bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–03–08
37 papers selected by
Christian Frezza, Universität zu Köln
  1. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  2. Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
  3. Weighing in on the incretin revolution.
  4. Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.
  5. Tiny extracellular vesicles drive big feeding effects.
  6. Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
  7. Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
  8. A glucocorticoid-FAS axis controls immune evasion during metastatic seeding.
  9. Acidic niche sugar shield blocks ferroptosis.
  10. Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.
  11. Regulatory T cells thrive in ammonia-rich tumors.
  12. Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
  13. Inflammation-Driven Field Cancerization in End-Stage Kidney Disease.
  14. Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.
  15. Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
  16. Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
  17. Neutrophil-mediated anti-tumoral effects of caloric restriction.
  18. GCN2 in proteostasis: structural logic, signalling networks and disease.
  19. STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
  20. A shift in the cellular redox state redirects aspartate for export under glucose deprivation.
  21. Dietary restriction in aging and longevity.
  22. The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
  23. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  24. Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.
  25. A closed tumor-immune-brain circuit in cancer cachexia.
  26. Function and regulation of the mitochondrial stress response.
  27. Precancerous niche remodelling dictates nascent tumour persistence.
  28. Optically Detected Magnetic Resonance Based Intracellular Thermometry Using Nanodiamonds Implanted in Adherent Cancer Cells.
  29. Stress-hormone signalling protects spreading cancer cells from immune system.
  30. Harnessing genomics for early cancer detection, risk stratification and prevention.
  31. Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
  32. MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.
  33. Vγ1 γδ T cells steer airway macrophages toward a profibrotic response in an autochthonous lung cancer mouse model.
  34. Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice.
  35. Homologous recombination deficiency and hemizygosity drive resistance in breast cancer.
  36. Single-cell thiol profiling enabled by live-cell labeling reveals metabolic heterogeneity in ferroptosis.
  37. The molecular basis of force selectivity by PIEZO2.
  1. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  2. Nat Cell Biol. 2026 Mar 06.
    Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS-STING and Toll-like receptors 3 and 4.
    Alexis Betrancourt, M Talha Cinko, Ana Beatriz Varanda, Maykel Arias, Iratxe Uranga-Murillo, Natacha Peña, Lucia-Maria Kaps, Long Fung Chau, Bianca Buratti, Johannes Brägelmann, Diego de Miguel, Kerstin Becker, Ramona Casper, Rocio Martin, Antonio Alcami, Brian J Ferguson, Julian Pardo, Eva Rieser, Henning Walczak.
      Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-like receptor (TLR) 3, TLR4 and cyclic GMP-AMP synthase (cGAS), together with the stimulator of IFN genes (STING), signal through TANK-binding kinase 1 (TBK1), which activates the type-I/III IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remains unresolved. Here we show that lysine-11 (K11)-linked ubiquitination drives TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-STING-induced signalosomes. This facilitates Optineurin recruitment to these complexes, in turn enabling recruitment and activation of TBK1 and IRF3, defining an uncharacterized signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS-STING, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for ANKIB1-generated K11-linked ubiquitination in the immune response activated by cGAS-STING, TLR3 and TLR4.
    DOI:  https://doi.org/10.1038/s41556-026-01886-z
  3. Nat Metab. 2026 Mar 04.
    Weighing in on the incretin revolution.
      
    DOI:  https://doi.org/10.1038/s42255-026-01490-3
  4. Nat Commun. 2026 Mar 06. pii: 1655. [Epub ahead of print]17(1):
    Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.
    S Kourtis, A Gañez Zapater, C R Elbæk, A Schmidt, R Ghose, A Coll Manzano, L Espinar Calvo, M Guirola, N Pardo-Lorente, M Garcia-Cao, M Pfeiffer, S Haynes, F Fontaine, A Müller, S Sdelci.
      Metabolic and epigenetic rewiring are hallmarks of cancer, with increasing evidence suggesting crosstalk between these processes. While previous studies have hinted at the role of metabolic enzymes in the nucleus, the extent and functional relevance of their nuclear localization remain unclear. In this study, we present a comprehensive chromatome proteomic analysis across cancer lineages and healthy samples, revealing that metabolic enzyme moonlighting on chromatin is widespread across various tissues and metabolic pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins notably depleted in lung cancer, suggesting a link between nuclear metabolism and cell identity. Further, we explore the dynamic chromatin association of one-carbon folate enzymes, demonstrating their involvement in DNA damage and repair processes. Finally, we asked whether restricting metabolic enzymes to specific subcellular compartments rewires the transcriptome, thereby decoupling the observed transcriptional changes from mere metabolite diffusion. Our findings propose and validate novel non-canonical nuclear roles for several metabolic enzymes, providing new insights into the functional relationship between metabolism and chromatin regulation. This study underscores the hypothesis that the nucleus is populated by metabolic enzymes, offering new avenues for understanding how nuclear metabolism impacts chromatin function and cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-69217-2
  5. Nat Metab. 2026 Mar 05.
    Tiny extracellular vesicles drive big feeding effects.
    Khadija Khan, Clair Crewe.
      
    DOI:  https://doi.org/10.1038/s42255-026-01472-5
  6. Nat Commun. 2026 Mar 05.
    Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
    Injae Chung, Caroline S Pereira, John J Wright, Guilherme M Arantes, Judy Hirst.
      Respiratory complex I is a multi-subunit energy-transducing membrane enzyme essential for mitochondrial and cellular energy metabolism. It couples NADH oxidation and ubiquinone-10 (Q10) reduction to the concomitant pumping of four protons to generate the proton-motive force that powers oxidative phosphorylation. Despite recent advances in structural knowledge of complex I, many mechanistic aspects including the reactive binding poses of Q10, how Q10 reduction initiates the proton transfer cascade, and how protons move through the membrane domain, remain unclear. Here, we use electron cryomicroscopy to determine structures of mammalian complex I, reconstituted into phospholipid nanodiscs containing exogenous Q10 and reduced by NADH, to global resolutions of 2.0 to 2.6 Å. Two conformations of a reduced Q10H2 molecule are observed, fully inserted into the Q-binding channel in the turnover-relevant closed state. By comparing the quinone species bound in oxidised and reduced complex I structures, paired with molecular dynamics simulations to investigate the charge states of key surrounding residues, we propose a series of substrate binding poses that Q10 transits through for reduction. Our highly hydrated structures exhibit near-continuous proton-transfer connections along the length of the membrane domain, enabling comparisons between them to assist in identifying the proton-transfer control points that are essential to catalysis.
    DOI:  https://doi.org/10.1038/s41467-026-70030-0
  7. Life Sci Alliance. 2026 May;pii: e202503602. [Epub ahead of print]9(5):
    Bridging nanomechanics and bioenergetics of single mitochondria by atomic force microscopy.
    Ekaterina O Zorikova, Sabita Chourasia, Irit Rosenhek-Goldian, Sidney R Cohen, Semen V Nesterov, Atan Gross.
      Mitochondria orchestrate energy conversion and cell fate, yet label-free approaches that report both functional and physical states at the single-organelle level are nonexistent. Here, we combine atomic force microscopy (AFM) imaging with single-mitochondrion phenotyping by quantifying stiffness, height, and spontaneous low-frequency height fluctuations at the nanoscale. Across respiratory activators, inhibitors, and uncouplers, the integrated 0- to 20-Hz fluctuation power correlates with mitochondrial membrane potential (ΔΨm) and does not covary with changes in mitochondrial height (a proxy for swelling). In liver mitochondria lacking mitochondrial carrier homolog 2 (MTCH2), a regulator of mitochondrial metabolism, dynamics, and apoptosis, AFM reveals a compact, mechanically stiff, high-fluctuation state consistent with hyperpolarization and distinct from inhibited/uncoupled signatures. Extending the assay to mitochondria isolated from mouse embryonic fibroblasts, AFM data can distinguish between genotypes: loss of the mitochondrial pro-fusion proteins mitofusin 1 or 2 (MFN1 or MFN2) yields stiff, low-fluctuation mitochondria with reduced ΔΨm, whereas MTCH2 loss produces stiff, high-fluctuation, high-ΔΨm mitochondria. These three label-free features provide reproducible single-organelle "fingerprints" that resolve bioenergetic states and molecular defects and complement fluorescence and respirometry.
    DOI:  https://doi.org/10.26508/lsa.202503602
  8. Nature. 2026 Mar 04.
    A glucocorticoid-FAS axis controls immune evasion during metastatic seeding.
    Monica Cassandras, Xavier Sanchez, Lauren Hsu, Yu Huang, Adam J Getzler, Debolina Ganguly, Pilar Baldominos, Ia Codinachs, Jeffrey Chuong, Elizabeth E Martin, Blake E Smith, Eleonora Marina, Milos Spasic, Xingping Qin, Heather A Parsons, Erica L Mayer, Kristopher A Sarosiek, Stephanie K Dougan, Elizabeth A Mittendorf, Sandra S McAllister, Ya-Chieh Hsu, Judith Agudo.
      Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.
    DOI:  https://doi.org/10.1038/s41586-026-10222-2
  9. Nat Cell Biol. 2026 Mar 05.
    Acidic niche sugar shield blocks ferroptosis.
    Mario Palma, Jessalyn M Ubellacker.
      
    DOI:  https://doi.org/10.1038/s41556-026-01899-8
  10. Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00106-6. [Epub ahead of print]
    Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.
    Marco Campisi, Tatsuya Osaki, Ian Dryg, Carla Stornante, Jacqueline Wolff, Jason Weirather, Nicholas Weaver, Mubin Tarannum, Ian Gillanders, Alan Bers, Eden Bobilev, Maia S Lineberry, Pieter Schol, Minyue Chen, Keiichi Ota, Sung R Park, Caroline G Fahey, Tran C Thai, Yixiang Li, Zhaorong Li, Ze-Hua Li, Sarah Shelton, Satomi Hirose, Clare Padrick, Elena Ivanova, Minh Ha, Shaobo Yang, Harrison Olszewski, Sophie Kivlehan, Patrick Lizotte, Kelsey Hagen, Iliana Gjeci, William Haller, Lauren M Zasadil, Talal El Zarif, Jacob E Berchuck, Erik H Knelson, Elliott J Brea, Igor Odintsov, Tianju Liu, Valeria Chiono, Bishma Tuladhar, Kenneth Ngo, Emily Rosentrater, Jeffrey Raizer, Neil Lineberry, Mriganka Sur, Kathleen Pfaff, Matthew Freedman, F Stephen Hodi, Michael Y Tolstorukov, Matthew G Oser, Michal Sheffer, Constantine S Mitsiades, Michael J Barnes, Vicky A Appleman, Prafulla C Gokhale, Roger D Kamm, Cloud P Paweletz, Rizwan Romee, Scott Rodig, David A Barbie, Navin R Mahadevan.
      Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-Ilow/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.
    Keywords:  3D microphysiological systems; STING agonism; natural killer cells; small cell lung cancer; spatial transcriptomics and proteomics; tumor-immune microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.008
  11. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00046-X. [Epub ahead of print]38(3): 447-448
    Regulatory T cells thrive in ammonia-rich tumors.
    Chenxian Ye, Greg M Delgoffe.
      In a recent issue of Cell, Gu et al. find that regulatory T (Treg) cells metabolize tumor-derived ammonia via the urea cycle and spermine synthesis, promoting immunosuppression through PPARγ-dependent oxidative phosphorylation. Inhibition of tumor glutamine metabolism reduces ammonia levels and overcomes Treg cell-mediated resistance to anti-PD-1 therapy.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.003
  12. Nat Commun. 2026 Mar 06. pii: 2244. [Epub ahead of print]17(1):
    Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
    Hongli Zhang, Zixuan Wang, Yiqi Zhao, Xiya Deng, Jian Zhang, Fei Shang, Hongjie Zhang, Yan Liu, Hongbo Wang, Yating Yang, Huiyu Lin, Bo Zhang, Ce Liu, Fan Guo, Ruolin Zhang, Qipeng Yuan, Yue Feng, Shi-Zhong Luo, Wei-Dong Chen, Yan-Dong Wang.
      Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.
    DOI:  https://doi.org/10.1038/s41467-026-70112-z
  13. Cancer Discov. 2026 Mar 02. 16(3): 426-427
    Inflammation-Driven Field Cancerization in End-Stage Kidney Disease.
    Rebecca A Sager, Katalin Susztak, A Ari Hakimi.
      In this issue, Takahashi, Tanaka, and colleagues provide a comprehensive genomic, transcriptomic, and spatial analysis of renal cell carcinomas (RCC) associated with end-stage renal disease. They demonstrate that the clonal expansion of a subset of proximal tubule cells, supported by an inflammatory microenvironment, gives rise to the cysts of acquired cystic kidney disease as well as to acquired cystic disease-associated RCC. See related article by Takahashi et al., p. 478.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2276
  14. Cell Rep. 2026 Mar 05. pii: S2211-1247(26)00139-7. [Epub ahead of print]45(3): 117061
    Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.
    Garrett F Beeghly, Irina Kopyeva, Jenny Deng, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.
      Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to insufficient experimental approaches to control for cell size. Here, we establish methods to culture large and small primary adipocytes isolated from the same adipose depot, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size-rather than body weight-drives distinct phenotypic cell states. Notably, large adipocytes increase extracellular vesicle-mediated lipid release. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression.
    Keywords:  CP: cancer; CP: metabolism; adipocyte; adipose tissue; breast cancer; extracellular vesicles; hypertrophy; lipid metabolism; obesity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117061
  15. Biomed Pharmacother. 2026 Mar 02. pii: S0753-3322(26)00159-9. [Epub ahead of print]197 119127
    Fumarate loss destabilizes mitochondria and activates cGAS-STING in OLP.
    Yanxing Hu, Huyan Chen, Chenyun Ding, Shengbo Zhang, Qing Chen, Hongying Sun, Qiaozhen Yang.
      Mitochondrial metabolism and innate immune signaling are increasingly recognized as intersecting pathways in chronic inflammatory disease. Here, we identify a metabolically driven mechanism linking the TCA cycle imbalance to mucosal inflammation in oral lichen planus (OLP). Multi-omics analysis revealed that fumarate hydratase (FH) is upregulated in OLP tissues and cells, leading to significant fumarate depletion. This metabolic shift induces mitochondrial dysfunction, characterized by enhanced oxidative phosphorylation, proton leak, and TFAM downregulation. These changes destabilize the mitochondrial genome, promote mtDNA leakage into the cytosol, and activate the cGAS-STING pathway, resulting in TBK1-IRF3- NF-κB -driven inflammatory responses. Genetic knockdown of FH or pharmacological supplementation with monomethyl fumarate (MMF) restored mitochondrial homeostasis, prevented mtDNA release, and attenuated immune activation. Furthermore, depletion of mtDNA using 2',3'-dideoxycytidine (ddC) validated the essential role of mtDNA in sustaining cGAS-STING dependent inflammation. Co-treatment with fumarate further suppressed cytosolic mtDNA and enhanced repression of innate signaling. These findings uncover a functional FH-fumarate-mtDNA-cGAS-STING axis in OLP and reveal fumarate as a key metabolic modulator of mitochondrial immune surveillance. Our work provides conceptual and therapeutic insight into the role of mitochondrial metabolism in non-infectious mucosal inflammation.
    Keywords:  Citric acid cycle; DNA; Fumarate hydratase; Inflammation; Lichen planus; Mitochondrial; Mitochondrial diseases; Oral
    DOI:  https://doi.org/10.1016/j.biopha.2026.119127
  16. Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627
    Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
    Akriti Prashar, Rosa Puertollano.
      Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102627
  17. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00047-1. [Epub ahead of print]38(3): 443-444
    Neutrophil-mediated anti-tumoral effects of caloric restriction.
    Chin Sern Yiong, Melissa Shu Feng Ng.
      Caloric restriction confers several benefits in cancer, but the underlying mechanisms are not understood. In this issue of Cell Metabolism, Gao et al. highlight a newly identified neutrophil-dependent pathway modulated by caloric restriction.1.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.004
  18. FEBS J. 2026 Mar 04.
    GCN2 in proteostasis: structural logic, signalling networks and disease.
    JiaYi Zhu, Stefan J Marciniak.
      Proteostasis is the finely tuned balance of protein synthesis, folding and degradation essential for cellular health. When this equilibrium is disrupted, misfolded proteins accumulate, triggering adaptive stress responses such as the unfolded protein response and the integrated stress response (ISR). Central to the ISR is the kinase GCN2, a sensor of amino acid deprivation and ribosomal stress. Upon activation, GCN2 phosphorylates eIF2α, dampening global translation while selectively enhancing the synthesis of the stress-responsive transcription factors ATF4 and CHOP. ATF4 orchestrates a broad transcriptional programme that supports amino acid metabolism, redox homeostasis, autophagy and proteasomal degradation, which are key processes for restoring proteostasis. Beyond its canonical role, GCN2 interfaces with other regulatory networks modulating mTORC1 to promote autophagic clearance of damaged proteins and organelles, facilitating stress granule formation, and integrating signals from oxidative and endoplasmic reticulum stress to rebalance the proteome. Dysregulated GCN2 activity has been implicated in diverse pathologies including neurodegeneration, cancer and pulmonary vascular disease, positioning it as a promising therapeutic target. In this review, we explore how GCN2 links nutrient sensing to translational control and metabolic adaptation, and how its central role in proteostasis may inform new strategies for treating diseases driven by protein misfolding and stress pathway imbalance.
    Keywords:  GCN2; amino acid sensing; integrated stress response; proteostasis; translational control
    DOI:  https://doi.org/10.1111/febs.70480
  19. Nat Commun. 2026 Mar 06.
    STIM1-Mitofusin2 interactions tether mitochondria and melanosome contacts that promote melanosome maturation.
    Isshin Shiiba, Yuto Ishikawa, Hijiri Oshio, Naoki Ito, Fuya Yamaguchi, Shun Nagashima, Hideya Ando, Keitaro Umezawa, Yuri Miura, Yuhei Araiso, Koki Nakamura, Yusuke Hirabayashi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondria form contact sites with multiple organelles to coordinate diverse cellular processes. Melanosomes, lysosome-related organelles, undergo stepwise maturation to synthesize and store melanin, but how they interact with mitochondria remains unclear. Here we show that mitochondria-melanosome contacts dynamically increase during melanosome maturation and are mediated by STIM1-MFN2 interactions. Using a NanoBiT-based reporter system, MiMSBiT (Mitochondria-Melanosome contact reporter applying NanoBiT), to monitor reversible mitochondria-melanosome contacts in living cells, we demonstrate that STIM1 localizes to melanosomes and promotes their contact with mitochondrial MFN2. A transient decrease in melanosomal lumen calcium induces STIM1 clustering and enhances its association with MFN2. These contacts locally increase mitochondrial ATP availability, leading to melanosome lumen acidification via proton channel activation. This acidification facilitates PMEL fibrillation, a key step in melanosome maturation. Together, our findings reveal a mechanism by which mitochondria-melanosome contacts regulate melanosome maturation.
    DOI:  https://doi.org/10.1038/s41467-026-70282-w
  20. Cancer Metab. 2026 Mar 03. pii: 4. [Epub ahead of print]14(1):
    A shift in the cellular redox state redirects aspartate for export under glucose deprivation.
    Barbara Konrad, Gabriele Bluemel, Theresa Haitzmann, Tobias Frech, Anke Vandekeere, Mélanie Planque, Visnja Bubalo, Katharina Schindlmaier, Vanessa Jäger, Michael A Dengler, Sarah Stryeck, Luka Brcic, Jörg Lindenmann, Philipp Stiegler, Doruntina Bresilla, Corina T Madreiter-Sokolowski, Tobias Madl, Thomas O Eichmann, Nikolaus Kneidinger, Sarah-Maria Fendt, Katharina Leithner.
      
    Keywords:  Adaptation; Aspartate; Aspartic acid; Cancer; Glucose deprivation; Metabolism
    DOI:  https://doi.org/10.1186/s40170-026-00420-x
  21. Nat Aging. 2026 Mar 06.
    Dietary restriction in aging and longevity.
    Tomas Schmauck-Medina, Sofie Lautrup, Andrea Di Francesco, Sarah J Mitchell, Christoffer Clemmensen, Linda Partridge, George S Roth, Rozalyn M Anderson, Julie A Mattison, Rafael de Cabo, John R Speakman, Arlan Richardson, Donald K Ingram, Richard Weindruch, Mark P Mattson, Evandro F Fang.
      Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.
    DOI:  https://doi.org/10.1038/s43587-026-01091-5
  22. Nat Aging. 2026 Mar 06.
    The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
    Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.
      Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01087-1
  23. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  24. Nat Metab. 2026 Mar 03.
    Early-activated extracellular matrix proteins shape the metabolic and spatial dynamics of the kidney fibrotic microenvironment.
    Yuan Gui, Wenxue Li, Jia-Jun Liu, Yuanyuan Wang, Cameron Jones, Riddhi Bansal, Samantha Mae Mallari, Henry Wells Shaffer, Yanbao Yu, Haiyan Fu, Tracy T Tang, Silvia Liu, Yansheng Liu, Dong Zhou.
      The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP-TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.
    DOI:  https://doi.org/10.1038/s42255-026-01458-3
  25. Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00105-4. [Epub ahead of print]
    A closed tumor-immune-brain circuit in cancer cachexia.
    Felix Clemens Richter, Joel Xu En Wong, Andreas Bergthaler.
      Cancer-associated cachexia is a complex metabolic syndrome leading to sustained body weight loss and tissue wasting. In this issue of Cancer Cell, Shi et al. identify a novel GDF15-driven tumor-immune-brain crosstalk, resulting in altered systemic metabolism and tissue catabolism.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.007
  26. Nat Struct Mol Biol. 2026 Mar 05.
    Function and regulation of the mitochondrial stress response.
    Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.
      As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.
    DOI:  https://doi.org/10.1038/s41594-026-01769-9
  27. Nature. 2026 Mar 04.
    Precancerous niche remodelling dictates nascent tumour persistence.
    G Skrupskelyte, J E Rojo Arias, H Ajith, Y Dang, D Rossetti, S Han, M K S Tang, M T Bejar, B Colom, J C Fowler, K Murai, W Knight, D Aust, M H H Schmidt, J Jászai, S Zeki, A Noorani, P H Jones, S Rulands, B D Simons, M P Alcolea.
      Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1-3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
    DOI:  https://doi.org/10.1038/s41586-026-10157-8
  28. ACS Appl Nano Mater. 2026 Feb 27. 9(8): 3590-3596
    Optically Detected Magnetic Resonance Based Intracellular Thermometry Using Nanodiamonds Implanted in Adherent Cancer Cells.
    John C Consiglio, Rostislav Boltyanskiy, Yuliya L Mindarava, Christian Laube, Wolfgang Knolle, Marjan Berishaj, Fedor Jelezko, Kayvan R Keshari.
      Intracellular temperature influences cell metabolism and the tumor microenvironment, but there is a lack of consensus on basic thermal properties of cells and a shortage of reliable measurement tools. We utilized nanodiamonds (NDs) containing fluorescent Nitrogen Vacancy centers (NVs) implanted in glioblastoma cells to measure intracellular temperature via Optically Detected Magnetic Resonance (ODMR) and used dual fluorescence and bright-field imaging to establish ND-mitochondria distances. Careful ND selection, improved curve fitting, and time averaging enable repeatable measurement of cellular responses. Upon mitochondrial uncoupling with 5 μM FCCP, we reproducibly observed ODMR shifts consistent with an ∼1.7 °C temperature increase.
    Keywords:  Intracellular thermometry; NV-center; glioblastoma; metabolism; nanodiamonds; optically detected magnetic resonance; quantum sensing
    DOI:  https://doi.org/10.1021/acsanm.5c05655
  29. Nature. 2026 Mar 04.
    Stress-hormone signalling protects spreading cancer cells from immune system.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-00650-5
  30. Nat Genet. 2026 Mar 02.
    Harnessing genomics for early cancer detection, risk stratification and prevention.
    Muxin Gu, Woody Z Zhang, Rebecca C Fitzgerald, Alexander M Frankell, George S Vassiliou.
      Therapeutic advances have improved cancer outcomes, but early-stage detection remains the single most important determinant of favorable prognoses across many cancer types. Cancer genomics has yielded detailed maps of somatic mutation and methylation patterns characteristic of different cancers, enabling the development of assays to detect mutation-bearing tumor-derived DNA in tissue biopsies, blood and other body fluids at the earliest stages of disease. In parallel, it has also become clear that small clones bearing cancer-associated mutations arise commonly in histologically normal tissues, a phenomenon that becomes universal in proliferative tissues with age but leads to cancer in only a small minority of individuals. This review article outlines established strategies for early cancer detection and highlights emerging insights into the genetics of precancerous mutant clones that have led to the recent development of prognostic frameworks for identifying high-risk individuals, making it increasingly possible to intercept evolving cancer at a premalignant or early malignant stage, when interventions are most effective.
    DOI:  https://doi.org/10.1038/s41588-026-02505-1
  31. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2516372123
    Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
    Ethan Levien, Joon Ho Kang, Kuheli Biswas, Scott R Manalis, Ariel Amir, Teemu P Miettinen.
      Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size homeostasis from bacteria to cancer. It remains unclear whether this variability arises from stochasticity in cell growth or division processes, or from cell-size-dependent growth regulation. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along long ancestral lineages. We first show that correlations between growth rates and cell-size nor asymmetric divisions explain cell-to-cell growth variability. We then isolate growth fluctuations by smoothing and detrending the growth rate dynamics using a Gaussian process regression. We find that these growth fluctuations drive cell-to-cell growth variability within ancestral lineages despite being independent of cell divisions, cell cycle, and cell size. Overall, our results provide a quantitative framework for understanding single-cell growth rates, and indicate that cell-intrinsic long-term patterns in growth are a byproduct of short-term growth fluctuations.
    Keywords:  cell divisions; cell growth; cell size; cellular noise; heterogeneity
    DOI:  https://doi.org/10.1073/pnas.2516372123
  32. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2524659123
    MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.
    Erin L Ramsey, Stephanie Dobersch, Brian Freie, Nan Hyung Hong, Xiaoying Wu, Sita Kugel, Robert N Eisenman, Patrick A Carroll.
      MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of messenger RNA (mRNA). MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Reestablishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Last, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.
    Keywords:  MYC network; MondoA inhibitor; MondoA/MLXIP; pancreatic cancer; stress response
    DOI:  https://doi.org/10.1073/pnas.2524659123
  33. Sci Adv. 2026 Mar 06. 12(10): eadu8802
    Vγ1 γδ T cells steer airway macrophages toward a profibrotic response in an autochthonous lung cancer mouse model.
    Ximena L Raffo-Iraolagoitia, Amanda J McFarlane, Sarah Laing, Ryan Corbyn, Lindsey W G Arnott, Frédéric Fercoq, Lynn McGarry, Judith Secklehner, Marco De Donatis, John B G Mackey, Bjorn Kruspig, Robert Wiesheu, Ya-Ching Hsieh, Robin Shaw, Kai Rakovic, John Le Quesne, Graeme Clark, Colin Nixon, Crispin Miller, Kristina Kirschner, Calum C Bain, Daniel J Murphy, Seth B Coffelt, Leo M Carlin.
      γδ T cells are important for host defense at the respiratory mucosa, acting directly or through interactions with other cells. However, how γδ T cells influence other immune cells in the lung remains unclear. Using a genetically engineered mouse model of lung cancer, we show that tumors drive expansion of both CD27+ and CD27- γδ T cells. Advanced microscopy techniques indicated that CD27- γδ T cells are enriched in tumors, whereas CD27+ γδ T cells are more prone to interact with macrophages in tumor-associated adventitial cuffs. SiglecFlow profibrotic airway macrophages were more prevalent in lung tumor-bearing mice than tumor-free mice. This profibrotic subset was reduced in lungs when the cancer model was crossed to Tcrd knockout mice or treated with Vγ1-depleting antibodies but not in TcrgV4/6 knockout mice. Thus, our findings implicate Vγ1 γδ T cells in driving tumor-associated airway macrophage functional imprinting. Determining the translatability to human health may offer new avenues for refining patient management and immunotherapeutic strategies.
    DOI:  https://doi.org/10.1126/sciadv.adu8802
  34. Cell. 2026 Mar 04. pii: S0092-8674(26)00103-0. [Epub ahead of print]
    Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice.
    Haijiao Zhao, Meimei Liao, Ran Huo, Ting He, Hongni Tian, Zeqi Li, Chen Chen, Ziqing Yu, Juan Chai, Xiaocui Song, Ruichao Shao, Shuhua Ying, Wen Gao, Ling Liu, Di Sang, Qi Li, Haohong Li, Fengchao Wang, Dapeng Ju, Eric Erquan Zhang.
      Age-related circadian disruptions accelerate physiological decline and shorten lifespan. Enhancing circadian amplitude has emerged as a promising strategy for ameliorating age-associated disorders. Here, we show that the circadian-phase-optimized administration of 3'-deoxyadenosine (3dA) strengthens circadian amplitude in hypothalamic paraventricular nucleus (PVN) neurons, mitigates aging biomarkers, and extends mouse lifespan. 3dA restores clock synchrony and hormonal rhythms, including corticosterone, and reduces epigenetic age as measured by DNA methylation clocks. Transcriptomic, hormonal, and epigenetic profiling reveal robust increases in PVN circadian amplitude following timed 3dA administration, and the PVN-specific knockout of RuvB-like ATPase 2 (Ruvbl2) establishes its genetic necessity by abolishing 3dA's benefits. Similarly, chemogenetic PVN activation reproduces 3dA's metabolic and physiological benefits. These findings identify the PVN clock as a pharmacological node linking circadian amplitude to organismal aging, suggest that targeting RUVBL2-dependent circadian transcription enhances network synchrony, and indicate that circadian interventions are promising therapeutic candidates for delaying aging and improving healthspan in aged male mice.
    Keywords:  3′-deoxyadenosine; RUVBL2; aging; amplitude enhancement; circadian rhythms; paraventricular nucleus
    DOI:  https://doi.org/10.1016/j.cell.2026.01.016
  35. Nature. 2026 Mar 04.
    Homologous recombination deficiency and hemizygosity drive resistance in breast cancer.
    Anton Safonov, Minna Lee, David N Brown, Luca Boscolo Bielo, Miika Mehine, Chaitanya Bandlamudi, Ben O'Leary, Hong Shao, Laia Vicente, Daniel Muldoon, Allen Zhu, Susana Ros, Antonio Marra, Pier Selenica, Ivan Bieche, Bradley Wubbenhorst, Emanuela Ferraro, Laura Courtois, Rania El Botty, Mehnaj Ahmed, Enrico Moiso, Julia Ah-Reum An, Mark T A Donoghue, Marie Will, Fresia Pareja, Emily Nizialek, Natalia Lukashchuk, Eleni Sofianopoulou, Yuan Liu, Xin Huang, Colombe Chappey, Anna D Staniszewska, Dara Ross, Diana Mandelker, Marc Ladanyi, Nikolaus Schultz, Michael F Berger, Maurizio Scaltriti, Jorge S Reis-Filho, Bob T Li, Kenneth Offit, Larry Norton, Ronglai Shen, Kara N Maxwell, Fergus Couch, Susan M Domchek, Elisabetta Marangoni, Sohrab Shah, Mark R Albertella, Violeta Serra, Britta Weigelt, David B Solit, Katherine L Nathanson, Mark E Robson, Nicholas C Turner, Sarat Chandarlapaty, Pedram Razavi.
      The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, yet their combined influence on tumour evolution and therapy resistance remains poorly defined. Through an integrated clinicogenomic analysis of more than 5,800 patients, we show that germline (g) pathogenic variants dictate the evolutionary trajectory of acquired resistance. We specifically find that gBRCA2-associated tumours are uniquely predisposed to develop acquired RB1 loss-of-function alterations, resulting in poor outcomes on standard-of-care frontline CDK4/6 inhibitor (CDK4/6i) combinations. This vulnerability is driven by a dual mechanism: baseline RB1 hemizygosity (heterozygous loss resulting in a single functional RB1 allele), which lowers the evolutionary barrier to biallelic inactivation, and ongoing homologous recombination deficiency, which promotes acquisition of RB1 loss-of-function alterations under the selective pressure of CDK4/6i. Preclinical models from gBRCA2 carriers showed near-uniform resistance to CDK4/6i, with consistent post-treatment Rb loss. Across multiple independent models and in our clinical data, PARP inhibition consistently outperformed CDK4/6i. Our findings suggest that prioritizing PARP inhibition in gBRCA2 carriers may intercept RB1-loss trajectories and delay resistance. More broadly, we establish a predictive framework for forecasting drug-resistant trajectories based on pre-treatment allelic configuration and mutational signatures.
    DOI:  https://doi.org/10.1038/s41586-026-10197-0
  36. Nat Commun. 2026 Mar 03.
    Single-cell thiol profiling enabled by live-cell labeling reveals metabolic heterogeneity in ferroptosis.
    Daiyu Miao, Qiuning Li, Yi Zhang, Shaojie Qin, Ying Wang, Xiaoyun Liu, Yu Bai.
      Thiols serve indispensable biochemical functions across catalysis, redox homeostasis and energy metabolism. However, profiling multiple thiols at the single-cell level remains challenging due to their trace amount and susceptibility to oxidation. Herein, we report an integrated strategy for thiol profiling at the single-cell level which combines live-cell labeling with organic mass cytometry. The live-cell labeling strategy facilitates the comprehensive measurement of intrinsic thiols with expanded coverage and improved sensitivity, while organic mass cytometry enables simultaneous quantification of 27 labeled thiols and 355 other metabolites from single cells. Assessment of metabolic fluctuation upon stimulation demonstrates practicability and accuracy of this integrated methodology which is capable of pathway activity monitoring, metabolic network mapping and untargeted metabolome profiling. Further application of this method in investigating RSL3-triggered ferroptosis reveals that RSL3 inhibits glutathione synthesis via nuclear factor E2-related factor 2- glutathione axis and results in heterogenous glutathione metabolism between subtypes.
    DOI:  https://doi.org/10.1038/s41467-026-70336-z
  37. Nature. 2026 Mar 04.
    The molecular basis of force selectivity by PIEZO2.
    Eric M Mulhall, Oleg Yarishkin, Rose Z Hill, Anna K Koster, Ardem Patapoutian.
      PIEZOs are mechanically gated ion channels that transduce force into electrochemical signals1. PIEZO1 responds to diverse stimuli including membrane stretch2 and shear stress3, whereas PIEZO2 is generally tuned to detect cellular indentation4,5. The functional specialization of PIEZO2 is proposed to underlie its distinct physiological roles, including mediating the sense of touch6,7. How PIEZO2 achieves this selectivity despite its close structural similarity to PIEZO1 is unclear. Here we combine single-molecule MINFLUX fluorescence nanoscopy with electrophysiology to link the conformational states of PIEZO2 to channel gating in intact cells. We find that PIEZO2 is intrinsically more rigid than PIEZO1, and that disparate mechanical stimuli paradoxically evoke opposite conformational and gating responses in each channel. These unique gating properties arise in part from a connection to the actin cytoskeleton, and we identify filamin-B (FLNB) as a molecular tether that is required for this interaction. This complex alters how force is transmitted to PIEZO2 and confers heightened sensitivity to and selectivity for cellular indentation. PIEZO2 and FLNB are co-expressed in somatosensory neurons and colocalize within tens of nanometres at the end organs of cutaneous mechanosensory afferents. These findings help to explain why PIEZO2 is a specialized mechanosensor and provide a molecular blueprint for understanding how cells decode diverse mechanical stimuli across tissues and organ systems.
    DOI:  https://doi.org/10.1038/s41586-026-10182-7
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒08 at 5:48.