bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–06–29
57 papers selected by
Christian Frezza, Universität zu Köln



  1. Nature. 2025 Jun 25.
      
    Keywords:  Cancer; Cell biology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01941-z
  2. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00576-7. [Epub ahead of print]35(12): R595-R597
      von der Malsburg et al. introduce the mitochondrial contact site and cristae organizing system, a complex that localises to the inner mitochondrial membrane at crista junctions and stabilises these curved membrane domains.
    DOI:  https://doi.org/10.1016/j.cub.2025.05.001
  3. Cell Metab. 2025 Jun 19. pii: S1550-4131(25)00294-3. [Epub ahead of print]
      The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.
    Keywords:  PRMT5; RIPK1; S-adenosylmethionine; TNF signaling; apoptosis; death domain; inflammation; methionine; methylation; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.014
  4. Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00500-3. [Epub ahead of print]
      Apoptosis-inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40/CHCHD4, the central component of the mitochondrial disulfide relay, accounts for some, but not all, aspects of AIFM1 function. We provide a high-confidence AIFM1 interactome that elucidates functional partners within the mitochondrial intermembrane space. We found that AIFM1 binding to adenylate kinase 2 (AK2), an essential enzyme that maintains cellular adenine nucleotide pools, depends on the AK2 C-terminal domain. High-resolution cryoelectron microscopy (cryo-EM) and biochemical analyses showed that both MIA40 and AK2A bind the AIFM1 C-terminal β-sheet domain. Their binding enhances NADH oxidoreductase activity by locking an active dimer conformation and, in the case of MIA40, affecting the cofactor-binding site. The AIFM1-AK2A interaction is important during mitochondrial respiration because AIFM1 serves as a recruiting hub within the IMS, regulating mitochondrial bioenergetic output by creating hotspots of metabolic enzymes.
    Keywords:  AIFM1; AK2; ATP; ATP transport; MIA40/CHCHD4; MICOS; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.036
  5. bioRxiv. 2025 Apr 26. pii: 2025.04.23.650241. [Epub ahead of print]
      Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that the BCAA isoleucine is a primary source of propionyl-CoA in PDA cells. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) without impacting histone acetylation on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. Mechanistically, we find that multiple enzymes of isoleucine catabolism unexpectedly localize to and carry out multi-step isoleucine oxidation within the nuclei of PDA cells. Importantly, nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that isoleucine-sensitive Kpr and its associated gene expression are driven by the MYST family of lysine acyltransferases (KATs), and that the BCKDHA subunit of the BCKDH complex interacts with KAT7 within the nuclear compartment. BCAA catabolism enzymes are apparent in the nuclei of PanIN lesions in mice and PDA tumors in patients, contrasting that in healthy pancreatic acinar and ductal cells. Collectively, these findings unveil a nuclear isoleucine catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.
    DOI:  https://doi.org/10.1101/2025.04.23.650241
  6. Cell. 2025 Jun 21. pii: S0092-8674(25)00637-3. [Epub ahead of print]
      Eukaryotic life evolved over a billion years ago when ancient cells engulfed and integrated prokaryotes to become modern mitochondria and chloroplasts. Sacoglossan "solar-powered" sea slugs possess the ability to acquire organelles within a single lifetime by selectively retaining consumed chloroplasts that remain photosynthetically active for nearly a year. The mechanism for this "animal photosynthesis" remains unknown. Here, we discovered that foreign chloroplasts are housed within novel, host-derived organelles we term "kleptosomes." Kleptosomes use ATP-sensitive ion channels to maintain a luminal environment that supports chloroplast photosynthesis and longevity. Upon slug starvation, kleptosomes digest stored chloroplasts for additional nutrients, thereby serving as a food source. We leveraged this discovery to find that organellar retention and digestion of photosynthetic cargo has convergently evolved in other photosynthetic animals, including corals and anemones. Thus, our study reveals mechanisms underlying the long-term acquisition and evolutionary incorporation of intracellular symbionts into organelles that support complex cellular function.
    Keywords:  cell biology; endosymbiosis; evolution; kleptoplasty; organellar ion channels; photosynthetic animal
    DOI:  https://doi.org/10.1016/j.cell.2025.06.003
  7. Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]
      Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
    Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.033
  8. Nature. 2025 Jun 25.
      Glioblastoma (GBM) is the most lethal primary brain malignancy1. Immunosuppression in the GBM tumour microenvironment (TME) is an important barrier to immune-targeted therapies, but our understanding of the mechanisms of immune regulation in the GBM TME is limited2. Here we describe a viral barcode interaction-tracing approach3 to analyse TME cell-cell communication in GBM clinical samples and preclinical models at single-cell resolution. We combine it with single-cell and bulk RNA-sequencing analyses, human organotypic GBM cultures, in vivo cell-specific CRISPR-Cas9-driven genetic perturbations as well as human and mouse experimental systems to identify an annexin A1-formyl peptide receptor 1 (ANXA1-FPR1) bidirectional astrocyte-GBM communication pathway that limits tumour-specific immunity. FPR1 inhibits immunogenic necroptosis in tumour cells, and ANXA1 suppresses NF-κB and inflammasome activation in astrocytes. ANXA1 expression in astrocytes and FPR1 expression in cancer cells are associated with poor outcomes in individuals with GBM. The inactivation of astrocyte-glioma ANXA1-FPR1 signalling enhanced dendritic cell, T cell and macrophage responses, increasing infiltration by tumour-specific CD8+ T cells and limiting T cell exhaustion. In summary, we have developed a method to analyse TME cell-cell interactions at single-cell resolution in clinical samples and preclinical models, and used it to identify bidirectional astrocyte-GBM communication through ANXA1-FPR1 as a driver of immune evasion and tumour progression.
    DOI:  https://doi.org/10.1038/s41586-025-09191-9
  9. Nat Commun. 2025 Jun 25. 16(1): 5379
      Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.
    DOI:  https://doi.org/10.1038/s41467-025-60603-w
  10. Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00507-6. [Epub ahead of print]
      ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.
    Keywords:  AIFM1; AK2; ATP synthesis; OXPHOS; adenylate kinase 2; apoptosis-inducing factor 1; cell signaling; crosslinking mass spectrometry; energy metabolism; mitochondria; mitochondrial; oxidative phosphorylation; protein structure; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.007
  11. Methods Mol Biol. 2025 ;2944 49-64
      Metabolism is a fundamental foundation of all living organisms. However, cancer cells can modulate their metabolic activity to maintain their enhanced bioenergetic needs associated with uncontrolled proliferation. Some hallmarks of cancer metabolism include enhanced glucose uptake capacity and aberrations in mitochondrial metabolic activity and ATP production. In this chapter, we will outline several methods for studying critical metabolic parameters in brain cancer cells.
    Keywords:  ATP; Cancer; Glucose uptake; Metabolism; Oxygen consumption
    DOI:  https://doi.org/10.1007/978-1-0716-4654-0_5
  12. Nat Metab. 2025 Jun 26.
      Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death. Mechanistically, we provide evidence of heterocellular crosstalk between intestinal fibroblasts and epithelial cells. In IBD tissues and mouse models of chronic colitis, acyl-CoA synthetase long-chain family 4 (ACSL4) is overexpressed in fibroblasts. ACSL4 in fibroblasts reprograms lipid metabolism and mediates intestinal epithelial cell sensitivity to ferroptosis. In mouse models, overexpressing ACSL4 in fibroblasts results in increased intestinal epithelial ferroptosis and worsened colitis, while pharmacological inhibition or deletion of fibroblast ACSL4 ameliorates colitis. Our work provides a targeted approach to therapeutic antioxidant treatments for IBD.
    DOI:  https://doi.org/10.1038/s42255-025-01313-x
  13. Mol Cell. 2025 Jun 16. pii: S1097-2765(25)00499-X. [Epub ahead of print]
      Cells possess numerous metabolite sensors that detect essential nutrients for growth, with many directly binding to metabolites and responding to their levels. Given the vital role of arginine in various physiological and pathological processes, we hypothesized that there may be undiscovered sensors that detect arginine deficiency. Through a series of unbiased screening strategies in human cancer cell line models, we identified Bcl2-associated athanogene (BAG) family molecular chaperone regulator 2 (BAG2) as an arginine sensor, which could directly bind to arginine at the glutamine residue 167 (Q167). Upon arginine deficiency, BAG2 releases sterile alpha motif domain-containing protein 4B (SAMD4B), leading to β-catenin degradation to stabilize ATF4 protein, enhancing cell survival. When arginine is abundant, a strengthened binding between BAG2 and SAMD4B prevents β-catenin degradation, activating the Wnt/β-catenin pathway to support cell growth. Overall, our findings uncover an arginine-sensing pathway consisting of BAG2 and SAMD4B that promotes cancer cell adaptation to nutritional stress.
    Keywords:  BAG2; SAMD4B; arginine; cancer; metabolism; metabolite sensing; metabolite sensor
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.035
  14. Cell Rep Med. 2025 Jun 19. pii: S2666-3791(25)00283-6. [Epub ahead of print] 102210
      CD38, an ecto-enzyme involved in NAD+ catabolism, is highly expressed in exhausted CD8+ T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However, the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here, we show that CD38+CD8+ T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD+ pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD+ as a vital metabolite to enhance those therapies.
    Keywords:  3D microfluidic culture; CD38; NAD(+); PD-1; T cell exhaustion; cytokines; ex vivo; immunotherapy; organotypic tumor spheroids
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102210
  15. Nat Commun. 2025 Jun 25. 16(1): 5388
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  16. Nat Immunol. 2025 Jun 27.
      CD8+ T cell exhaustion (Tex) limits immune control of cancer, but the underlying molecular drivers are unclear. In the present study, we identified the prostaglandin I2 (prostacyclin) receptor PTGIR as a cell-intrinsic regulator of T cell exhaustion. Transcriptomic profiling of terminally exhausted (Ttex) CD8+ T cells revealed increased activation of the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response pathway. Enhancing NRF2 activity (by conditional deletion of Kelch-like ECH-associated protein 1 (KEAP1)) boosts glutathione production in CD8+ T cells but accelerates terminal exhaustion. NRF2 upregulates PTGIR expression in CD8+ T cells. Silencing PTGIR expression enhances T cell effector function (that is, interferon-γ and granzyme production) and limits Ttex cell development in chronic infection and cancer models. Mechanistically, PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of Tex cells. These findings identify PTGIR as a NRF2-dependent immune checkpoint that regulates balance between effector and exhausted CD8+ T cell states.
    DOI:  https://doi.org/10.1038/s41590-025-02185-9
  17. bioRxiv. 2025 Apr 07. pii: 2025.02.20.639106. [Epub ahead of print]
      The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
    DOI:  https://doi.org/10.1101/2025.02.20.639106
  18. Entropy (Basel). 2025 Jun 15. pii: 638. [Epub ahead of print]27(6):
      Information theory has long been integrated into the study of biological ageing, for example, in examining the roles of genetic and epigenetic fidelity in cellular and organismal longevity. Here, we introduce a theoretical model that interprets ageing in multicellular systems through the lens of Fisher information. Previous theories have suggested that the ageing of multicellular organisms is an inevitable consequence of the inherent tension between individual cell reproduction and the homeostasis of the multicellular system. Utilising concepts from information theory and statistical mechanics, we show that Fisher information parametrises the dynamics of this tension through non-monotonic behaviour, which depends on an optimal balance of competition and cooperation between cells. Moreover, Fisher information suggests that the ability to infer true biological age from a sample evolves through complex dynamics over an organism's lifespan.
    Keywords:  Fisher information; ageing; cancer; senescence; somatic evolution
    DOI:  https://doi.org/10.3390/e27060638
  19. Trends Cancer. 2025 Jun 25. pii: S2405-8033(25)00152-9. [Epub ahead of print]
      Impaired cellular metabolism contributes to the age-related decline in T cell function, undermining the response to immunotherapy in older patients with cancer. In a recent study, Hope et al. report that a reduction in intracellular NAD+ levels compromises metabolic fitness and drives immunosenescence. Notably, restoring NAD+ levels can reverse age-related chimeric antigen receptor (CAR)-T deterioration, suggesting a promising 'metabolic immunotherapy' that widely benefits older patients with cancer.
    Keywords:  CAR-T therapy; NAD(+); aging; metabolic immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.009
  20. Trends Endocrinol Metab. 2025 Jun 24. pii: S1043-2760(25)00128-6. [Epub ahead of print]
      Heme has remarkable functions in mitochondrial energetics. Recently, Duerre et al. found that branched-chain amino acids (BCAA) are preferentially utilized for heme biosynthesis to facilitate mitochondrial thermogenesis in brown fat. Disrupting heme biosynthesis shifts the metabolic fate of BCAAs toward histone propionylation, inhibiting the transcription of thermogenic genes.
    Keywords:  branched-chain amino acids; brown adipose tissue; heme synthesis; histone propionylation; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2025.06.005
  21. Int J Biol Macromol. 2025 Jun 22. pii: S0141-8130(25)06027-1. [Epub ahead of print]319(Pt 2): 145472
      Ferroptosis is a regulated cell death pathway characterized by iron-dependent accumulation of lipid peroxides and distinct mitochondrial morphological alterations, including reduced volume, increased membrane density, elevated membrane potential, cristae loss, and outer membrane rupture. These features starkly contrast with those observed in apoptosis, autophagy, and necrosis. As the cellular energy hub and metabolic nexus, mitochondria play multifaceted regulatory roles in ferroptosis through their integration of metabolic networks and redox homeostasis. This review systematically examines mitochondrial mechanisms driving ferroptosis progression, focusing on three key aspects: (1) metabolic reprogramming involving amino acid, lipid, and glucose metabolism; (2) dynamic regulation of reactive oxygen species (ROS) through electron transport chain activity and antioxidant defenses; and (3) iron/calcium ion flux mediated by mitochondrial membrane transporters and storage proteins. Notably, we propose a novel perspective emphasizing the unique contribution of mitochondrial membrane lipid peroxidation-driven by localized iron pools and specialized phospholipid composition-as a critical amplifier of ferroptotic signaling, distinct from cytoplasmic peroxidation pathways. By elucidating these mechanisms, our analysis identifies mitochondria-targeted strategies-such as ROS scavengers, iron chelators, and cristae-stabilizing compounds-as promising therapeutic avenues for ferroptosis-associated pathologies, including neurodegenerative diseases, ischemia-reperfusion injury, and drug-resistant cancers. This review provides a framework for understanding mitochondrial specificity in ferroptosis regulation and advances translational opportunities for modulating this pathway in clinical contexts.
    Keywords:  Cell metabolism; Ferroptosis; Mitochondria; ROS
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145472
  22. Nat Commun. 2025 Jun 26. 16(1): 5369
      Melanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combining Braf activation with heterozygous loss of Pten. Here we show that similar tumors can arise in albino mice bearing only a Braf mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only a Braf mutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling "neural crest-like" cells in human and mouse melanomas. These exist in normal mouse skin, expand upon Braf activation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-025-60742-0
  23. J Cell Biol. 2025 Aug 04. pii: e202409103. [Epub ahead of print]224(8):
      Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.
    DOI:  https://doi.org/10.1083/jcb.202409103
  24. Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00688-6. [Epub ahead of print]44(7): 115917
      α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.
    Keywords:  CP: Metabolism; CP: Stem cell research; OGFOD1; RPS23; Scutellarin; isocitrate dehydrogenase; mesenchymal stem cells; protein homeostasis; senescence; α-ketoglutaric acid
    DOI:  https://doi.org/10.1016/j.celrep.2025.115917
  25. Nat Struct Mol Biol. 2025 Jun 27.
      Cilia are microtubule-based organelles that have important roles in cell sensing, signaling and motility. Recent studies have revealed the atomic structures of many multicomponent ciliary complexes, elucidating their mechanisms of action. However, little is known about the structure, proteome and function of full-length radial spoke 3 (RS3), a conserved complex that transmits mechanochemical signals to coordinate ciliary motility. Here, we combined single-particle cryo-electron microscopy, cryo-electron tomography, proteomic analysis and computational modeling to determine the three-dimensional structure and atomic model of RS3 from mouse respiratory cilia. We reveal all RS3 components, including regulatory and metabolic enzymes such as a protein kinase A subunit, adenylate kinases (AKs) and malate dehydrogenases. Furthermore, we confirm RS3 loss in AK7-deficient mice, which exhibit motility defects. Our findings identify RS3 as an important regulatory and metabolic hub that maintains sufficient adenosine triphosphate for sustained ciliary beating, providing insights into the etiology of ciliopathies.
    DOI:  https://doi.org/10.1038/s41594-025-01594-6
  26. Curr Biol. 2025 Jun 23. pii: S0960-9822(25)00443-9. [Epub ahead of print]35(12): R626-R637
      A major challenge in biology is comprehending how complex multicellular novelties evolve. Central to this problem is explaining how qualitatively new phenotypic traits - typically the focus of comparative developmental and macroevolutionary studies above the species level - can become established through population genetic processes. Here, we suggest that a resolution may be found by acknowledging the fundamental entities from which functional organismal phenotypes are constructed. We argue that these are not genes, proteins or cell types, but rather gene expression programs (GEPs): sets of co-expressed transcripts that collectively encode cellular subfunctions. We advance that, because GEPs are the smallest, elemental functional units underlying phenotypes, it follows that they represent the substrate upon which population genetic processes must act to explain the origin of evolutionary novelty at the cellular level and above. Novelty arises through the evolution of novel GEPs, through novel synergisms between GEPs that become co-expressed within the same cell or through interactions between different GEPs juxtaposed in cooperating cells within organs. The revolution in single cell biology offers the chance to trace evolution at the resolution of GEPs in populations and across clades, potentially unifying our view of multicellular phenotypic evolution.
    DOI:  https://doi.org/10.1016/j.cub.2025.04.014
  27. mSystems. 2025 Jun 24. e0052125
      Virus-infected cells, called virocells, impact host metabolic functions, resources, and ecosystem processes, but the effects of nutrient limitation remain less well understood. Here, we leverage transcriptomic, proteomic, and endo- and exo-metabolomic data from two Pseudoalteromonas virocells independently infected by unrelated dsDNA viruses, PSA-HS2 (HS2-virocells) and PSA-HP1 (HP1-virocells), to examine how phosphate limitation affects virocell resource manipulation intra- and extracellularly. Intracellularly, we find that (i) HP1-virocells boost amino acid production toward the end of the infection cycle but deplete amino acid pools relative to HS2-virocells; (ii) both virocells dampen the production of de novo nucleotide synthesis proteins; (iii) HS2-virocells switch from de novo synthesis to recycling of phospholipids, whereas HP1-virocells decrease both activities; (iv) all cells (virocells and uninfected cells), but HP1-virocells especially, increase membrane fluidity; and (v) both virocells increase iron storage. Extracellularly, (i) polyphenols, a stress marker, increased in all cells, particularly in HP1-virocells, and (ii) only HP1-virocells showed elevated unsaturated hydrocarbons and oxygen-rich metabolites, which are likely byproducts of intracellular metabolic activity. These findings advance our understanding of how environmental conditions shape virocell activities in ecologically relevant nutrient-limited conditions and reveal distinct responses of virocells to infection by unrelated viruses.IMPORTANCEThis study addresses a knowledge gap in understanding how nutrient limitation shapes virus-infected bacterial cell (virocell) metabolism and its ecosystem footprints. Using multi-omics approaches, we examined how two different viruses (PSA-HP1 and PSA-HS2) independently infecting the same marine heterotrophic bacterium (Pseudoalteromonas) respond to phosphorus limitation. Building upon our previous work, we show how virocell metabolic reprogramming manipulates cellular resources and alters the extracellular environment. Intracellularly, while both virocells reprogram similar metabolic pathways, they manipulate key resources (nucleotides, amino acids, lipids, and iron) distinctly under nutrient limitation. Extracellularly, each virocell generates unique dissolved organic matter metabolites, with a differential expression of stress markers under phosphorus limitation, indicating environment-specific ecosystem footprints. These results provide fundamental insights into how virocell metabolic reprogramming and resource manipulation combine to produce ecosystem-scale metabolic outputs.
    Keywords:  environment; microbe; multi-omics; phage; virocells
    DOI:  https://doi.org/10.1128/msystems.00521-25
  28. Science. 2025 Jun 26. 388(6754): 1357-1358
      Study shows the organelles traveling through "bridges" into nearby cancer cells.
    DOI:  https://doi.org/10.1126/science.aea0605
  29. Nature. 2025 Jun 25.
      
    Keywords:  Cancer; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01718-4
  30. Nat Cell Biol. 2025 Jun 26.
      Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.
    DOI:  https://doi.org/10.1038/s41556-025-01693-y
  31. Cell Death Differ. 2025 Jun 23.
      As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.
    DOI:  https://doi.org/10.1038/s41418-025-01532-5
  32. EMBO J. 2025 Jun 23.
      Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.
    Keywords:  Cell Cycle; Cell Cycle Checkpoints; DNA Damage; Mitosis
    DOI:  https://doi.org/10.1038/s44318-025-00495-0
  33. Nat Rev Drug Discov. 2025 Jun 26.
      The depletion or accumulation of metabolites in the tumour microenvironment is one of the hallmarks of cancer, but targeting cancer cell metabolism therapeutically must also take into account the impact on metabolic pathways in immune cells. As we understand more about immunometabolism, opportunities arise for synergies between agents that modulate metabolism and immunotherapy. In this Review, we discuss the pivotal role of metabolic pathways in both cancer and immune cells in shaping the tumour microenvironment. We survey major anabolic and catabolic pathways and discuss how metabolic modulators and dietary nutrients can improve the anticancer immune response and overcome drug resistance mechanisms. Agents in the clinic include inhibitors of the adenosine and tryptophan pathways, and we discuss opportunities and challenges for successful drug development in the context of immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapies.
    DOI:  https://doi.org/10.1038/s41573-025-01227-z
  34. Science. 2025 Jun 26. eadv2367
      FOXA1 is altered in 10 to 40% of prostate cancers, yet its oncogenic mechanisms remain uncharacterized in vivo. We developed knock-in mouse models representing distinct classes of FOXA1 mutations. Histopathological and multi-omic analyses of prostate tissues and organoids revealed that Class 1 mutations, in conjunction with p53 inactivation, drive androgen-dependent adenocarcinomas through co-activation of mTORC1/2 and oncogenic AR signaling stemming from chimeric AR-half enhancers. In contrast, Class 2 mutations induce intra-luminal plasticity by reprogramming differentiated luminal cells into a progenitor-like state through activation of KLF5 and AP-1 neo-enhancer circuitries, which enables enhanced survival and proliferation even under castrate androgen levels. Our findings establish FOXA1 as a multifaceted oncogene, with distinct mutational classes divergently evolving to drive prostate tumorigenesis or therapy-resistant progression.
    DOI:  https://doi.org/10.1126/science.adv2367
  35. PLoS Comput Biol. 2025 Jun;21(6): e1013090
      Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called "MitoTracer", which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013090
  36. J Cell Biol. 2025 Aug 04. pii: e202408025. [Epub ahead of print]224(8):
      Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson's disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy-a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognizes its substrates for ubiquitination. Here, we characterize a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results may explain fast kinetics of Miro1 ubiquitination by Parkin in recombinant assays and provide a biochemical explanation for Miro1-dependent Parkin recruitment to the mitochondrial membrane observed in cells. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.
    DOI:  https://doi.org/10.1083/jcb.202408025
  37. Nature. 2025 Jun 25.
      The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.
    DOI:  https://doi.org/10.1038/s41586-025-09176-8
  38. Nat Metab. 2025 Jun 27.
      Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1038/s42255-025-01320-y
  39. Nat Genet. 2025 Jun 23.
      Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (n = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment.
    DOI:  https://doi.org/10.1038/s41588-025-02233-y
  40. Nat Rev Mol Cell Biol. 2025 Jun 23.
      Intracellular membrane contact sites (MCSs) between organelles have crucial roles in cellular signalling and homeostasis. These sites, which are often disrupted in pathological conditions, enable the exchange of ions, lipids and metabolites between membrane-bound compartments, helping cells adapt to varying physiological conditions. Specific tether proteins and complexes stabilize these interactions and mediate responses to different intracellular or extracellular stimuli. The study of MCSs has progressed in recent years, owing to the development of new methods such as genetically encoded reporter constructs, advanced imaging techniques, including super-resolution microscopy and electron tomography, and proteomic approaches based on mass spectrometry. These tools have enabled unprecedented visualization and quantification of organelle interactions, as well as identification of the molecular players involved. This Expert Recommendation aims to define and map the 'organelle contactome', describing key proteins involved in contact site formation and the roles of MCSs in cellular function. We also explore contact site dynamics and detail advantages and disadvantages of the methodologies for studying them. Importantly, we consolidate open questions in contact site research and discuss challenges and limitations of the current experimental approaches.
    DOI:  https://doi.org/10.1038/s41580-025-00864-x
  41. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  42. Nat Commun. 2025 Jun 23. 16(1): 5338
      Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report that apical size reduction via macropinocytosis serves as a malleable and less destructive form of tissue remodeling that can alleviate the need for cell loss. We find that macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane. This drives a reduction in apical surface which alleviates crowding. We report that this mechanism regulates the long-term organization of the developing epithelium and controls the timing of proliferation-induced cell extrusion. Additionally, we observe a wave of macropinocytosis in response to acute external compression. In both scenarios, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to both developmental and external compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
    DOI:  https://doi.org/10.1038/s41467-025-60724-2
  43. PLoS Biol. 2025 Jun;23(6): e3003207
      Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.
    DOI:  https://doi.org/10.1371/journal.pbio.3003207
  44. Nature. 2025 Jun 25.
      Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1-3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4-8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin-CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin-CDK acts as a 'signal relayer'. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.
    DOI:  https://doi.org/10.1038/s41586-025-09172-y
  45. Proc Natl Acad Sci U S A. 2025 Jul;122(26): e2502423122
      Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
    Keywords:  MRI; cancer metabolism; nuclear medicine; prostate cancer; spectroscopy
    DOI:  https://doi.org/10.1073/pnas.2502423122
  46. Nature. 2025 Jun 25.
      Postmitotic neurons have high levels of methylated cytosine and its oxidized intermediates such as 5-hydroxymethylcytosine1. However, the functional relevance of these epigenetic modifications of DNA are poorly understood. Here we show that some cytidine analogues, such as cytarabine, cause DNA double-strand breaks during TET-mediated active 5-methylcytosine demethylation by interrupting TDG-dependent base excision repair. These double-strand breaks are frequently converted into deletions and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage due to cytarabine. In Purkinje cells, TET targets highly expressed gene bodies marked by enhancer-associated histone modifications. Many of these genes control movement coordination, which explains the long-recognized cerebellar neurotoxicity of cytarabine2. We show that other cytidine analogues, such as gemcitabine, cause only single-strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons. The results also provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.
    DOI:  https://doi.org/10.1038/s41586-025-09210-9
  47. Cancer Cell. 2025 Jun 20. pii: S1535-6108(25)00255-7. [Epub ahead of print]
      Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments for mice with choroid plexus carcinoma, and the prediction of potential new treatments for patients with medulloblastoma and triple-negative breast cancer. Thus, RECODR may unravel the complexity of cancer treatment resistance by detecting context-specific changes in gene interactions that determine the resistant phenotype.
    Keywords:  DNA repair; cancer; choroid plexus; choroid plexus carcinoma; combination therapy; graph networks; machine learning; radiation; treatment resistance; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.005
  48. Sci Adv. 2025 Jun 27. 11(26): eads6132
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  49. Biochim Biophys Acta Bioenerg. 2025 Jun 23. pii: S0005-2728(25)00030-1. [Epub ahead of print] 149564
      Studies by microbiologists in the 1970s provided robust estimates for the energy supply and demand of a prokaryotic cell. The amount of ATP needed to support growth was calculated from the chemical composition of the cell and known enzymatic pathways that synthesize its constituents from known substrates in culture. Starting in 2015, geneticists and evolutionary biologists began investigating the bioenergetic role of mitochondria at eukaryote origin and energy in metazoan evolution using their own, widely trusted-but hitherto unvetted-model for the costs of growth in terms of ATP per cell. The more recent model contains, however, a severe and previously unrecognized error that systematically overestimates the ATP cost of amino acid synthesis up to 200-fold. The error applies to all organisms studied by such models and leads to conspicuously false inferences, for example that the synthesis of an average amino acid in humans requires 30 ATP, which no biochemistry textbook will confirm. Their ATP 'cost' calculations would require that E. coli obtains ~100 ATP per glucose and that mammals obtain ~240 ATP per glucose, untenable propositions that invalidate and void all evolutionary inferences so based. By contrast, established methods for estimating the ATP cost of microbial growth show that the first mitochondrial endosymbionts could have easily doubled the host's available ATP pool, provided (i) that genes for growth on environmental amino acids were transferred from the mitochondrial symbiont to the archaeal host, and (ii) that the host for mitochondrial origin was an autotroph using the acetyl-CoA pathway. SIGNIFICANCE STATEMENT: Life is a chemical reaction. It requires energy release in order to proceed. The currency of energy in cells is adenosine triphosphate ATP. Five decades ago, microbiologists were able to measure and understand the amount of ATP that cells require to grow. New studies by evolutionary biologists have appeared in the meantime that brush aside the older microbiological findings, using their own methods to calculate the ATP cost of growth instead. Science is, however, an imperfect undertaking. The new studies contain a major error, similar to conflating centimeters with yards. The error affects many publications and their conclusions. Using the old methods, we can still meaningfully study the role of energy in evolution, including the origin of complex, nucleus-bearing cells.
    Keywords:  ATP costs; Bioenergetics; Costs of a gene; Energy in evolution; Eukaryogenesis; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149564
  50. Nat Genet. 2025 Jun 27.
      Mutations are often thought of as untargeted and non-adaptive, but in rare cases, organisms perform programmed, targeted and adaptive rearrangements of their own DNA sequences. Notable examples include the somatic diversification of immunoglobulin genes, which is the foundation of the vertebrate immune system, and natural CRISPR spacer arrays in bacteria, which recognize and cleave foreign DNA. These systems, along with a dozen known analogs scattered across the tree of life, often underlie critical biological functions, particularly in host-pathogen conflicts. In this Review, we compare the mechanisms by which organisms edit their own genomes. We show that superficially dissimilar editing systems often rely on surprisingly similar genetic mechanisms, regardless of function or taxon. Finally, we argue that the recurrence of editing in host-pathogen conflicts and the bias to a handful of well-studied organisms strongly suggest that new editing systems will be found in understudied pathogens and their hosts.
    DOI:  https://doi.org/10.1038/s41588-025-02230-1
  51. Trends Biochem Sci. 2025 Jun 20. pii: S0968-0004(25)00130-6. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1016/j.tibs.2025.05.010
  52. Nat Struct Mol Biol. 2025 Jun 25.
      The failure to clear dysfunctional mitochondria, cell death and inflammation have been linked in neurodegenerative disease, but their relationship and role in these conditions is not fully understood. Loss of Vps13d prevents clearance of mitochondria, and mutations in human VPS13D have been associated with neurological movement disorders. To investigate the relationship between mitochondrial health, inflammation and neurodegeneration, we created a conditional Vps13d-knockout mouse. Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration. Vacuolar protein sorting 13D (VPS13D) deficiency also caused mitochondrial ultrastructural defects and dysfunction in neurons followed by gasdermin E processing, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor (STING) signaling, microglial activation and cell death. Gasdermin E localization with mitochondria in Vps13d-mutant neurons was required for elevated extracellular mitochondrial DNA that promoted activation of microglia. Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model, indicating that microglia promote cell death in this model of neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s41594-025-01602-9
  53. Nat Cell Biol. 2025 Jun 27.
      Lipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)-PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.
    DOI:  https://doi.org/10.1038/s41556-025-01672-3
  54. Nat Cancer. 2025 Jun 27.
      Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR::ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a 'multipotency score' most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-025-00987-2
  55. Cell Host Microbe. 2025 Jun 13. pii: S1931-3128(25)00209-4. [Epub ahead of print]
      Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for controlling bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side product of glycolysis. We show that despite this toxicity, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system, including glyoxalase 1 (GLO1). Dampening methylglyoxal generation in mice resulted in enhanced survival of Listeria monocytogenes and Mycobacterium tuberculosis, whereas mice lacking Glo1 have increased methylglyoxal levels and improved infection control. Furthermore, bacteria unable to detoxify methylglyoxal (ΔgloA) exhibit attenuated virulence but are partially rescued in mice that cannot enter glycolysis and generate methylglyoxal. This loss of bacterial GloA results in up to a 1,000-fold greater genomic mutation frequency during infection. Collectively, these results suggest that methylglyoxal is an antimicrobial innate effector that defends against bacterial pathogens.
    Keywords:  bacterial pathogens; glycolysis; innate immunity; methylglyoxal
    DOI:  https://doi.org/10.1016/j.chom.2025.05.026
  56. Dev Cell. 2025 Jun 13. pii: S1534-5807(25)00327-2. [Epub ahead of print]
      Autophagosome formation involves multiple sequential steps that need to be coordinated and linked. Here, we describe in mammalian cells that the transferrin receptor (TfR) links LC3 family conjugation to phagophore membranes, an early step in autophagosome biogenesis, with subsequent autophagosome closure. TfR depletion impairs autophagic flux and its overexpression stimulates this catabolic process in an iron-independent manner. TfR is ubiquitinated by the ubiquitin ligase MARCH8 in the RAB11A-LC3B-positive membranes that are conjugated by LC3 family members from which phagophores emanate. Ubiquitinated TfR recruits the VPS34 component VPS15, enabling phosphatidylinositol 3-phosphate (PI(3)P) synthesis on nascent autophagosome membranes. This PI(3)P is not only important for LC3-lipid conjugation but also for subsequent phagophore closure, where TfR-dependent PI(3)P recruits the endosomal sorting complexes required for transport (ESCRT) complex. This TfR activity occurs after endocytosis of iron-containing transferrin, its canonical function, as TfR only binds VPS15 after iron detachment from transferrin that is enabled by pH lowering in the endocytic compartment.
    Keywords:  ESCRT complex; PI(3)P; autophagosome closure; autophagy; transferrin receptor
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.016
  57. Nat Aging. 2025 Jun 27.
      Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43587-025-00909-y