bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–04–05
sixty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Sulfur partitioning from cysteine controls T cell proliferation and effector function.
  2. MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
  3. Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
  4. ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas.
  5. Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
  6. Mitochondrial genomes on a string of pearls.
  7. The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.
  8. NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
  9. Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
  10. Single-cell spatial atlas of the aging human breast.
  11. Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway.
  12. Metabolism modulates stress and neoplasia.
  13. Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
  14. DNA damage burden causes selective CUX2 neuron loss in neuroinflammation.
  15. A splicing factor's unexpected detour to the mitochondrial surface.
  16. Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.
  17. The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
  18. Mitochondria power immunity against cancer.
  19. Specialized high-capacity mitochondria fuel cell invasion.
  20. Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability.
  21. Why selection for mitochondrial quality drives the evolution of sexes.
  22. Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
  23. Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer.
  24. The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice.
  25. High-fat diet causes rapid loss of intestinal group 3 innate lymphoid cells through microbiota-driven inflammation and mitochondrial stress.
  26. A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy.
  27. Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
  28. U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
  29. Epigenetic remodeling induced by fatty acids: Chromatin modifications and cellular senescence during lipid overload.
  30. Pearling drives mitochondrial DNA nucleoid distribution.
  31. Protein lactylation: a metabolic signal driving cancer therapy resistance.
  32. HR3/RORα-mediated cholesterol sensing regulates TOR signaling.
  33. Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.
  34. Cellular and spatial remodeling of aging breast tissue revealed.
  35. Precision from broad strokes: How the non-specific interactions of metabolites and macromolecules can regulate biology.
  36. Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.
  37. Microscopy in mitochondrial research - a comprehensive review.
  38. Unexpected role of the integrated stress response in cancer immune evasion.
  39. Metastasis as a Multiorgan Disease: Toward Organ-Informed Precision Oncology.
  40. Intercompartmental communication in senescence.
  41. Mitonuclear dynamics in unisexual vertebrates.
  42. Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
  43. The functional importance of mitochondrial sequences with dual functions: overlapping protein-protein and protein-RNA gene sequences as test cases.
  44. Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
  45. Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion.
  46. Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
  47. Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
  48. Redefining cancer drivers with tissue-specific context.
  49. NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.
  50. Whole-body molecular and cellular mapping of the laboratory mouse.
  51. The lipid transfer protein STARD7 controls intestinal tumor development in a context-dependent manner.
  52. Sensitivity of genome-wide tests for mitonuclear genetic incompatibilities.
  53. Memory T cell aging and rejuvenation.
  54. Single-cell phenotypic heterogeneity shapes quorum signaling dynamics in Pseudomonas aeruginosa.
  55. The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
  56. The case for space as a model of accelerated aging.
  57. Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
  58. Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication.
  59. Sexual dimorphism shapes renal metabolic adaptation to a ketogenic diet.
  60. Single-cell and spatial profiling in cancer biology and clinical oncology.
  61. Single-cell spatial transcriptomics reveals tumor microenvironment heterogeneity in primary and lymph node-metastatic small cell lung cancer.
  62. Tetraploids or polyploid giants: who is truly dangerous?
  1. Cell. 2026 Mar 31. pii: S0092-8674(26)00279-5. [Epub ahead of print]
    Sulfur partitioning from cysteine controls T cell proliferation and effector function.
    Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Isha Maloo, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, Joseph Longo, Lisa M DeCamp, Eric H Ma, Ryan D Sheldon, Russell G Jones, David E Sanin, Ananya Majumdar, Erika L Pearce.
      Delineating how acquired nutrients are partitioned into different intracellular pathways and how these various fates support distinct functions in T cells is limited. We show that CD8+ T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8+ T cells promotes exhaustion and dampens anti-cancer immunity, whereas blocking cysteine flux into GSH or enforcing FeS metabolism enhances tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human hepatocellular carcinoma. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain the beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.
    Keywords:  CD8+ T cells; Fe-S clusters; T cell exhaustion; anti-tumor immunity; cysteine; glutathione; immunometabolism; iron uptake; lipid peroxidation; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2026.03.012
  2. Nat Struct Mol Biol. 2026 Apr 01.
    MitoPerturb-Seq identifies gene-specific single-cell responses to mitochondrial DNA depletion and heteroplasmy.
    Stephen P Burr, Kathryn Auckland, Angelos Glynos, Abhilesh Dhawanjewar, Cameron Ryall, Wei Wei, Antony Hynes-Allen, Malwina Prater, Matylda Sczaniecka-Clift, Julien Prudent, Patrick F Chinnery, Jelle van den Ameele.
      Mitochondria contain their own genome, mitochondrial DNA (mtDNA), which is under strict control by the cell nucleus. mtDNA occurs in many copies per cell and mutations often only affect a proportion of them, giving rise to heteroplasmy. mtDNA copy number and heteroplasmy level together shape the tissue-specific impact of mtDNA mutations, eventually giving rise to both rare mitochondrial and common neurodegenerative diseases. Here, we use MitoPerturb-Seq for CRISPR-Cas9-based, high-throughput single-cell interrogation of the nuclear genes and pathways that sense and control mtDNA copy number and heteroplasmy. We screened a panel of mtDNA maintenance genes in mouse cells with a heteroplasmic mtDNA mt-Ta mutation. This revealed both common and perturbation-specific aspects of the integrated stress response to mtDNA depletion caused by Tfam, Opa1 and Polg knockout. These responses are only partially mediated by ATF4 and cause cell-cycle stage-independent slowing of cell proliferation. MitoPerturb-Seq, thus, provides experimental insight into disease-relevant mitochondrial-nuclear interactions and may inform development of therapies targeting cell-type- and tissue-specific vulnerabilities to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41594-026-01779-7
  3. Trends Biochem Sci. 2026 Mar 28. pii: S0968-0004(26)00007-1. [Epub ahead of print]
    Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
    Jiayi Chen, Xin Pan.
      How cells sense energy status to precisely regulate organelle fate is a central question in life sciences. Recent work by Zhang et al. reframes cytosolic acetyl-coenzyme A (AcCoA) from a metabolic substrate into a signaling metabolite that directly regulates mitophagy, thereby establishing a molecular link between nutrient sensing and mitochondrial homeostasis.
    Keywords:  NLRX1; cytosolic AcCoA; mitophagy
    DOI:  https://doi.org/10.1016/j.tibs.2026.01.007
  4. Nat Metab. 2026 Apr 01.
    ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas.
    Marc Hennequart, Loic Mervant, Julie Stockis, Jack Coomes, Martha M Zarou, Louise Gerard, Virginie Tevel, Valérie Migeot, Steven E Pilley, Younghwan Lee, Paul C Driscoll, Nathalie M Legrave, Christiaan F Labuschagne, Fabio Zani, Alejandro Huerta Uribe, Rute Machado De Morais Ferreira, Eric C Cheung, Ilaria Malanchi, James I MacRae, Oliver D K Maddocks, Timotheus Y F Halim, Karen H Vousden.
      Acinar-to-ductal metaplasia (ADM) contributes to pancreatic repair after injury1. However, persistent ADM, combined with KRAS mutation, leads to the development of precancerous pancreatic intraepithelial neoplasia (PanIN) that can progress into pancreatic ductal adenocarcinoma (PDAC)2. While PDAC development is well documented, the metabolic rewiring that occurs during early events such as ADM is poorly understood. Here we show that aldehyde dehydrogenase 1 family member L2 (ALDH1L2), an NADPH-producing mitochondrial enzyme of the one-carbon pathway, limits reactive oxygen species (ROS) and formate production in pancreatic acinar cells. However, ALDH1L2 expression decreases progressively during ADM and is completely absent in pancreatic ductal cells. ALDH1L2 loss elevates ROS and promotes ADM in a model of pancreatitis and accelerates tumour progression in models of pancreatic cancer. We also show that formate increases during PDAC progression in mice and humans. Overall, our findings identify ROS as a driver of ADM and suggest that circulating formate may serve as a biomarker for PDAC progression.
    DOI:  https://doi.org/10.1038/s42255-026-01456-5
  5. bioRxiv. 2026 Mar 28. pii: 2026.03.27.714830. [Epub ahead of print]
    Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
    Guy B Kunzmann, William E Leiter, Sophie E Durn, Amy M Weeks, Jason R Cantor.
      Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein (UBL) covalently attached to substrates through a dedicated enzymatic cascade (UFMylation) and removed by specific proteases. Despite a key role in endoplasmic reticulum (ER)-ribosome homeostasis, the basis by which this UBL supports cell fitness remains elusive, as the essentiality of UFMylation machinery varies widely across hundreds of cancer lines. Here, we trace a conditional dependence on the UFMylation pathway to the availability of alanine, an amino acid provided by human plasma-like medium but absent from most conventional synthetic media. We show that by facilitating the clearance of stalled ribosomes at the ER, dynamic UFMylation maintains cellular levels of glutamic-pyruvic transaminase 2 (GPT2), the primary enzyme responsible for de novo alanine synthesis in most human cancer lines. This buffering preserves the alanine pools required to sustain protein synthesis under alanine-restricted conditions. Beyond GPT2, UFM1 deficiency leads to widespread proteomic remodeling that spans diverse processes, including mitochondrial translation. Our results reveal that despite primarily targeting ER-localized ribosomes, the UFMylation system orchestrates a multi-organelle proteostasis network whose client composition and contributions to cell fitness are shaped by intrinsic factors and nutrient conditions.
    DOI:  https://doi.org/10.64898/2026.03.27.714830
  6. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  7. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00163-2. [Epub ahead of print]86(7): 1260-1274.e4
    The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.
    Maimon E Hubbi, Catherine L Wang, Yasir Suhail, Nadia L Almasri, Jane Xie, Erin E Hollander, Kshitiz, Alexander Muir, Ben Z Stanger, Chi V Dang.
      Ferroptosis is an iron-dependent form of cell death converging on lipid peroxidation first identified by examining compounds with enhanced lethality to KRAS mutant cells. Despite over 90% of pancreatic ductal adenocarcinoma (PDAC) tumors harboring KRAS mutations, PDAC exhibits relative resistance to ferroptosis compared with other tumor types, and the mechanisms behind this resistance remain unclear. Here, we report that exposure to pancreatic tumor interstitial fluid in synergy with hypoxia induced robust protection against ferroptosis in a manner dependent on the hypoxia-inducible transcription factor 2 (HIF-2). HIF-2 upregulates the expression of both components of the system Xc- cystine transporter and transsulfuration pathway enzymes CBS and CTH to increase intracellular cysteine levels, enabling anti-ferroptotic glutathione production. HIF-2 also induces the Parkin mitophagy factor and suppresses mitochondrial function and reactive oxygen species (ROS) generation. Altogether, our findings uncover an unforeseen role of the HIF-2 transcription factor as a coordinator of anti-ferroptotic mechanisms in pancreatic cancer.
    Keywords:  HIF-2 transcription factor; ferroptosis; hypoxia; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.007
  8. Nat Metab. 2026 Apr 01.
    NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
    Megan D Radyk, Barbara S Nelson, Mariana Tannus Ruckert, Christopher J Halbrook, Mengrou Shan, Jonathan M Alektiar, Brooke L Lavoie, Lucie Salvatore, Wei Yan, Matthew D Perricone, Kathryn Buscher, Alexander Wood, Hanna S Hong, Peter Sajjakulnukit, Li Zhang, Gabriel Corfas, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.
      Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.
    DOI:  https://doi.org/10.1038/s42255-026-01496-x
  9. Trends Endocrinol Metab. 2026 Apr 02. pii: S1043-2760(26)00068-8. [Epub ahead of print]
    Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
    Nicolai R Hathiramani, Alexandra E Jerrett, Jessica B Spinelli.
      To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosynthesis. SLC25A45 enables certain tissues to constitutively utilize fatty acids as fuel and, upon bioenergetic crisis, mediates a fuel switch that restores homeostasis.
    Keywords:  GLP-1RA; TML transporter; carnitine biosynthesis; cold adaptation; fuel switching; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2026.03.007
  10. Nat Aging. 2026 Mar 31.
    Single-cell spatial atlas of the aging human breast.
    Pulkit Gupta, Eric Lee, Neus Masqué Soler, Ellen Schrader, Xiao Qian Wang, Shimrit Mayer, Cristina Flores, Sean Beatty, Andrew Roth, Samuel Aparicio, H Raza Ali.
      Breast cancer can develop over a wide age range and tumors in younger women differ from those in older women. Aging alters the spatial context of early tumors and may explain these differences, but breast tissue aging remains poorly characterized. Here, using imaging mass cytometry to profile the spatial expression of 40 proteins, we explore age-related remodeling of normal breast tissues in over 3 million cells from 527 reduction mammoplasties. Aged breast tissue was less cellular and less proliferative for all cell types (epithelial, stromal and immune). Tissue architecture was restructured with fewer heterotypic epithelial cell-cell interactions, far fewer lobules and increased fat. Older tissues had a more inflammatory microenvironment with increased M2 macrophages and granzyme B+ T cells, contrasted by younger tissues in which B cells were most enriched. Our multiscale atlas extensively details an unexpected general decline of breast tissue with age and reveals its changing spatial context.
    DOI:  https://doi.org/10.1038/s43587-026-01104-3
  11. Trends Biochem Sci. 2026 Mar 30. pii: S0968-0004(26)00037-X. [Epub ahead of print]
    Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway.
    Serim Yang, Tong Bian, Roberto Zoncu.
      Primary nutrient sensors directly bind metabolites and undergo conformational changes that signal through core pathways to coordinate metabolic and cellular outcomes. Sensing of amino acids, lipids, sugars, and nucleotides is critical for the master growth regulatory Ser/Thr kinase, mechanistic target of rapamycin complex 1 (mTORC1), to promote growth and proliferation. Systematic proteomic and bioinformatic studies have accelerated the discovery of primary nutrient sensors upstream of mTORC1, whereas structural biology has shed light on how binding to their cognate metabolites triggers mTORC1-dependent signaling responses. This review focuses on recently reported amino acid and lipid sensors upstream of mTORC1 and highlights structural and functional features of these sensors that illuminate fundamental principles of nutrient detection and signal transduction.
    Keywords:  CASTOR1; LYCHOS; amino acid sensors; cholesterol sensors; metabolites; primary nutrient sensor
    DOI:  https://doi.org/10.1016/j.tibs.2026.02.009
  12. Nat Metab. 2026 Apr 01.
    Metabolism modulates stress and neoplasia.
    Michael C Noji, Kathryn E Wellen.
      
    DOI:  https://doi.org/10.1038/s42255-026-01500-4
  13. Science. 2026 Apr 02. 392(6793): eadv6582
    Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity.
    Zhiyuan You, Jiyeon Kim, Chuansheng Guo, Haoran Hu, Nicole M Chapman, Xiaoxi Meng, Hao Shi, Yan Wang, Cliff Guy, Anil Kc, Jia Li, Jordy Saravia, Gustavo Palacios, Sherri Rankin, Camenzind G Robinson, Hongbo Chi.
      Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8+ T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD+/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.
    DOI:  https://doi.org/10.1126/science.adv6582
  14. Nature. 2026 Apr 01.
    DNA damage burden causes selective CUX2 neuron loss in neuroinflammation.
    Laura Morcom, Wenlong Xia, Zhaoyang Xu, Yashika Awasthi, Celine Geywitz, Matthew O Ellis, Tomas Noli, Amel Zulji, Daniel Yamamoto, Gemma C Girdler, Li Kai, Keying Zhu, Mingming Wei, Xiao-Yan Tang, Kimberly K Hoi, Julio Gonzalez-Maya, Greg J Duncan, Adrien M Vaquie, Diana Gold Diaz, Riki Kawaguchi, Erdong Liu, Yu Sun, Denny Yang, Gregory D Jordan, I-Ling Lu, Staffan Holmqvist, Theresa Bartels, Katherine Ridley, Jennifer Ja-Yoon Choi, Santos J Franco, Eric J Huang, Ben Emery, Daniel Geschwind, Lucas Schirmer, Gabriel Balmus, Brian Popko, Stephen P J Fancy, David H Rowitch.
      Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood. Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2 and layer 3 (L2/3) excitatory neurons (L2/3ENs) that express CUT-like homeobox 2 (CUX2) are selectively vulnerable to degeneration2. Here we report that L2/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs were recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and activating transcription factor 4 (Atf4) were essential for resilience of L2/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to elevate levels of reactive oxygen species, leading to DNA damage-mediated neuronal death in vitro, and caused selective depletion of L2/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3ENs contributes to selective vulnerability in neuroinflammatory injury.
    DOI:  https://doi.org/10.1038/s41586-026-10310-3
  15. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196
    A splicing factor's unexpected detour to the mitochondrial surface.
    Ana-Maria Raicu, L Stirling Churchman.
      In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.011
  16. Bioinform Adv. 2026 ;6(1): vbag084
    Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.
    Jonathan K Yan, Ying Yang, Wenqi Wang.
       Motivation: Cancer metastasis is a leading cause of cancer-related deaths, while its underlying mechanisms remain incompletely understood. To colonize distant organs, cancer cells reprogram their metabolism to adapt to diverse environmental challenges. Therefore, elucidating the metabolic pathways that drive cancer metastasis will uncover novel biomarkers and therapeutic targets.
    Results: We integrated published datasets and systematically analyzed metabolites across multiple cancer cell lines. This large-scale bioinformatic analysis revealed distinct metabolites and metabolic pathways associated with organ-specific metastasis, and underscored the crucial role of tissue of origin in shaping the metabolic landscape of metastatic tumors. Notably, the transsulfuration pathway (also known as the cysteine and methionine metabolism) was strongly enriched in cancer cells with high metastatic potential. We validated this finding in pancreatic cancer, where the pathway enzyme cystathionine β-synthase (CBS) and its metabolic products were highly expressed in metastatic cancer cells. Targeting the transsulfuration pathway either by methionine deprivation or pharmacological inhibition of CBS significantly impaired the migration and invasion of metastatic pancreatic cancer cells. Taken together, our study not only provides a global view of the altered metabolic landscape in metastasis but also identifies the transsulfuration pathway as an oncogenic driver and a therapeutic target for pancreatic cancer metastasis.
    Availability and implementation: Related data used in this study can be found in the following link: https://github.com/jkyan08/metastasis-associated-metabolic-landscape.
    DOI:  https://doi.org/10.1093/bioadv/vbag084
  17. J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413
    The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
    Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.
      Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.
    Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.jbc.2026.111413
  18. Science. 2026 Apr 02. 392(6793): 24-25
    Mitochondria power immunity against cancer.
    Irene S Molina, Malay Haldar.
      A subset of dendritic cells relies on mitochondrial fitness to trigger antitumor responses in mice.
    DOI:  https://doi.org/10.1126/science.aeg4325
  19. Curr Biol. 2026 Apr 01. pii: S0960-9822(26)00310-6. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Laura C Kelley, Caitlin Y Su, Jake Leyhr, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive. How cells produce high ATP levels to power invasion is understudied. By endogenously tagging 20 mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP levels to fuel invasion. These electron transport chain (ETC)-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through an Src kinase directs microtubule polarization, facilitating metaxin adaptor complex-dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP levels by generating and localizing high-capacity mitochondria. This might be a common strategy used by other cells to meet the energetically demanding processes.
    Keywords:  ATP; basement membrane; cell invasion; cell specification; electron transport chain; live imaging; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.cub.2026.03.023
  20. Nat Commun. 2026 Mar 30.
    Mutant ribosomal protein RPS15 drives B cell malignancy through oxidative stress and genomic instability.
    Catherine Gutierrez, Marwan Kwok, Neil Ruthen, Peyton Waddicor, Christina Curran, Tamara Ouspenskaia, Doris Fu, Brendan Smalec, Samantha Sedor, Binyamin A Knisbacher, Anat Biran, Adi Nagler, Filip Garbicz, Tomasz Sewastianik, Johany Penailillo, Fabienne Lucas, Shanye Yin, Aviv Liani, Sarah Chen, Gregory Lazarian, Elizabeth Witten, Nathan Dangle, Ella L Brunsting, Mei Zheng, Emma S Lin, Madison J Lee, Blake Wells, Lucas Pomerance, María Hernández-Sánchez, Shuqiang Li, Ziao Lin, Aziz Al'Khafaji, Lili Wang, Sudhir Thakurela, Kenneth J Livak, Donna Neuberg, Florence Cymbalista, Gad Getz, Aviv Regev, Stirling Churchman, Elisa Ten Hacken, Ruben Carrasco, Sichen Shao, Catherine J Wu.
      Ribosomal protein mutations are increasingly associated with cancer risk and thought to perturb ribosome function. At the same time, they reportedly activate p53, a critical anti-cancer barrier. To determine how these mutations overcome this protective block to enable tumorigenesis, we generate an in vivo model of the hotspot ribosomal protein RPS15-S138F mutation identified as a putative driver of chronic lymphocytic leukemia. Under pre-leukemic conditions, this mutation induces ribosome biogenesis defects and altered translation resulting in oxidative stress, DNA damage and induction of a p53-dependent response that promote initial cellular hypo-proliferation. However, a subset of aged mice with mutated Rps15 eventually develop B-cell leukemia (37% penetrance), which exhibits increased Myc activity with strong pro-survival and proliferation signatures. Mutant RPS15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, DNA damage response defects and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-026-70655-1
  21. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250076. [Epub ahead of print]381(1947):
    Why selection for mitochondrial quality drives the evolution of sexes.
    Nick Lane, Andrew Pomiankowski.
      The evolution of sexes is closely tied to uniparental inheritance (UPI) of mitochondrial DNA (mtDNA), where only females transmit mtDNA. Unlike nuclear DNA, mtDNA is highly polyploid and never evolved to be part of meiotic sex. Modelling shows that UPI increases mtDNA mutational variance, enhancing selection for high-quality mtDNA and promoting the emergence of sexes from mating types in unicellular eukaryotes. Paternal control of mitochondrial transfer favours some degree of mtDNA leakage, whereas maternal control favours strict UPI, leading to sexual conflict driving turnover in transmission mechanisms. In multicellular organisms, mitotic segregation of mtDNA increases variance in gametes, again facilitating selection. Surprisingly, germline evolution seems to reflect mtDNA mutation rates: plants and sessile metazoans have low rates and produce gametes from somatic cells, while bilaterians and ctenophores with higher rates sequester germlines with restricted cell division. High mtDNA ploidy in oocytes allows early embryonic cell division without replication, reducing mutational variance across tissues and enhancing somatic fitness. Germline mtDNA quality is maintained by mitotic over-proliferation of germ cells and the selective transfer of mtDNA into primordial oocytes linked with massive apoptotic germ-cell atresia. Overall, selection for mtDNA quality elucidates the evolution of sexes and the architecture of the female germline. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  Balbiani body; germline; mitochondria; mitochondrial mutation; mtDNA; oogenesis; sexes; uniparental inheritance
    DOI:  https://doi.org/10.1098/rstb.2025.0076
  22. Autophagy. 2026 Mar 31. 1-3
    Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
    Polyxeni Papadea, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
    Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations
    DOI:  https://doi.org/10.1080/15548627.2026.2650772
  23. Annu Rev Biochem. 2026 Apr 03.
    Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer.
    Ashok R Venkitaraman.
      Cancer cells acquire hallmark behaviors through adaptations that extend beyond genetic and epigenetic changes. Proteostasis-the biochemical network governing protein synthesis, folding, trafficking, and degradation-is a fundamental, yet underappreciated, mediator of these adaptations that merits consideration as a hallmark-enabling mechanism. Metabolic alterations impose proteotoxic stress, globally rewire protein homeostasis, and selectively modulate key oncogenic and tumor suppressive proteins. A unifying framework is proposed wherein metabolic deregulation of proteostasis operates throughout carcinogenesis: early, by enhancing accumulation of premalignant clones bearing cancer-driving somatic mutations in response to environmental and systemic metabolic stress, and later, by buffering proteotoxic stress to sustain malignant growth in hostile tissue environments. This perspective connects cancer risk with genetic background, diet, microbiome-derived metabolites, and metabolic disease, introduces metabolic bypass of tumor suppression as an alternative to classical genetic models, and highlights the metabolism-proteostasis interface as a promising target for cancer prevention and therapy.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-052148
  24. J Clin Invest. 2026 Apr 02. pii: e191101. [Epub ahead of print]
    The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice.
    Young Do Koo, Romilia Tatiana Castillo, Asha Sukumaran Nair, Michael Garneau, Chad Gochee, Zachary V Campbell, Tashya Shreyas Vakil, Jua Ha, Alex Marti, Jamie Soto, Debajyoti Das, Nuria Martinez-Lopez, Shipra Sharma, Yennifer Delgado, Callie Phung, Immy A Ashley, Edmund D Kapelczak, Rashel Jacobo, Eric T Weatherford, Dao-Fu Dai, Jihane N Benhammou, Andrea G Marshall, Antentor Hinton, Ling Yang, Renata O Pereira, Tara TeSlaa, Mehdi Bouhaddou, Rajat Singh, E Dale Abel.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.
    Keywords:  Autophagy; Cell biology; Endocrinology; Hepatology; Obesity
    DOI:  https://doi.org/10.1172/JCI191101
  25. Immunity. 2026 Mar 30. pii: S1074-7613(26)00084-1. [Epub ahead of print]
    High-fat diet causes rapid loss of intestinal group 3 innate lymphoid cells through microbiota-driven inflammation and mitochondrial stress.
    Eva C Torrico, Paulien Kaptein, Fatiha Laalouhmi, Vanessa Mitsialis, Sara El Guendouzi, Abdellatif El Khayari, Chaymae El Baha, Elly D Htite, Sophie Chawluk, Christian D Gauthier, Nadhir M Djekidel, Patrick Da Silva, Toby B Lanser, Ankur Gupta, Kisha Sivanathan, Marilia Garcia De Oliveira, Amir H Maghzi, Ali Tavakkoli, Mozhdeh Sojoodi, Motaz Qadan, Shirong Liu, Rafael M Rezende, Laura M Cox, Lloyd Bod, Alexandra Schnell, Anya Song, Isabelle Pierre, Pegah Jabbari-Lak, Veronika V Heil, Luisa S Lemos, Joshua Keegan, Jenny P Nguyen, Laura A Cahill, Rajesh Krishnan Kumar, Chantal Kuhn, Gaganvir Parmar, Gopal Murugaiyan, James A Lederer, Scott B Snapper, Roni Nowarski, Rachid El Fatimy, Howard L Weiner, Selma Boulenouar.
      Group 3 innate lymphoid cells (ILC3s) are key sensors of the intestinal environment, integrating dietary and microbial cues to maintain intestinal immunity. We found that intestinal ILC3s were reduced in overweight and obese humans and in high-fat diet (HFD)-fed mice. ILC3 loss occurred independently of caloric excess, weight gain, or glucose intolerance. Instead, impairment arose within hours of HFD consumption and was initiated by microbiota-driven intestinal barrier permeability and concomitant activation of inflammatory mononuclear phagocytes (MNPs). This response to inflammation impaired fatty acid oxidation in lipid-loaded ILC3s, resulting in mitochondrial damage and cell death. Intestinal ILC3 cell death was rescued by removal of excess fats from the diet. ILC3s from individuals with obesity also exhibited impaired fatty acid oxidation. Together, our findings define a malleable mechanism whereby dietary fats and microbial cues drive ILC3 maladaptation and death, with consequences for intestinal homeostasis.
    Keywords:  ILC3s; MNPs; TLR4; fatty acid oxidation; group 3 innate lymphoid cells; high-fat diet; intestinal inflammation; lipid metabolism; lipid peroxides; lipopolysaccharides; microbiota; mitochondria; mononuclear phagocytes; obesity
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.014
  26. Cell. 2026 Mar 30. pii: S0092-8674(26)00269-2. [Epub ahead of print]
    A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy.
    Zeda Zhang, Yu-Jui Ho, Xin Fang, Minseo Kim, Marguerite Li, Wei Luan, Clemens Hinterleitner, Sascha Haubner, Friederike Kogel, Edwin C Pratt, Elif Ozcelik, José Reyes, Qingwen Jiang, Vincent W Yang, Yu-Jung Chen, Tao Wang, Haijiao Liu, Haonan Hu, Xueqian Zhuang, Jin Park, Stella V Paffenholz, Kevin Chen, Qing Chang, Amanda Kulick, Jing Zhang, Eric Chan, Eric Rosiek, Ning Fan, Riley A Williams, Adam C Wang, Samuel Freeman, Sha Tian, Gertrude Gunset, Andreina Garcia Angus, Nicolas Lecomte, Selma Yeni Yildirim, Emily Ali, Michelle Wu, Ileana C Miranda, Cristina R Antonescu, Olca Basturk, Zeynep Tarcan, Natasha Rekhtman, Christina Wilson, Merve Basar, Jennifer L Sauter, Hikmat A Al-Ahmadie, Samuel Singer, Christine Iacobuzio-Donahue, Charles Rudin, Elisa de Stanchina, Karuna Ganesh, Paul B Romesser, Britta Weigelt, Dan Dongeun Huh, Josef Leibold, Judith Feucht, Ignacio Vázquez-García, Matthew J Bott, Dmitriy Zamarin, Sohrab P Shah, Jason S Lewis, Corina Amor, Dana Pe'er, Jorge Mansilla-Soto, Aveline Filliol, Michel Sadelain, Scott W Lowe.
      Chimeric antigen receptor (CAR) T cells have transformed hematologic cancer therapy but remain limited in solid tumors by antigen heterogeneity and a suppressive, pro-fibrotic microenvironment. We previously identified the urokinase plasminogen activator receptor (uPAR) as upregulated in senescent, pro-fibrotic cells and showed that uPAR-directed CAR T cells could safely reverse fibrosis in mice. Integrative analyses now reveal that uPAR is broadly expressed in solid tumors enriched for TP53 and RAS pathway mutations. These tumors adopt a progenitor-like state supported by a niche of uPAR-positive stromal cells with senescence features. Human uPAR CAR T cells eliminate tumor cells and their stromal support, induce durable regressions across diverse models, eradicate systemic metastases, and are potentiated by senescence-inducing therapies. Importantly, these cells achieve robust antitumor activity without sustained myelosuppression in mice reconstituted with human immune systems. Together, these findings establish uPAR as a broadly applicable CAR T target capable of overcoming major barriers in solid tumor therapy.
    Keywords:  CAR T cells; fibrosis; p53; senescence; senolytic; tumor microenvironment; uPAR
    DOI:  https://doi.org/10.1016/j.cell.2026.03.002
  27. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250075. [Epub ahead of print]381(1947):
    Segregation of mtDNA mutations protects mitochondria across kingdoms, with impacts from longevity to agriculture and evolvability.
    Iain G Johnston.
      Mitochondrial DNA (mtDNA) encodes essential bioenergetic and metabolic machinery across eukaryotes, but it is susceptible to mutational damage. The high copy number, physical location and inheritance patterns of mtDNA mean that specialist approaches to mitigate such damage are needed. A common theme across many species is segregation or 'sorting out' of different mtDNA types-generating variance in mutant frequencies within and between generations, so that multiscale selection can act to remove deleterious mutations. Eukaryotes with different physiologies and ecologies use different strategies for this segregation. This article attempts to review and-with the aid of some bioinformatics and new modelling results-synthesize the ways that this segregation is achieved across different eukaryotic organisms. In parallel, the importance of segregation in human disease, longevity, agriculture and for biology on a rapidly changing planet is discussed. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  bottleneck; cross-eukaryote; evolution; mitochondria; mtDNA
    DOI:  https://doi.org/10.1098/rstb.2025.0075
  28. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00162-0. [Epub ahead of print]86(7): 1293-1310.e14
    U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs.
    Gloria R Garcia, Murali Palangat, Josquin Moraly, Benjamin T Donovan, Bixuan Wang, Ira Phadke, David Sturgill, Jiji Chen, Guofeng Zhang, Ronald J Holewinski, Brittney Short, Gustavo A Rivero, David M Swoboda, Naomi Taylor, Kathy McGraw, Daniel R Larson.
      The mechanisms underlying molecular targeting to mitochondria remain enigmatic, yet this process is crucial for normal cellular function. The RNA-binding proteins U2AF1 and U2AF2 form a heterodimer (U2AF) that shuttles between the nucleus and cytoplasm, regulating splicing in the nucleus and translation in the cytoplasm. Our study in human bronchial epithelial cells (HBECs) identifies an unexpected role for U2AF in mitochondrial function. We demonstrate that U2AF interacts with nuclear-encoded mitochondrial (NE-mt) mRNAs and proteins, inhibits translation, localizes to the mitochondria, and regulates mRNA localization to mitochondria. Moreover, an oncogenic point mutation in U2AF1(S34F) disrupts this regulation, leading to altered mitochondrial structure, increased translation, large changes in the mitochondria proteome, and oxidative phosphorylation (OXPHOS)-dependent metabolic rewiring, recapitulating changes observed in bone marrow progenitors from patients with myelodysplastic syndromes. These findings reveal a non-canonical role for U2AF, where it modulates multiple aspects of mitochondrial function by regulating the translation and mitochondrial localization of nuclear-encoded mRNAs.
    Keywords:  U2AF1; cancer; mRNA localization; metabolism; mitochondria; myeloid leukemia; translation
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.006
  29. Ageing Res Rev. 2026 Mar 27. pii: S1568-1637(26)00107-8. [Epub ahead of print]118 103115
    Epigenetic remodeling induced by fatty acids: Chromatin modifications and cellular senescence during lipid overload.
    Karla Estephanía Ávila-Galicia, Adriana Alarcón-Aguilar, Ernesto Soto-Reyes, Mina Königsberg.
      Cellular senescence is a stable cell state sustained by specific gene expression programs that are established and maintained through dynamic changes in chromatin organization. Importantly, these programs are highly dependent on the nature of the senescence-inducing stimulus. In recent years, lipid overload has emerged as a relevant metabolic stress capable of inducing senescence across multiple cell types and tissues, particularly in the context of obesity and high-fat diets. Accumulating evidence indicates that this process is tightly linked to metabolic rewiring, which directly impacts chromatin-modifying enzymes and chromatin remodelers through fluctuations in key metabolites such as acetyl-CoA, NAD⁺, and α-ketoglutarate. In this review, we integrate current evidence on how fatty acid-driven metabolic alterations reshape chromatin dynamics to promote and stabilize cellular senescence.
    Keywords:  Aging; Cellular senescence; Chromatin; Diet; Epigenomics; Fatty acids; High-fat; Obesity
    DOI:  https://doi.org/10.1016/j.arr.2026.103115
  30. Science. 2026 Apr 02. 392(6793): 102-109
    Pearling drives mitochondrial DNA nucleoid distribution.
    Juan C Landoni, Matthew D Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J Obara, Andrew S Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm, Suliana Manley.
      The distribution of mitochondrial DNA-containing nucleoids is essential for mitochondrial function and genome inheritance; however, no known mechanisms can explain nucleoid segregation or their regular positioning. In this work, we found that mitochondria frequently undergo a reversible biophysical instability termed "pearling," transforming from a tubular into a regularly spaced beads morphology. Physiological pearling imposed a characteristic length scale and simultaneously mediated nucleoid disaggregation and established internucleoid distancing with high precision. Pearling onset was triggered by calcium influx, whereas the density of lamellar cristae invaginations modulated pearling prevalence and preserved nucleoid spacing following recovery. The dysregulation of mitochondrial calcium influx or inner membrane cristae integrity caused aberrant nucleoid clustering. Our results identify pearling as a mechanism governing nucleoid distribution and inheritance and offer insights into its regulation.
    DOI:  https://doi.org/10.1126/science.adu5646
  31. Cell Death Discov. 2026 Mar 31.
    Protein lactylation: a metabolic signal driving cancer therapy resistance.
    Silvia D'amico, Sara Giovannini, Gerry Melino, Angelo Peschiaroli, Francesca Bernassola.
      Unlike normal cells, which primarily rely on oxidative phosphorylation, cancer cells reprogram their metabolism by preferentially utilizing glycolysis even in the presence of oxygen to generate ATP. As a result, cancer cells and the tumor microenvironment typically accumulate high levels of lactate. Although initially considered a mere byproduct of glucose metabolism, lactate has recently emerged as an important metabolic intermediate involved in many intracellular pathways and protein modifications. Lysine lactylation is indeed a newly identified, metabolism-linked post-translational modification in which lactate is covalently bound to specific lysine residues. This review provides an overview of the current understanding of how lysine lactylation mechanistically contributes to therapeutic resistance in tumor cells. Remarkably, protein lactylation is emerging as a promising druggable approach for overcoming therapy resistance. Hence, here, we also highlight new strategies that target lactylation with pharmacological inhibitors to counteract drug resistance in cancer.
    DOI:  https://doi.org/10.1038/s41420-026-03050-w
  32. Nat Commun. 2026 Mar 30.
    HR3/RORα-mediated cholesterol sensing regulates TOR signaling.
    Mette Lassen, Keith Pardee, Ivan Bradic, Lisa H Pedersen, Olga Kubrak, Nadja Ahrentløv, Sebastian Clancy, Takashi Koyama, Aleksandar Necakov, Suya Liu, Arnis Kuksis, Gilles Lajoie, Aled Edwards, Aurelio A Teleman, Martin R Larsen, Henry M Krause, Michael J Texada, Kim Rewitz.
      Cells and organisms adjust their growth based on the availability of cholesterol, which is essential for cellular functions. However, the mechanisms by which cells sense cholesterol levels and translate these into growth signals are not fully understood. We report that cholesterol rapidly activates the master growth-regulatory TOR pathway in Drosophila tissues. We identify the nuclear receptor HR3, an ortholog of mammalian RORα, as an essential factor in cholesterol-induced TOR activation. We demonstrate that HR3 binds cholesterol and promotes TOR-pathway activation through a non-genomic mechanism acting upstream of the Rag GTPases while also restraining longer-term responses through genomic regulation. We also find that RORα is necessary for cholesterol-mediated TOR activation in human cells, suggesting that HR3/RORα-mediated signaling represents a conserved mechanism for cholesterol sensing that couples cholesterol availability to TOR-pathway activity. These findings advance our understanding of how cholesterol influences cell growth, with implications for cholesterol-related diseases and cancer.
    DOI:  https://doi.org/10.1038/s41467-026-71059-x
  33. Res Sq. 2026 Mar 25. pii: rs.3.rs-9077389. [Epub ahead of print]
    Acid Ceramidase Inhibition Disrupts Ceramide Homeostasis and Induces Mitochondrial Apoptosis in IDH1-Mutant Oligodendroglioma.
    Mioara Larion, Helena Muley, Faris Zaibaq, Meili Zhang, Dionne Davis, Michael Kruhlak, Samarth Mathur, Adrian Lita, Hua Song, Wei Zhang, Zalman Wong, Taylor Harmon, Lumin Zhang, Chen Cam-El Makranz, Aiguo Li, George Karadimov, Fengchao Lang, Christel Herold-Mende, Chunzhang Yang, Tyrone Dowdy.
      Oligodendroglioma is genetically defined by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) and 1p/19q codeletion. We previously showed that in IDH1-mutant oligodendroglioma, the oncometabolite D-2-hydroxyglutarate biases the sphingosine-1-phosphate-to-ceramide rheostat toward ceramides. Taking advantage of this intrinsic metabolic vulnerability, we investigated whether further elevating ceramide levels through inhibition of acid ceramidase could exacerbate this imbalance and promote apoptotic cell death. Analysis of patient datasets demonstrated that acid ceramidase is expressed at higher levels in both low- and high-grade gliomas compared with normal tissue. Pharmacologic inhibition of acid ceramidase with SABRAC preferentially reduced viability in human IDH1-mutant oligodendroglioma cell lines. In these sensitive models, acid ceramidase inhibition markedly increased ceramide levels and induced coordinated sphingolipid remodeling. Subcellular imaging using a fluorescent ceramide analogue demonstrated increased ceramide localization to lysosomes and mitochondria following acid ceramidase inhibition. This was accompanied by cytochrome c redistribution, executioner caspase activation, and caspase-dependent apoptotic cell death, consistent with engagement of intrinsic mitochondrial apoptosis. Transcriptomic and biochemical analyses further revealed activation of endoplasmic reticulum stress and unfolded protein response signaling, including PERK- and IRE1α-associated programs, suggesting coordinated multi-organelle stress responses under sustained ceramide elevation. These mechanistic effects translated into a survival benefit in oligodendroglioma xenograft-bearing mice. Together, these findings suggest that IDH1-mutant oligodendroglioma harbors a pre-existing heightened sensitivity to ceramide stress and identify acid ceramidase as a therapeutically actionable target in this disease.
    DOI:  https://doi.org/10.21203/rs.3.rs-9077389/v1
  34. Nat Aging. 2026 Mar 31.
    Cellular and spatial remodeling of aging breast tissue revealed.
      
    DOI:  https://doi.org/10.1038/s43587-026-01111-4
  35. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00166-8. [Epub ahead of print]86(7): 1197-1199
    Precision from broad strokes: How the non-specific interactions of metabolites and macromolecules can regulate biology.
    Maya Emmons-Bell, Juan Manuel Schvartzman.
      In a recent article in Nature, Zabala-Letona et al.1 propose that polyamines-small, positively charged metabolites-regulate RNA splicing by electrostatically shielding acidic sites on spliceosome proteins from kinase-mediated phosphorylation. This work adds to a growing body of evidence suggesting that metabolites can regulate cell biology through non-specific macromolecular interactions.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.010
  36. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250079. [Epub ahead of print]381(1947):
    Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.
    Jade R Kannangara, Hansong Ma, Damian K Dowling.
      Mitochondrial DNA (mtDNA) variation is increasingly recognized for its role in shaping evolutionary changes at the species and population levels. Yet, its evolutionary relevance within individuals remains less explored. Eukaryotic cells typically carry multiple copies of mtDNA. When these copies differ in sequence, heteroplasmy arises-a form of intra-organismal genetic diversity with potentially profound biological implications. To elucidate the evolutionary significance of heteroplasmy in animals, we first review how natural selection shapes adaptive mtDNA dynamics at broader biological levels, via cases of mito-nuclear coadaptation, environmental-mediated and sex-specific selection and balancing selection. We then explore whether analogous selective pressures may operate at the intra-individual level. Heteroplasmy introduces the potential for multi-level selection-from the genome to the organism-potentially yielding synergistic or antagonistic evolutionary outcomes. This framework encompasses both the selfish transmission of certain mtDNA variants and emerging evidence for adaptive shifts in heteroplasmy levels under environmental stress. These findings are supported by theoretical models suggesting that paternal mtDNA transmission-historically viewed as a stochastic anomaly-may confer adaptive benefits under specific ecological and evolutionary contexts by introducing intra-individual mtDNA diversity. Collectively, these insights suggest that heteroplasmy may act as an underappreciated reservoir of adaptive potential, enhancing the evolutionary capacity of organisms in a changing world. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  adaptation; adaptive; environmental change; evolution; heteroplasmy; mito-nuclear; mitochondria; mtDNA; selfish; selfish drive
    DOI:  https://doi.org/10.1098/rstb.2025.0079
  37. J Cell Sci. 2026 Mar 15. pii: jcs263933. [Epub ahead of print]139(6):
    Microscopy in mitochondrial research - a comprehensive review.
    Prasanna Katti, Prasanna Venkhatesh, C Nivedya, Andrea Marshall, Amber Crabtree, Zahra Elly Soltani, Olga Korolkova, Vineeta Sharma, Suraj Thapliyal, Karthik Naik, Kit Neikirk, Rodolpho Ornitz Oliveira Souza, Sepiso K Masenga, Nelson Wandira, Magdalene Ameka, Okwute M Ochayi, Christian A Combs, Lucy Collinson, Nalan Liv, Antentor Hinton.
      Mitochondria are highly dynamic, double-membrane organelles that play integral roles beyond energy production. Mitochondria adapt their morphology to meet diverse cellular demands, and highly plastic mitochondrial networks interact and communicate with various cellular components to maintain cellular health. Advances in both light and electron microscopy (EM) have greatly enhanced our understanding of mitochondrial structure and function. However, the small diameter of mitochondrial tubules, often near the diffraction limit of light, poses challenges for visualizing submitochondrial structures and protein distributions with conventional microscopy. Recently, super-resolution microscopy has offered unprecedented insights into mitochondrial dynamics, interactions and architecture. In this Review, we discuss how imaging techniques have advanced our understanding of mitochondrial biology. We critically assess the contributions of two-dimensional EM to elucidating the native architecture of cristae and respiratory chain complexes. Additionally, we explore how three-dimensional EM and super-resolution methods have reshaped our comprehension of mitochondrial network dynamics, heterogeneity and interactions with other cellular components. Finally, we discuss the strengths and limitations of various approaches, considering their potential to overcome current challenges and open new avenues in mitochondrial research, and illuminate how advanced microscopy continues to drive discoveries in mitochondrial biology with implications for metabolic diseases and aging.
    Keywords:  CLEM; Confocal; EM; Mitochondria; Super-resolution microscopy; Volume EM
    DOI:  https://doi.org/10.1242/jcs.263933
  38. Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]
    Unexpected role of the integrated stress response in cancer immune evasion.
    Lucia Borriello, Lorenzo Galluzzi.
      Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.
    Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
  39. Cancer Discov. 2026 Apr 01. 16(4): 656-659
    Metastasis as a Multiorgan Disease: Toward Organ-Informed Precision Oncology.
    Anish Thomas, Chirayu Mohindroo, Yue Huang, Julien Sage, Joan Massagué.
      Metastasis is a multiorgan disease in which disseminated cancer cells undergo profound, tissue-specific reprogramming that reshapes their identity, vulnerabilities, and therapeutic responses. We argue for an organ-informed precision oncology framework that integrates these site-imposed programs into treatment design.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2052
  40. FEBS Open Bio. 2026 Mar 30.
    Intercompartmental communication in senescence.
    Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.
      Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.
    Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence
    DOI:  https://doi.org/10.1002/2211-5463.70236
  41. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250081. [Epub ahead of print]381(1947):
    Mitonuclear dynamics in unisexual vertebrates.
    Randy L Klabacka, Geoffrey E Hill, Damian K Dowling, Joel Sharbrough, Robert D Denton, Joshua M Hall, Justin C Havird.
      Sex and mitochondria are inextricably linked in the eukaryotic tree of life, a confounding situation given the uniparental inheritance of mitochondria and the biparental inheritance that sexual reproduction entails. Unisexual vertebrate lineages, which arise via hybridization and asexually pass on their genetic material to clonal descendants, provide a unique opportunity to study mitochondrial evolution without potentially confounding effects of sex. Hybridity and clonality set unisexual vertebrates apart from other vertebrates and establish a distinct genetic environment that shapes their evolution, especially dynamics between mitochondrial and nuclear genomes. Here, we provide a perspective on the mitonuclear genomic interactions experienced by unisexual vertebrates and the implications of these interactions on mitochondrial function and integration into organismal performance and fitness. Building upon the hypothesis that sexual reproduction arose to maintain coadaptation between co-functioning nuclear and mitochondrial genes, we propose that unisexual vertebrates may be confined to predominantly 'young' lineages because mitonuclear incompatibilities-arising from either hybridity or clonality-increase the probability of extinction over time (the Mitonuclear Erosion Hypothesis). We provide a multidisciplinary collection of strategies to disentangle the effects of clonality and hybridity and quantify the relative degree to which these characteristics contribute to differences in mitochondrial function, organismal performance and fitness. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  asexual reproduction; mitochondrial function; mitonuclear incompatibility; unisexual; vertebrates
    DOI:  https://doi.org/10.1098/rstb.2025.0081
  42. Science. 2026 Apr 02. 392(6793): eaea8782
    Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
    Lucas C Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A Debeaubien, Tristan Croll, D John Lee, Christopher Arthur, Thomas E Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli.
      The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.
    DOI:  https://doi.org/10.1126/science.aea8782
  43. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250074. [Epub ahead of print]381(1947):
    The functional importance of mitochondrial sequences with dual functions: overlapping protein-protein and protein-RNA gene sequences as test cases.
    Noam Shtolz, Li Horovitz, Yuval Caruchero, Dan Mishmar.
      Human mitochondrial DNA (mtDNA) contains 13 protein-coding subunits of the oxidative phosphorylation pathway, 22 tRNA and two rRNA genes. However, accumulating evidence suggests that mtDNA encodes additional overlapping genetic elements, including mitochondrial-derived peptides (MDPs) and alternative reading frames. Here, we assessed signatures of selection across 66 328 human mtDNAs and studied the potential impact of disease-causing mutation within these mtDNA overlapping sequences. By employing frame-specific dN/dS analysis for the overlapping reading frames, and codon position-specific diversity calculations we found that SHLP6 and SHLP3 (within 16S rRNA) display significant signatures of purifying selection. Mutational asymmetry analysis revealed purifying selection in both frames and strands of GAU/COX1, while other alternative reading frames show asymmetric patterns, supporting negative selection primarily on the encompassing canonical gene. Analysis of mito-ribosome profiling (HEK293 cells) revealed translation initiation signatures only for SHLP6 and ALTND4, providing functional support for their translation in HEK293 cells. Analysis of disease-causing mutations revealed that several such mutations have predicted deleterious effects on both canonical and alternative sequences, though canonical genes tend to be more frequently affected. Taken together, we provide evolutionary and functional evidence supporting biological relevance of certain MDPs and underline the need to re-evaluate the functionality of mutations in such sequences. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  mitochondria; mtDNA; mutations; overlapping sequences; selection
    DOI:  https://doi.org/10.1098/rstb.2025.0074
  44. iScience. 2026 Apr 17. 29(4): 115184
    Accumulated mtDNA mutations are linked to specific impairments in NADH-linked respiration.
    Edziu Franczak, McLane M Montgomery, Zoe S Terwilliger, Raphael T Aruleba, Polina Krassovskaia, Ilya N Boykov, James T Hagen, Emely A Pacheco, Brett R Chrest, Tonya N Zeczycki, Kayla J Vandiver, P Darrell Neufer, Joseph M McClung, Kelsey H Fisher-Wellman.
      Oxidative phosphorylation (OxPhos) relies on coordinated synthesis of nuclear- and mitochondrial-encoded protein subunits comprising mitochondrial respiratory complexes. Despite a causal link between accumulated mtDNA mutations and age-related diseases, the impact of mtDNA mutation burden on cellular bioenergetics across major organ systems remains only partially resolved. Herein, we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of heightened mtDNA mutation burden across 8 murine tissues using the polymerase γ (PolG) mutator mouse, incapable of mtDNA proofreading. Despite reductions in OxPhos protein expression, maximal mitochondrial respiratory capacity remained largely intact in PolG Mut mice. Further analysis revealed partial functional deficits in NADH-linked respiration exhibited in brown adipose, colon, kidney, lung, and bone marrow-derived mononuclear cells. In contrast, respiration routed from CII-CIII-CIV was largely preserved across all tissues. Together, these findings suggest that NADH oxidation at respiratory complex I (CI) is the primary functional consequence of heightened mtDNA mutational load.
    Keywords:  Biochemistry; Genomics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115184
  45. Cell Rep Med. 2026 Mar 26. pii: S2666-3791(26)00121-7. [Epub ahead of print] 102704
    Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion.
    Juan Liu, Weiwei Wang, Yvonne Sun, Shan Huang, Arnav Borole, Haiyan Zheng, Wenwei Hu, Zhaohui Feng.
      Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine synthesis, is frequently overexpressed in cancers and promotes cancer progression. Its oncogenic role has been largely attributed to its enzymatic activity. Here, we uncover a critical noncanonical function of PHGDH in cancer; PHGDH upregulates PD-L1 expression to promote cancer immune evasion independently of its enzymatic function. Mechanistically, PHGDH binds to the serine/threonine kinase RAF1 and disrupts its interaction with 14-3-3, thereby activating RAF1 and its downstream MEK/ERK signaling to induce PD-L1 expression. Elevated PHGDH levels correlate with increased PD-L1 expression in clinical tumor samples. In preclinical mouse models, tumors with high PHGDH expression exhibit increased sensitivity to PD-1/PD-L1 blockade. Combining PHGDH inhibitors with PD-1/PD-L1 blockade significantly improves antitumor effects compared to individual treatments. These results identify PHGDH as an important PD-L1 regulator, reveal a critical noncanonical mechanism underlying PHGDH's oncogenic function, and propose a potential therapeutic strategy for cancers with PHGDH overexpression.
    Keywords:  PD-L1; PHGDH; immune evasion; immune therapy; metabolism; noncanonical function; serine synthesis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102704
  46. iScience. 2026 Apr 17. 29(4): 115193
    Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
    Eoghan J Mulholland-Illingworth, Joshua W Moore, Muyang Lin, Raheleh Amirkhah, Lucile Grzesiak, Amelia Ligeza, Joshua A Bull, Joseph Boen, Gabriel N Valbuena, Michael A Gillespie, Tamsin R M Lannagan, Kathryn Gilroy, Megan L Mills, Shania M Corry, Rachel A Ridgway, Hayley L Belnoue-Davis, Philip D Dunne, Owen J Sansom, Helen M Byrne, Simon J Leedham.
      Colorectal cancer (CRC) is a complex ecosystem shaped by bidirectional interactions between epithelium and the tumor microenvironment, prominently mediated by TGFβ signaling. Cancer-associated fibroblasts (CAFs) are regulators of epithelial plasticity and immune cell recruitment; yet, their diversity has impacted translationally applicable spatial analysis. Here, we distil the fibroblast continuum into two overarching CAF populations that are largely transcriptomically distinct and are marked by PDGFRA+ and ACTA2+ expression, enabling robust spatial identification using single immunohistochemical markers. We show that TGFβ signaling drives dynamic transitions between these states. In a preclinical model, selective ALK5 inhibition remodels CAF composition in vivo, reconfiguring local immune neighborhoods and indirectly altering epithelial stem cell states. Finally, we demonstrate that multiscale spatial analysis provides a quantitative readout of stromal-immune-epithelial remodeling following therapy. These findings establish a simplified, translationally relevant CAF framework and highlight spatially resolved stromal dynamics as measurable indicators of therapeutic response in CRC.
    Keywords:  cancer; health sciences; medicine; oncology
    DOI:  https://doi.org/10.1016/j.isci.2026.115193
  47. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00266-4. [Epub ahead of print]45(4): 117188
    Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
    Maciej Garczyk, Gonçalo Outeiro-Pinho, Muthita Pitaktrairat, Bárbara Sofia Soares Da Silva, Giusy Di Conza, Karolina Niewola-Staszkowska, Marcel A Deken, Zoë Johnson, Asmita Thapa, Flavia Fico, Matteo Rossi Sebastiano, Inés Reynoso-Moreno, Daniele Pellegata, Giorgio Ramadori, Beat Gloor, Martin Wartenberg, Jürg Gertsch, Georgia Konstantinidou.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal fibrosis that promotes immune exclusion and treatment resistance, yet the upstream drivers of this pro-fibrotic cascade remain poorly defined. Here, we identify phosphoinositide 3-kinase δ (PI3Kδ) as a previously unrecognized driver of fibrosis in PDAC. Pharmacological inhibition of PI3Kδ reduces collagen deposition while enhancing the infiltration of activated CD8+ T cells, thereby reprogramming the tumor microenvironment toward an antitumor state. Mechanistically, we reveal that PI3Kδ regulates the biosynthesis of lysophosphatidic acid (LPA), a key lipid mediator of stromal remodeling, by controlling phosphatidylcholine-derived precursors in both cancer cells and stromal fibroblasts. By regulating both LPA-driven stromal remodeling and immune suppression, PI3Kδ emerges as a central regulator of the PDAC tumor microenvironment. Co-inhibition of autotaxin, an enzyme contributing to LPA production, and PI3Kδ further amplifies stromal disruption and improves chemo-immunotherapy efficacy in preclinical PDAC models. These findings position PI3Kδ as a central therapeutic target in PDAC, offering a dual-action strategy to simultaneously dismantle stromal fibrosis and immune suppression.
    Keywords:  CP: cancer; CP: immunology; immunosuppression; pancreatic ductal adenocarcinoma; targeted therapies; tumor lipid metabolic regulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117188
  48. Cancer Cell. 2026 Apr 02. pii: S1535-6108(26)00161-3. [Epub ahead of print]
    Redefining cancer drivers with tissue-specific context.
    Maria Kalyva, Nicholas McGranahan.
      In this issue of Cancer Cell, Bandlamudi and colleagues analyze over 50,000 tumors spanning 64 cancer types, revealing how tissue context dictates the prevalence and evolutionary timing of somatic driver alterations. Their findings underscore the need to move away from a purely gene-centric view of oncology toward a context-aware framework.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.007
  49. Nat Commun. 2026 Mar 28.
    NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.
    Mingzhou Li, Yunfei Ni, Jieqiong Wu, Xin Zou, Yining Chen, Junfeng Qiu, Yifang Li, Huayu Cai, Li Wang, Feifei Wang, Hongxia Zhang, Fangyi Han, Jinghao Huang, Zilong Chen, Bingyu Xu, Li Liang.
      Radiotherapy effectively treats colorectal cancer (CRC), but local recurrence remains common and abscopal effects-regression of tumors distant from irradiated sites-are rarely observed even with immune checkpoint inhibitors. Here we show that the protein kinase NEK8, highly expressed in CRC, promotes radioresistance by suppressing anti-tumor immunity. In radiation-resistant tumors, NEK8 phosphorylates lactate dehydrogenase A (LDHA), driving lactate overproduction. This metabolite promotes histone modifications that silence antigen presentation machinery, while extracellular lactate directly impairs CD8+ T cell function, collectively excluding CD8+ T cell from the tumor microenvironment. Pharmacological inhibition of NEK8 using CX6258 restores CD8+ T cell infiltration and enhances both local and systemic tumor control following radiotherapy. These findings establish NEK8 as a promising therapeutic target for overcoming radioresistance and inducing abscopal responses in CRC.
    DOI:  https://doi.org/10.1038/s41467-026-70657-z
  50. Cell. 2026 Mar 27. pii: S0092-8674(26)00273-4. [Epub ahead of print]
    Whole-body molecular and cellular mapping of the laboratory mouse.
    Margarette H Clevenger, Denis Cipurko, Ashwini Patil, Bohan Li, Michihiro Takahama, Linghan Mei, Madison Plaster, Gabriella Richey, Tadafumi Kawamoto, Feng Bao, Nicolas Chevrier.
      The laboratory mouse is a key model system for biomedical research, yet body-wide measurement tools are lacking. Here, we generate spatiotranscriptomics profiles of whole-mouse sections that accurately capture histological regions. We spatially assign 379 cell types across whole-mouse section profiles by building a reference dataset of 59M single cells coupled with a scalable computational method for cell-type assignment. Moreover, we exploit these whole-mouse profiles to create a machine learning pipeline, LABEL, which enables pan-body annotation of tissues and cell types on histology images from H&E-stained sections. Lastly, we apply whole-mouse spatial profiling to map systemic inflammation in endotoxemia, which delineates organism-wide changes in gene expression programs across tissues and cell types. Together, our work paves the way for body-wide studies of the molecular and cellular processes that govern the organismal biology of the laboratory mouse across space, time, and conditions.
    Keywords:  Array-seq; endotoxemia; inflammation; machine learning; spatial transcriptomics; whole-body
    DOI:  https://doi.org/10.1016/j.cell.2026.03.006
  51. EMBO Mol Med. 2026 Mar 30.
    The lipid transfer protein STARD7 controls intestinal tumor development in a context-dependent manner.
    Kateryna Shostak, Yu Chen, Chloé Maurizy, Gilles Rademaker, Xinyi Xu, Arnaud Blomme, Pierre Close, Olivier Renson, Matthias Van Hul, Patrice D Cani, Sebastian Klein, Alexandra Florin, Reinhard Büttner, Didier Cataldo, Philippe Delvenne, Ivan Nemazanyy, Caroline Wathieu, Alexandre Hego, Sandra Ormenese, Olivier Peulen, Marc Thiry, Roopesh Krishnankutty, Jair Marques, Alex von Kriegsheim, Alain Chariot.
      The role of phosphatidylcholine transporters such as Stard7 in intestinal cancer development is unknown. To explore this issue, we generated a mouse model lacking Stard7 in intestinal epithelial cells (IECs). Loss of Stard7 impaired mitochondrial Complex I activity, led to a severe metabolic and lipid reprogramming, enhanced mitochondrial ROS production and potentiated an mTORC1/ATF4 signature. As a result, levels of enzymes involved in serine biosynthesis were enhanced in Stard7-deficient IECs. We next assessed the consequences of Stard7 deficiency in both Wnt-dependent tumor initiation and in inflammation-driven tumor development. Strikingly, despite generating similar molecular signatures, Stard7 deficiency inhibited tumor development in Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-treated mice but promoted Wnt-driven cancer initiation in the intestine. Apc+/Min mice lacking Stard7 in IECs developed more tumors in the distal colon as well as a specific microbiota signature. Collectively, our results suggest that the genetic status critically controls the effects of Stard7 deficiency on intestinal tumor development.
    Keywords:  Inflammation-driven Intestinal Cancers; STARD7; Wnt-driven Tumor Initiation; mTORC1
    DOI:  https://doi.org/10.1038/s44321-026-00409-5
  52. Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250084. [Epub ahead of print]381(1947):
    Sensitivity of genome-wide tests for mitonuclear genetic incompatibilities.
    Shady A Kuster, Molly Schumer, Justin Havird, Daniel B Sloan.
      Mismatches between interacting mitochondrial and nuclear gene products in hybrids have been proposed to disproportionately contribute to early species boundaries. Under this model, genetic incompatibilities emerge when mitochondrial haplotypes are in a cellular context without their coevolved nuclear-encoded mitochondrial (n-mt) proteins. Some case studies have shown that such disruptions in mitonuclear coevolution can contribute to reproductive isolation, but whether mitonuclear incompatibilities generate selection that impacts multiple n-mt loci and/or causes broad, genome-wide contributions to speciation is unclear. Here, we leverage a system with several hybridizing species pairs (Xiphophorus fishes) that have known mitonuclear incompatibilities of large effect. We divided nuclear-encoded genes into three classes based on level of interaction with mitochondrial gene products. We found only inconsistent statistical support for a difference between these classes in the degree of positive covariation in mitonuclear ancestry. We discuss evidence that these analyses are sensitive to the amount of non-synonymous divergence between parent species in interacting n-mt genes or the age of the hybridization event. Overall, our results imply that genome-wide scans focused on enrichment of broad functional gene classes may often be insufficient for detecting a history of mitonuclear coevolution, even when strong selection is acting on mitonuclear incompatibilities at multiple loci. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.
    Keywords:  genomics; hybrid incompatibilities; mitochondrial evolution; mitonuclear coevolution; n-mt genes
    DOI:  https://doi.org/10.1098/rstb.2025.0084
  53. Immunity. 2026 Mar 30. pii: S1074-7613(26)00088-9. [Epub ahead of print]
    Memory T cell aging and rejuvenation.
    Sarah Adamo, Joel G Rurik, Claire E Gustafson, Marcus Buggert.
      Aging reshapes T cell immunity, as evidenced by eroding naive diversity and remodeled memory hierarchies. This generates an experienced yet constrained repertoire, with weakened protection against novel infections and malignancies and blunted vaccine responsiveness. However, the pace and extent of decline vary widely between individuals. Such heterogeneity signals a recalibration of immune priorities that favors persistence over plasticity of memory T cells. Here, we discuss how aging shapes memory T cell compartments-from repertoire contraction and differentiation to altered metabolic, transcriptional, and epigenetic states. We further examine how chronic inflammation, antigen persistence, and niche remodeling converge to drive dysfunction or resilience. Finally, we outline strategies to rejuvenate T cell immunity during aging to preserve adaptive competence across the lifespan.
    Keywords:  T cells; adaptive competence; aging; memory; rejuvenation
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.018
  54. Nat Commun. 2026 Mar 31.
    Single-cell phenotypic heterogeneity shapes quorum signaling dynamics in Pseudomonas aeruginosa.
    Danielle G Lange, Vadim Litvinov, Daniel Dar.
      Quorum sensing (QS) coordinates collective bacterial behavior, yet how individuality arises within a system built to unify action remains unclear. Using imaging-transcriptomics, we profile the QS response of Pseudomonas aeruginosa at single-cell resolution and uncover heterogeneity across all stages of QS. We find that most cells cooperate, but their contributions vary widely due to transcriptional noise. In contrast, expression of QS signal synthases, particularly in the Las and PQS systems, shows extreme cell-cell variability indicative of active differentiation. We show that cellular memory from prior growth cycles shapes QS dynamics by generating signaling-primed cells, yet it does not influence the de novo formation of hypersignaling cells. This differentiation is robust to exogenous autoinducers and conserved across diverse lab and clinical isolates. Together, our findings reveal a deliberately heterogeneous entry point embedded within an otherwise synchronizing program, shedding light on how individuality shapes cooperation and conflict in bacterial populations.
    DOI:  https://doi.org/10.1038/s41467-026-71109-4
  55. Sci Adv. 2026 Apr 03. 12(14): eaea4279
    The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
    Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Eric Hwang, Claire S Chung, Jaye L Weinert, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.
      Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
    DOI:  https://doi.org/10.1126/sciadv.aea4279
  56. Nat Aging. 2026 Apr 03.
    The case for space as a model of accelerated aging.
    Max Manwaring-Mueller, Huixun Du, Taylor R Valentino, Matias Fuentealba, Alexander Chebykin, Fei Wu, David Furman, Daniel A Winer.
      Aging is a complex biological and societal challenge, where modest advances can yield substantial clinical and economic benefits. While model organisms have uncovered key mechanisms of aging, their physiological relevance to humans remains limited. Astronauts offer a uniquely informative human model: despite being healthy and highly selected, they exhibit many hallmarks of aging and experience comparable declines in cardiovascular, musculoskeletal, cognitive and immune function-often on accelerated timelines. These changes are largely driven by four core exposures of the space environment: microgravity, circadian disruption, ionizing radiation and social isolation. Here, by tracing how environmental factors affect biological processes such as mitochondrial dysfunction, altered cytoskeletal dynamics, chronic inflammation and other canonical hallmarks of aging, we position spaceflight as a powerful model for human aging-one that unites environmental stress biology, multi-omic systems approaches and clinical research to advance both astronaut health and the healthspan of aging populations on Earth.
    DOI:  https://doi.org/10.1038/s43587-026-01105-2
  57. Aging Cell. 2026 Apr;25(4): e70462
    Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.
    Yiting Lei, Meng Yang, Xiaoyun Jiang, Yujie Zhang, Yuzhi Chen, Weiheng Xie, Qihui Dai, Weihong Qin, Xiuqin Deng, Xiaojun Zhang, Zhongjun Zhou, Gonghua Huang, Xinguang Liu.
      Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.
    Keywords:  Pck1; TCA cycle; aging; cGAS/STING signaling; cellular senescence; white adipose tissue
    DOI:  https://doi.org/10.1111/acel.70462
  58. Cell Host Microbe. 2026 Mar 27. pii: S1931-3128(26)00091-0. [Epub ahead of print]
    Bacterial 2',3'-cGAMP activates a SAVED effector to form membrane-disrupting filaments and restrict phage replication.
    Uday Tak, Kate Schinkel, Peace Walth, Jian Wei Tay, Erik W Hartwick, Aaron T Whiteley.
      Mammalian cells initiate antiviral signaling when cyclic GMP-AMP synthase (cGAS) detects cytoplasmic DNA and synthesizes 2',3'-cyclic GMP-AMP (2',3'-cGAMP), which activates stimulator of interferon genes (STING). Similarly, bacteria use cyclic oligonucleotide-based antiphage signaling systems (CBASS) to detect phage using ancestral cGAS/DncV-like nucleotidyltransferases (CD-NTases), but they are not known to use 2',3'-cGAMP. Here, we discover a bacterial CD-NTase that produces 2',3'-cGAMP to activate a Saf-2TM-SMODS-associated fused to various effector domains (SAVED) effector (CD-NTase-associated protein 14 [Cap14]), which initiates membrane disruption to restrict phage replication. Cryo-electron microscopy (cryo-EM) reveals that Cap14 binds 2',3'-cGAMP to form a filament, while electrophysiology suggests that cGAMP activates membrane disruption. Swapping the Cap14 transmembrane domain with a nuclease domain yields a functional chimera that exclusively responds to 2',3'-cGAMP. We hypothesize that other predicted transmembrane effectors in CBASS operons disrupt membranes, and we confirm this by showing that bacterial STING homologs with transmembrane domains restrict phage through membrane disruption. These findings expand our understanding of cGAS-STING-like pathways in bacterial immunity.
    Keywords:  2TM-STING; CBASS; Cap13; Cap14; Saf-2TM-SAVED; antiphage; cGAMP; cGAS; innate immunity; phage
    DOI:  https://doi.org/10.1016/j.chom.2026.03.004
  59. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00268-8. [Epub ahead of print]45(4): 117190
    Sexual dimorphism shapes renal metabolic adaptation to a ketogenic diet.
    Miranda E Kelly, Lauren A Hoffner, Cuauhtemoc B Ramirez, Alexis L Anica, Joohwan Kim, Gregory Tong, Yeojin Kim, Vyshnavi Mannepalli, Wonsuk Choi, Ki-Hong Jang, Yasmine H Alam, Sunhee Jung, Johnny Le, Miranda L Lopez, Varvara I Rubtsova, Hosung Bae, Yujin Chun, Won-Suk Song, Ian J Tamburini, Victor L Schuster, Hoda Anton-Culver, Wei Ling Lau, Thomas F Martinez, Gina Lee, Cholsoon Jang.
      While kidneys are essential for maintaining systemic metabolic homeostasis and exhibit sexual dimorphism, the effects of sex and environmental factors, such as diet, on renal metabolism remain unclear. Using kidney-specific arteriovenous (AV) metabolomics, in vivo isotope tracing, and transcriptomics, we discover profound sex differences in kidney metabolic reprogramming under ketogenic diet (KD) in C57BL/6J mice. Tissue metabolomics shows the accumulation of aldosterone and acylcarnitines exclusively in female kidneys under a normal chow (NC) diet, suggesting basal sex differences in sodium and fatty acid metabolism. Under KD, AV metabolomics reveals that only female kidneys activate ketogenesis and gluconeogenesis, supported by transcriptional sex differences in related rate-limiting enzymes and transporters. Given the widespread public and clinical interest in KD for treating epilepsy, metabolic disorders, and cancers, our findings underscore the importance of considering sex differences in kidney metabolism as a fundamental variable when interpreting KD's diverse effects on pathophysiology and therapeutics.
    Keywords:  CP: metabolism; aldosterone; arteriovenous; gluconeogenesis; ketogenesis; ketogenic diet; ketone body; kidney; metabolic flux; metabolomics; sex difference
    DOI:  https://doi.org/10.1016/j.celrep.2026.117190
  60. Nat Cancer. 2026 Apr 03.
    Single-cell and spatial profiling in cancer biology and clinical oncology.
    Chris J Frangieh, Joy Linyue Fan, Johannes C Melms, Parin Shah, Elham Azizi, Benjamin Izar.
      Multiple single-cell and spatial genomics tools have transformed our ability to deconvolve intricate diseases, including cancer. Analysis of complex, multimodal data has provided insights into genomics, cellular states and interactions in tumor ecosystems, enabling the dissection of salient biology and expanding our understanding of drug response, resistance and target discovery. However, several challenges remain before these methods can achieve their full clinical potential. Here, we discuss opportunities, barriers and potential solutions, including sample acquisition and preservation approaches, profiling methods and analytical tools for heterogeneous populations, and we provide recommendations for robust, reproducible use of these technologies in clinical settings.
    DOI:  https://doi.org/10.1038/s43018-026-01142-1
  61. Cell Rep Med. 2026 Mar 30. pii: S2666-3791(26)00130-8. [Epub ahead of print] 102713
    Single-cell spatial transcriptomics reveals tumor microenvironment heterogeneity in primary and lymph node-metastatic small cell lung cancer.
    Zicheng Zhang, Dongfang Wu, Ruanqi Chen, Modi Zhai, Fan Yang, Jiaqian Wang, Lei Guo, Li Liu, Jianming Ying, Lin Yang, Meng Zhou.
      Lymph node metastasis (LNM) is a critical prognostic and therapeutic determinant in small cell lung cancer (SCLC), yet its spatial cellular ecosystem remains poorly understood. Here, we perform single-cell spatial transcriptomics using the CosMx Spatial Molecular Imager on 105 primary and metastatic lymph node specimens from 75 SCLC patients, generating a comprehensive atlas of over 600,000 cells. We identify three LNM-enriched malignant subclusters with distinct metabolic and angiogenic programs that spatially correlate with immune exclusion features. Spatial analysis reveals vascular-immune crosstalk, wherein endothelial cells orchestrate immune activation through avoidance of malignant cells while forming functional perivascular niches with cytotoxic T cells during LNM. Cellular neighborhood analysis delineates distinct multicellular niches and identifies a pan-immune hotspot (PIHs-1) whose abundance is an independent predictor of survival. This study provides a high-resolution spatial map of the SCLC tumor microenvironment during LNM and establishes spatially defined architectures as both mechanistic insights and translatable biomarkers.
    Keywords:  lymph node metastasis; small cell lung cancer; spatial molecular imaging; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102713
  62. Trends Cell Biol. 2026 Mar 28. pii: S0962-8924(26)00034-6. [Epub ahead of print]
    Tetraploids or polyploid giants: who is truly dangerous?
    Mathew Bloomfield, Shivam Vora, Dinethra Epa, Brian Gabrielli, Daniela Cimini.
      Tetraploidy, resulting from a single whole-genome duplication (WGD) event, contributes to tumorigenesis by promoting genomic instability and functional diversity. In general, WGD beyond tetraploidy limits proliferative and tumorigenic potential, but an increasing number of studies suggest that polyploid giant cancer cells (PGCCs)-large, highly polyploid (≥8N) cells formed in response to chemotherapy-produce daughter cells with reduced DNA content that drive cancer progression. In this opinion article, we examine the literature on tetraploid cells and PGCCs from a cell biology perspective. It is our opinion that the role of tetraploidy in cancer is supported by findings from cell lines, animal models, and tumor sequencing data, while definitive evidence that viable progeny from PGCCs can promote cancer progression in human tumors is lacking.
    Keywords:  PGCC; WGD; cancer progression; polyploid giant cancer cell; tetraploid; whole-genome doubling
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.003
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒05 at 5:04.