithelial-mesenchymal units as basic tissue niches, which we functionally characterize in both mouse and human models. We also demonstrate that the mesenchymal lineage diversifies into various specialized subtypes during development, but this complexity diminishes over time, ultimately converging into a few fibroblast subtypes in adulthood. Together, our findings reveal how different progenitor lineages codevelop and organize into structured communities that establish a functional pancreas, providing a framework to guide in vitro organogenesis and tissue engineering for pancreatic diseases.
    DOI:  https://doi.org/10.1126/sciadv.adx5791
  39. J Adv Res. 2025 Nov 07. pii: S2090-1232(25)00877-X. [Epub ahead of print]
    Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway.
    Yu-Xin Zhang, Hui Wan, Guan-Yue Shan, Zhi-Cheng Gao, Hai-Jun Li.
      Ammonia (NH3), a core toxic byproduct of amino acid metabolism in the body, poses a severe threat to cell survival when its homeostasis is disrupted. Maintaining low systemic ammonia concentrations is crucial. Under physiological conditions, the kidneys regulate ammonia metabolism precisely through glutaminase 1 (GLS1)-mediated ammonia production and the urea cycle, ensuring efficient detoxification. Hyperuricemic nephropathy (HN), a common complication of hyperuricemia, impairs patient health significantly. However, whether and how ammonia toxicity triggers cell death under this pathological condition remains unclear. Here, we demonstrated that HN promoted ammonia-dependent cell death by blocking autophagic flux, revealing a novel mechanism of HN injury. In vivo and in vitro models were used to evaluate the lysosome mitochondria damage and autophagic flux arrest mechanism caused by ammonia metabolism disorder through ultrastructural analysis, fluorescent probe and autophagic flux detection, and the causal association was verified by ammonia scavengers and gene intervention. Mechanistically, chronic hyperuricemic stress accelerates renal glutaminolysis to mitigate injury and generate sufficient ATP, resulting in excessive mitochondrial ammonia production. The ammonia accumulated undergoes RHCG-dependent transmembrane transport, causing lysosomal alkalinization and dysfunction, further resulting in mitochondrial ammonia retention and swelling. This ultimately inhibited autolysosomal disassembly, which impaired the clearance of damaged mitochondria and constitutes autophagic flux blockade, consequently driving cell death. These findings identified a distinct form of cell death in HN, mechanistically divergent from previously known mechanisms such as apoptosis or pyroptosis. It redefined HN pathogenesis through a metabolic lens, identifying druggable targets to mitigate renal damage in hyperuricemic patients.
    Keywords:  Ammonia metabolism; Autophagic flux; Hyperuricemic nephropathy; Lysosomal alkalinization; Mitochondrial damage
    DOI:  https://doi.org/10.1016/j.jare.2025.11.003
  40. Nat Commun. 2025 Nov 13. 16(1): 9822
    Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.
    Stefanie M Bader, Lena Scherer, Reet Bhandari, Allan J Motyer, James P Cooney, Liana Mackiewicz, Merle Dayton, Dylan Sheerin, David V L Romero, Jan Schaefer, Jiyi Pang, Siqi Chen, Kael Schoffer, Le Wang, Xinyi Jin, Daniel Batey, Raymond K H Yip, Ishrat Zaman, Pradeep Rajasekhar, Matthew J Gartner, Stephen Wilcox, Lachlan Whitehead, Smitha Rose Georgy, Ana Maluenda, Kathryn C Davidson, Cody C Allison, Rory Bowden, Kerstin Brinkmann, Marie-Liesse Asselin-Labat, Belinda Phipson, Maria C Tanzer, Marco J Herold, Andre L Samson, James E Vince, Andreas Strasser, Marc Pellegrini, Marcel Doerflinger.
      Inflammation and excess cytokine release are hallmarks of severe COVID-19. While programmed cell death is known to drive inflammation, its role in SARS-CoV-2 pathogenesis remains unclear. Using gene-targeted murine COVID-19 models, we here find that caspase-8 is critical for cytokine release and inflammation. Loss of caspase-8 reduces disease severity and viral load in mice, and this occurs independently of its apoptotic function. Instead, reduction in SARS-CoV-2 pathology is linked to decreased IL-1β levels and inflammation. Loss of pyroptosis and necroptosis mediators in gene-targeted animals provides no additional benefits in mitigating disease outcomes beyond that conferred by loss of caspase-8. Spatial transcriptomic and proteomic analyses of caspase-8-deficient mice confirm that improved outcomes are due to reduced pro-inflammatory responses, rather than changes in cell death signalling. Elevated expression of caspase-8 and cFLIP in infected lungs, alongside caspase-8-mediated cleavage of N4BP1, a suppressor of NF-kB signalling, indicates a role of this signalling axis in pathological inflammation. Collectively, these findings highlight non-apoptotic functions of caspase-8 as a driver of severe COVID-19 through modulation of inflammation, not through the induction of apoptosis.
    DOI:  https://doi.org/10.1038/s41467-025-65098-z
  41. Cell Death Dis. 2025 Nov 10. 16(1): 816
    Lead induces cell-autonomous proliferation and metabolic reprogramming of hepatocytes.
    Marina Serra, Alfredo Smiriglia, Cristina Migliore, Andrea Caddeo, Nicla Lorito, Gabriele Tani, Giorgia Zedda, Amedeo Columbano, Andrea Perra, Silvia Giordano, Marta Anna Kowalik, Andrea Morandi.
      Reprogramming of energy metabolism is widely recognized as a hallmark of cancer cells. However, recent evidence indicates that metabolic reprogramming also occurs in vivo in differentiated rat hepatocytes following administration of the primary mitogen lead nitrate (LN). It remains unclear whether this phenomenon results from a direct action of LN on hepatocytes or is mediated by non-parenchymal liver cells. In our study, we investigated the cell-autonomous effects of LN using immortalized non-tumorigenic rat (RNT) and human (THLE-2) hepatocytes. LN treatment induced cancer-like metabolic features in non-tumorigenic hepatocytes, including increased glycolysis, activation of both oxidative and non-oxidative pentose phosphate pathways (PPP), and reduced oxidative phosphorylation (OXPHOS). Additionally, LN increased several targets of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2), a key regulator of cellular defense against stress. We found that activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway was associated with increased hepatocyte proliferation. Importantly, silencing NRF2 completely abolished the LN-induced metabolic reprogramming. In contrast, triiodothyronine (T3), a liver mitogen that does not activate NRF2, failed to trigger metabolic reprogramming. Overall, our findings demonstrate that LN directly drives both proliferation and metabolic reprogramming in hepatocytes, independently of microenvironmental or immune signals. NRF2 plays a central role as a key driver of these cancer-like metabolic shifts, even in non-tumorigenic cells.
    DOI:  https://doi.org/10.1038/s41419-025-08134-6
  42. Cell. 2025 Nov 13. pii: S0092-8674(25)01151-1. [Epub ahead of print]188(23): 6393-6410
    Bridging single cells to organs: Mesoscale modules as fundamental units of tissue function.
    Yun Chen, Ronald N Germain, Ginger L Hunter, Rajan P Kulkarni, Arthur D Lander, Pedro Lowenstein, Jeremy E Purvis, Harikesh S Wong.
      Recent studies at molecular and genomic scales have enriched our understanding of life's most fundamental building block: the cell. However, bridging the gap between single-cell phenotypes and the emergent functions of tissues and organs remains a formidable challenge. Here, we suggest that the conceptual span from cells to tissues and organs is so large as to warrant intermediate stepping stones. Drawing inspiration from "network motifs"-discrete units of cell-level function that emerge from the interactions of a handful of genes or enzymes-we argue that similarly identifiable units of tissue-level function, which we term "mesoscale modules," emerge from coordinated "interactions" among relatively small numbers of cells and their extracellular milieu. We outline several such modules and propose that a concerted effort to study them will deepen our foundational understanding of tissue and organ functions. By developing these mesoscale insights, we anticipate a more tractable and mechanistic approach to complex human conditions rooted in tissue- and organ-scale dysregulation, including developmental defects, cancer, cardiovascular disease, immune-related disorders, infectious disease, and aging.
    Keywords:  emergent properties; mesoscale modules; network motifs; systems biology; tissue biology
    DOI:  https://doi.org/10.1016/j.cell.2025.10.012
  43. PLoS Biol. 2025 Nov;23(11): e3002749
    Chemical modulation of gut bacterial metabolism induces colanic acid and extends the lifespan of nematode and mammalian hosts.
    Guo Hu, Marzia Savini, Matthew Brandon Cooke, Xin Wei, Dinghuan Deng, Shihong M Gao, Ruyue Alps Xia, Youchen Guan, Alice X Wen, Xin Yu, Jin Wang, Chao Jiang, Christophe Herman, Jiefu Li, Meng C Wang.
      Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induced transcription of the capsular polysaccharide synthesis (cps) operon responsible for CA biosynthesis in commensal E. coli at 37 °C, and attenuated age-related metabolic changes. We also found that low-dose cephaloridine overcomes the temperature-dependent inhibition of CA biosynthesis and promotes its induction through a mechanism mediated by the membrane-bound histidine kinase ZraS, independently of cephaloridine's known antibiotic properties. Our work lays a foundation for microbiota-based therapeutics through chemical modulation of bacterial metabolism and highlights the promising potential of leveraging bacteria-targeting drugs in promoting host longevity.
    DOI:  https://doi.org/10.1371/journal.pbio.3002749
  44. PLoS Biol. 2025 Nov 12. 23(11): e3003492
    Evolving life-history traits promote biodiversity via eco-evolutionary feedback mechanisms.
    P Catalina Chaparro-Pedraza, Claudia Bank.
      To what extent is biodiversity shaped by environmental conditions, and to what extent is it the result of self-organization? Both natural processes and organismal properties may contribute to promoting diversity. Here, we show that one such process, namely natural selection, and an organismal property, namely life history, interact in a feedback mechanism that promotes the emergence of diversity. We illustrate how this mechanism operates using various models of ecological diversification driven by intraspecific resource competition, in which both a niche trait that determines resource use and a life history trait can evolve. We find that natural selection acting on life history traits leads to increased competition, which, in the presence of ecological opportunity, facilitates niche diversification. As a consequence, the environmental conditions for diversification are more restrictive in the absence of life history evolution than in its presence. Our findings indicate a strong influence of life history evolution on ecological processes that in turn shape the origin of biodiversity. Our results call for a better integration of life history evolution and niche diversification in both theoretical and empirical realms.
    DOI:  https://doi.org/10.1371/journal.pbio.3003492
  45. JCI Insight. 2025 Nov 11. pii: e189683. [Epub ahead of print]
    Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
    Ulalume Hernández-Arciga, Jun Kyoung Kim, Jacob L Fisher, Alexander Tyshkovskiy, Alibek Moldakozhayev, Catherine Hall, Souvik Ghosh, Yashvandhini Govindaraj, Ian J Sipula, Jake Kastroll, Diana Cooke, Jinping Luo, Jonathan K Alder, Stacey J Sukoff Rizzo, Gene P Ables, Eunhee Choi, Vadim N Gladyshev, Michael J Jurczak, Marc Tatar, Andrey A Parkhitko.
      Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. Yet, long-lived loss-of-function mutants often produce insulin-resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin-sensitivity, growth and reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R). We produced two knock-in mouse strains that carry the homologous KID Arg/Cys substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce pERK but ERK was less phosphorylated in cells with IGF-1R heterodimers. Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At four months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin, FGF21, and reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
    Keywords:  Aging; Glucose metabolism; Insulin; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.189683
  46. Trends Pharmacol Sci. 2025 Nov;pii: S0165-6147(25)00231-7. [Epub ahead of print]46(11): 1041-1043
    Neuron-tumor crosstalk fuels small cell lung cancer.
    Canhui Cao.
      Small cell lung cancer (SCLC) progression relies on neuronal activity, yet the mechanisms remain unclear. Two recent studies by Savchuk et al. and Sakthivelu et al. reveal that SCLC co-opts vagal and sympathetic inputs and forms glutamatergic or GABAergic synapse-like connections with neurons, uncovering direct neuron-tumor crosstalk as a key driver of malignancy and a potential therapeutic vulnerability.
    Keywords:  nervous system; neuron–cancer crosstalk; receptors; small cell lung cancer; vagus nerve
    DOI:  https://doi.org/10.1016/j.tips.2025.10.007
  47. Nat Rev Neurosci. 2025 Nov 12.
    Time, space, memory and brain-body rhythms.
    György Buzsáki.
      Time and space are crucial concepts in neuroscience, because our personal memories are tied to specific events that occur 'in' a particular space and on a 'timeline'. Thus, we seek to understand how the brain constructs time and space and how these are related to episodic memory. Place cells and time cells have been identified in the brain and have been proposed to 'represent' space and time via single-neuron or population coding, thus acting as hypothetical coordinates within a Newtonian framework of space and time. However, there is a fundamental tension between the linear and unidirectional flow of physical time and the variable nature of experienced time. Moreover, modern physics no longer views space as a fixed container and time as something in which events occur. Here, I articulate an alternative view: that time (physical and experienced) is an abstracted relational measure of change. Physical time is measured using arbitrary units and artificial clocks, whereas experienced time is linked to a hierarchy of brain-body rhythms that provide a range of reference scales that reflect the full span of experienced time. Changes in body and brain circuits, tied to these rhythms, may be the source of our subjective feeling of time.
    DOI:  https://doi.org/10.1038/s41583-025-00987-2
  48. Nat Genet. 2025 Nov 11.
    Stable clonal contribution of lineage-restricted stem cells to human hematopoiesis.
    Tetsuichi Yoshizato, Christer Nilsson, Francesca Grasso, Kari Högstrand, Stefania Mazzi, Axel Winroth, Madeleine Lehander, Indira Barbosa, Gunilla Waldin, Teresa Mortera-Blanco, Monika Jansson, Mikaela Hillberg Widfeldt, Affaf Aliouat, Margs S Brennan, Ellen Markljung, Amy Hillen, Edwin Chari, Eva Hellström-Lindberg, Warren W Kretzschmar, Petter S Woll, Sten Eirik W Jacobsen.
      Dynamic steady-state lineage contribution of human hematopoietic stem cell (HSC) clones needs to be assessed over time. However, clonal contribution of HSCs has only been investigated at single time points and without assessing the critical erythroid and platelet lineages. Here we screened for somatic mutations in healthy aged individuals, identifying expanded HSC clones accessible for lineage tracing of all major blood cell lineages. In addition to HSC clones with balanced contribution to all lineages, we identified clones with all myeloid lineages but no or few B and T lymphocytes or all myeloid lineages and B cells but no T cells. No other lineage restriction patterns were reproducibly observed. Retrospective phylogenetic inferences uncovered a 'hierarchical' pattern of descendant subclones more lineage biased than their ancestral clone and a more common 'stable' pattern with descendant subclones showing highly concordant lineage contributions with their ancestral clone, despite decades of separation. Prospective lineage tracing confirmed remarkable stability over years of HSC clones with distinct lineage replenishment patterns.
    DOI:  https://doi.org/10.1038/s41588-025-02405-w
  49. Cell Metab. 2025 Nov 13. pii: S1550-4131(25)00445-0. [Epub ahead of print]
    From microbiome to metabolism: Bridging a two-decade translational gap.
    Matthias Van Hul, Patrice D Cani.
      The mapping of the human genome sparked high expectations for biomedical breakthroughs, yet attention has since shifted toward the human microbiome as a key player in health and disease. Pioneering studies revealed striking inter-individual variability and numerous associations between gut microbiota and a wide range of conditions (i.e., obesity, diabetes, cardiovascular and inflammatory bowel diseases, autism, allergies, neurodegenerative diseases, and cancers). However, the field has faced a deluge of correlative "dysbiosis" studies with limited causal evidence. Although animal models have provided crucial mechanistic insights, translating these findings to humans has proven challenging. Interventions such as fecal microbiota transplantation, prebiotics, probiotics, and postbiotics often yield inconsistent or modest effects in clinical trials. This gap highlights the need for precision, functional profiling, and integration of multi-omics , for instance, through artificial intelligence. In this perspective, we discuss what microbiome research offers as a transformative shift and how we conceptualize disease, favoring systems biology and personalized interventions over reductionist approaches.
    Keywords:  circadian rhythm; glutamine; intestinal clock; sleep-wake cycle
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.011
  50. Immunity. 2025 Nov 11. pii: S1074-7613(25)00473-X. [Epub ahead of print]58(11): 2609-2612
    Aging and immunity.
    Christoph A Thaiss, Ye Tian, Daniel A Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W Lowe, Guang-Hui Liu.
      Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.019
  51. PLoS Comput Biol. 2025 Nov 10. 21(11): e1013666
    Inferring pathway activity from single-cell and spatial transcriptomics data with PaaSc.
    Xiqi Liao, Yuyang Hong, Yan Feng, Henghui Li, Hai Fang, Jiantao Shi.
      Recent advances in single-cell and spatial transcriptomics have revolutionized our understanding of cellular heterogeneity. However, translating high-dimensional data into functional pathway insights remains challenging. To address this obstacle, we developed PaaSc (Pathway activity analysis of Single-cell), a computational method for inferring pathway activity at single-cell resolution. PaaSc employs multiple correspondence analysis to simultaneously project cells and genes into a common latent space and selects pathway-associated dimensions through linear regression to infer pathway activity scores. We validated PaaSc across diverse benchmarking datasets, including those that jointly profiled protein and RNA levels, as well as large-scale cancer scRNA-seq cohorts. Compared with state-of-the-art methods, PaaSc demonstrated superior performance in multiple applications: scoring cell type-specific gene sets, identifying cell senescence-associated pathways, and exploring GWAS trait-associated cell types. Importantly, PaaSc maintained accuracy despite batch effects and demonstrated robust performance across different data modalities, including scATAC-seq and spatial transcriptomics data. Our results demonstrate that PaaSc accurately captures dynamic cellular states and spatial patterns, thereby advancing our understanding of cellular dynamics, aging, and disease mechanisms.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013666
  52. Diabetes. 2025 Nov 10. pii: db250496. [Epub ahead of print]
    β-Hydroxybutyrylation Links Ketone Metabolism to Mitochondrial Remodeling in Diabetic Cardiomyopathy.
    Haoran Jing, Meixin Shi, Ye Wang, Rongyi Cao, Xiaoxue Li, Xin Zhong, Shiyun Dong, Can Wei.
      Diabetic cardiomyopathy (DbCM) is characterized by metabolic remodeling and energetic stress independent of coronary artery disease. Increased reliance on fatty acid and ketone body metabolism has been observed in DbCM, but the regulatory mechanisms linking altered substrate use to myocardial dysfunction remain poorly understood. In particular, lysine β-hydroxybutyrate (Kbhb), a ketone body-derived, posttranslational modification, has emerged as a potentially critical regulator but has not been fully investigated. We conducted a comprehensive multiomics study integrating metabolomics, transcriptomics, proteomics, and Kbhb-specific proteomics on myocardial tissues in a well-established mouse model of DbCM. Kbhb-modified proteins were systematically mapped and quantified, followed by motif, subcellular localization, and protein-protein interaction analyses. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Kbhb profiling revealed extensive mitochondrial protein modification, with Atp5f1a-K239 identified as a key modification site strongly correlated with β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb as a potential metabolic-epigenetic modifier linking ketone body availability to the regulation of mitochondrial proteins in DbCM. Our findings provide novel insights into metabolic-epigenetic cross talk and identify potential therapeutic targets for interventions to restore mitochondrial function in alleviating diabetic heart disease.
    ARTICLE HIGHLIGHTS: We performed a multiomics study to better understand dysfunctions in diabetic cardiomyopathy (DbCM) and specifically identify links between lysine β-hydroxybutyrylation (Kbhb), a ketone body-derived, posttranslational modification, and cardiac dysfunction. DbCM cardiac tissue exhibited coordinated upregulations of fatty acid β-oxidation, ketone metabolism, and tricarboxylic acid cycle activity at the transcriptomic, proteomic, and metabolomic levels. Mitochondrial proteins showed that high Kbhb modification and modification of the Atp5f1a-K239 site were strongly correlated with high β-hydroxybutyrate and isocitric acid concentrations. This study identifies Kbhb modification of mitochondrial proteins as a potential mechanism linking ketone body availability to mitochondrial function in DbCM.
    DOI:  https://doi.org/10.2337/db25-0496
  53. Nat Genet. 2025 Nov 14.
    Uniform dynamics of cohesin-mediated loop extrusion in living human cells.
    Thomas Sabaté, Benoît Lelandais, Marie-Cécile Robert, Michael Szalay, Jean-Yves Tinevez, Edouard Bertrand, Christophe Zimmer.
      Most animal genomes are partitioned into topologically associating domains (TADs), created by cohesin-mediated loop extrusion and defined by convergently oriented CCCTC-binding factor (CTCF) sites. The dynamics of loop extrusion and its regulation remain poorly characterized in vivo. Here we tracked the motion of TAD anchors in living human cells to visualize and quantify cohesin-dependent loop extrusion across multiple endogenous genomic regions. We show that TADs are dynamic structures whose anchors are brought in proximity about once per hour and for 6-19 min (~16% of the time). Moreover, TADs are continuously extruded by multiple cohesin complexes. Remarkably, despite strong differences in Hi-C patterns across chromatin regions, their dynamics is consistent with the same density, residence time and speed of cohesin. Our results suggest that TAD dynamics is primarily governed by the location and affinity of CTCF sites, enabling genome-wide predictive models of cohesin-dependent chromatin interactions.
    DOI:  https://doi.org/10.1038/s41588-025-02406-9
  54. Sci Adv. 2025 Nov 14. 11(46): eady4521
    Serine tRNAs compete to regulate the mRNA translation of serine-sensitive codons.
    Veronica Costiniti, Wyatt C Tran, Nandhini Rajesh Babu, Evgeny Kanshin, Beatrix Ueberheide, Alec C Kimmelman, Robert S Banh.
      Differential mRNA translation efficiency (mTE) of codons is important in regulating protein synthesis and cellular states and can change in response to amino acid availability. While the mTE of codons is canonically associated with their corresponding transfer RNA (tRNA) isoacceptors, its regulation by amino acids in mammalian cells remains unexplored. We found that ELAC2, a 3' tRNA maturation endonuclease, decreases the mTE of UC[C/U] serine (Ser) codons in response to Ser limitation. Ablation of ELAC2 restored UC[C/U] mTE but reduced the mTE of AG[U/C] Ser codons. Among the tRNASer isoacceptors, tRNASer(GCU) decreased the most in ELAC2-deficient cells. Unexpectedly, tRNASer(GCU) delivery restored AG[U/C] mTE and reduced UC[C/U] mTE in ELAC2-deficient cells. Last, we deciphered the effects of Ser-sensitive codons on mRNA translation and the human proteome. Our study revealed that in response to Ser limitation, regulation of tRNASer(GCU) levels fine-tune the mTE of UC[C/U] or AG[U/C] Ser-sensitive codons and shapes the proteome.
    DOI:  https://doi.org/10.1126/sciadv.ady4521
  55. Nat Med. 2025 Nov 14.
    Understanding end-of-life cancer biology.
    Camila Hidalgo Salinas, Ammar A Javed, Anirban Maitra.
      
    DOI:  https://doi.org/10.1038/s41591-025-04052-4
  56. Int J Mol Sci. 2025 Oct 31. pii: 10629. [Epub ahead of print]26(21):
    Manipulation with Mutational Status of VHL Regulates Hypoxic Metabolism and Pro-Angiogenic Phenotypes in ccRCC Caki-1 Cells.
    Pavel Abramov, Alexandr Mazur, Aleksey Starshin, Svetlana Zhenilo, Egor Prokhortchouk.
      Clear cell renal cell carcinoma (ccRCC), accounting for 80-90% of renal malignancies, is frequently driven by VHL inactivation-either through mutation or promoter hypermethylation-resulting in constitutive HIF2α activation and pseudohypoxic signaling. VHL gene inactivation is a hallmark of von Hippel-Lindau syndrome, a hereditary disorder predisposing patients to ccRCC and other tumors, underscoring its central role in disease pathogenesis. While VHL dysfunction promotes aggressive tumor phenotypes, the therapeutic potential of VHL restoration remains underexplored. Here, using the Cas9 induced VHL-mutation in the Caki-1 cell line model, we demonstrate that VHL inactivation augments hypoxia-like pathways and enhances anaerobic glycolysis. Rescue of functional VHL reversed these activation patterns and modulated the expression of genes associated with angiogenesis. Using single cell transcriptomics, we show that the VHL-positive and -negative Caki-1 cells are characterized with different proportions of benign and aggressive cells as seen by analysis of specific gene expression. Furthermore, the identified angiogenesis-related genes were linked to affect clinical outcomes in ccRCC patients, suggesting that VHL restoration may mitigate high-risk molecular features.
    Keywords:  VHL; hypoxia; renal cancer; single-cell
    DOI:  https://doi.org/10.3390/ijms262110629
  57. Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):
    Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
    Margherita Zamberlan, Martina Semenzato.
      Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.
    Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes
    DOI:  https://doi.org/10.3390/ijms262110581
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