bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–05–17
fifty-five papers selected by
Christian Frezza, Universität zu Köln
  1. Whole-blood NAD+ levels do not reflect healthy ageing.
  2. MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
  3. Mitochondrial transfer technologies with molecular insights into clinical applications.
  4. Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
  5. The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
  6. MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
  7. Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
  8. Metabolic underpinnings of cuproptosis.
  9. Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.
  10. When calcium calls the shots in FAD-dependent respiration.
  11. CD8+ T cells turn resilient under stress.
  12. Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.
  13. Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.
  14. In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
  15. m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation.
  16. RNA imbalance as a hallmark of cellular ageing.
  17. Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer.
  18. AMPK: a master regulator of mitochondrial quality and quantity.
  19. Urinary detection of therapy-induced senescence and fibrosis using an injectable albumin-based nanoprobe.
  20. Amino acid metabolism at the senescence-cancer interface.
  21. A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.
  22. Post-translational modifications as key regulators of proline metabolism.
  23. NAD+ supply and redox state limit developmental speed in the Drosophila eye.
  24. 170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
  25. Heme, copper, and a new way to kill cancer cells.
  26. Evidence for negative selection against somatic mutations induced in normal fibroblasts by N-ethyl-N-nitrosourea.
  27. Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.
  28. The cGAS-STING Pathway in the Tumor Immune Microenvironment: Multidimensional Regulation and Therapeutic Implications.
  29. Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
  30. Metabolic vulnerabilities and therapeutic opportunities in diffuse large B-cell lymphoma.
  31. Beyond Correlation: Constraint Architecture Explains Proteome-Metabolome Decoupling.
  32. Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
  33. Stem cells as an essential mediator of the exercise-tumorigenesis link.
  34. The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.
  35. Epitranscriptomic control of cancer: the emerging roles of m⁵C and ac⁴C RNA modifications.
  36. Mitochondria and Qi: Merging Eastern and Western Medicine.
  37. Tracking the fates of cystine in tumours.
  38. Time matters: circadian genetics and the molecular logic of human health and disease.
  39. Aging dictates tumor-specific genomic alterations across cancer types.
  40. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
  41. Biology Needs Philosophy, But What Philosophy?
  42. Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.
  43. A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression.
  44. Evolutionary genetics of ageing.
  45. Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
  46. AI-predicted spatial transcriptomics unlocks breast cancer biomarkers from pathology.
  47. Ecotypes of triple-negative breast cancer in response to chemotherapy.
  48. Harnessing a snake metabolite to control food intake.
  49. Tissue rigidity phase transition shapes morphogen gradients.
  50. Sphingolipid regulation by yeast Mdm1 supports adaptive remodeling of the methionine transporter Mup1.
  51. Sleep chart of biological ageing clocks in middle and late life.
  52. Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
  53. Nicotinic Acetylcholine Receptor Signaling Activates Beige Adipocytes and Mediates Systemic Metabolism.
  54. Decoding Human Longevity: Genetic and Molecular Insights from Accelerated to Successful Ageing.
  55. Recent advances in integrative cryoEM/ET toward visualizing the molecular sociology of cellular organelles.
  1. Nat Metab. 2026 May 14.
    Whole-blood NAD+ levels do not reflect healthy ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01540-w
  2. Nat Metab. 2026 May 13.
    MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
    Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.
      Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.
    DOI:  https://doi.org/10.1038/s42255-026-01513-z
  3. Stem Cells. 2026 May 07. pii: sxag026. [Epub ahead of print]
    Mitochondrial transfer technologies with molecular insights into clinical applications.
    Vahan Martirosian, Berney Peng, Michael A Teitell.
      Mitochondria are essential cell signaling, survival, and bioenergetic organelles that uniquely harbor a maternally inherited, multicopy genome called mitochondrial DNA (mtDNA). The occurrence or accumulation of mtDNA mutations underlies a spectrum of inherited and acquired mitochondrial syndromes and diseases and is increasingly recognized as a source of metabolic plasticity, clonal fitness, and therapy tolerance in cancer. Recent studies have revealed mitochondrial transfer as a potential mode of intercellular communication that could compensate for mtDNA mutation-associated mitochondrial dysfunction. Transfer of mitochondria can restore homeostasis in stressed recipient cells by rebuilding respiratory capacity, rebalancing redox state, and reshaping cell fate. Reported mechanisms of transfer include tunneling nanotubes, extracellular vesicles, cell fusion, and others, such as macropinocytosis. Here, we review and evaluate emerging technologies developed for mitochondrial transfer studies and define the impact of transfer on cell physiology and pathology. We discuss translational opportunities for mitochondrial transfer-based interventions, as well as how mitochondrial exchange may represent a new framework for understanding tumor heterogeneity, adaptation, and aggressiveness.
    Keywords:  Mitochondria; Mitochondrial transfer; mtDNA; techniques; transplantation
    DOI:  https://doi.org/10.1093/stmcls/sxag026
  4. Dev Cell. 2026 May 13. pii: S1534-5807(26)00123-1. [Epub ahead of print]61(5): 1146-1161.e8
    Single-molecule mitochondrial DNA imaging reveals heteroplasmy dynamics shaped by developmental bottlenecks and selection in vivo.
    Rajini Chandrasegaram, Sara Gottardo, Abhilesh Dhawanjewar, Antony M Hynes-Allen, Beitong Gao, Suvagata Roy Chowdhury, Luis-Carlos Tábara, Michele Frison, Stavroula Petridi, Patrick F Chinnery, Julien Prudent, Hansong Ma, Jelle van den Ameele.
      Mitochondrial DNA (mtDNA) exists in many copies per cell, with cell-to-cell variability in mutation load, which is known as heteroplasmy. Developmental and age-related expansion of heteroplasmic mtDNA mutations contributes to the pathogenesis of mitochondrial and neurodegenerative diseases. Here, we describe an approach for in situ sequence-specific detection of single mtDNA molecules (mtDNA-single-molecule fluorescent in situ hybridization [smFISH]). We apply this method to visualize and measure mtDNA and heteroplasmy levels in situ at single-cell resolution in whole-mount Drosophila tissue and cultured human cells. In Drosophila, we identify a somatic mtDNA bottleneck during neurogenesis. This amplifies heteroplasmy variability between neurons, as predicted by a mathematical bottleneck model, predisposing individual neurons to a high mutation load. However, both during neurogenesis and oogenesis, mtDNA segregation is accompanied by purifying selection, promoting wild-type (WT) over pathogenic mtDNA. mtDNA-smFISH thus elucidates how developmental cell-fate transitions, accompanied by changes in cell morphology, behavior, and metabolism, can shape the transmission and selection of deleterious mtDNA variants.
    Keywords:  Drosophila; bottleneck; heteroplasmy; mitochondria; mitochondrial DNA; mitochondrial disease; neurogenesis; oogenesis; purifying selection; single-molecule fluorescent in situ hybridization
    DOI:  https://doi.org/10.1016/j.devcel.2026.03.011
  5. Aging Cell. 2026 05;25(5): e70534
    The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
    Prasanna Katti, Praveena Prasad, Sepiso K Masenga, Prasanna Venkhatesh, Zer Vue, Andrea G Marshall, Benjamin Rodriguez, Han Le, Edgar Garza-Lopez, Alexandria Murphy, Brenita Jenkins, Ashlesha Kadam, Jianqiang Shao, Amber Crabtree, Pamela Martin, Chantell Evans, Mark A Phillips, David Hubert, Nelson Wandira, Okwute M Ochayi, Dhanendra Tomar, Clintoria R Williams, Jennifer Gaddy, Briar Tomeau, LaCara Bell, Taneisha Gillyard, Markis' Hamilton, Vineeta Sharma, Mohd Mabood Khan, Elma Zaganjor, Olujimi A Ajijola, Estevão Scudese, Tyne W Miller Fleming, André Kinder, Chandravanu Dash, Anita M Quintana, Bret C Mobley, Julia D Berry, Pooja Jadiya, Dao-Fu Dai, Annet Kirabo, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Renata Oliveira Pereira, Debra D Murray, Joyonna Gamble-George, Melanie R McReynolds, Antentor Hinton.
      Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age-related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block face-scanning electron microscope and manual segmentation using the Amira software were employed to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health.
    Keywords:  3DEM; MICOS complex; kidney; metabolism; mitochondria
    DOI:  https://doi.org/10.1111/acel.70534
  6. Trends Cell Biol. 2026 May 13. pii: S0962-8924(26)00065-6. [Epub ahead of print]
    MitoSafe hypothesis: safeguarding mitochondrial morphology and innate immunity.
    Nora Haggerty, Kentaro Nakamura, Hiromi Sesaki, Miho Iijima.
      Mitochondria divide and fuse, and the balance between these processes maintains mitochondrial morphology and function. Although the core fusion and division machinery is well established, how cells sense mitochondrial morphology and actively adjust it remains unclear. In this Opinion article, we propose a new conceptual framework, termed 'Mitochondrial Safeguard (MitoSafe)', in which cells monitor mitochondrial size and rebalance division and fusion through four branches: activation of fusion or inhibition of division in small mitochondria and activation of division or inhibition of fusion in enlarged mitochondria. Recent findings show that fusion is suppressed once mitochondria exceed a healthy size threshold. Dysregulation of this branch of MitoSafe, involving Parkin, PINK1, SLC25A3, SOD1, and cytochrome-c oxidase, causes mitochondrial enlargement, mitochondrial DNA release, and stimulator of interferon genes (STING)-mediated inflammation.
    Keywords:  OMA1; PINK1; Parkin; dynamin-related GTPase; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.007
  7. Mitochondrion. 2026 May 12. pii: S1567-7249(26)00057-7. [Epub ahead of print]90 102167
    Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
    Ayumu Sugiura, Kohta Nakamura, Heidi M McBride, Yasushi Okazaki.
      Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.
    Keywords:  Lysosomes; Mitochondria; Mitochondrial-derived vesicles; Peroxisomes
    DOI:  https://doi.org/10.1016/j.mito.2026.102167
  8. Cell Chem Biol. 2026 May 14. pii: S2451-9456(26)00144-3. [Epub ahead of print]
    Metabolic underpinnings of cuproptosis.
    Dadi Jiang, Li Zhuang, Albert C Koong, Boyi Gan.
      Cuproptosis is a recently defined form of regulated cell death (RCD) driven by copper-induced mitochondrial proteotoxic stress. Distinct from other RCD pathways such as apoptosis and ferroptosis, cuproptosis arises when copper binds to lipoylated metabolic enzymes in mitochondria, leading to their aggregation, loss of iron-sulfur cluster proteins, and metabolic collapse. This discovery establishes a mechanistic link between metal homeostasis and mitochondrial metabolism, positioning cuproptosis as a "cell-sabotage" pathway in which essential metabolic processes become self-destructive when dysregulated. In this review, we synthesize recent advances in understanding the molecular and metabolic basis of cuproptosis, its intersection with other metabolic cell death pathways such as ferroptosis, and its emerging therapeutic relevance in cancer. We further discuss the potential involvement of cuproptosis-like mechanisms in neurodegenerative disorders and highlight the outstanding questions and translational challenges that will guide future efforts to exploit this unique metabolic vulnerability for disease intervention.
    Keywords:  cancer; cell metabolism; copper; cuproptosis; mitochondria
    DOI:  https://doi.org/10.1016/j.chembiol.2026.04.009
  9. J Clin Invest. 2026 May 15. pii: e194687. [Epub ahead of print]136(10):
    Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.
    Pauline Morigny, Honglei Ji, Laura Cussonneau, Sabrina Zorzato, Yun Kwon, Fabien Riols, Doris Kaltenecker, Alisa Maier, Vignesh Karthikaisamy, Samantha Corrà, Tanja Krauss, Claudine Seeliger, Syed Qaaifah Gillani, Joël J Tissink, Sandra Lacas-Gervais, Tuna Felix Samanci, Adriano Maida, Raul Terron-Exposito, Angela Trinca, Christine von Toerne, Leonardo Nogara, Melina Claussnitzer, Olga Prokopchuk, Jeannine Bachmann, Mauricio Berriel Diaz, Laure B Bindels, Ondrej Kuda, Hans Hauner, Mark Haid, Stephan Herzig, Carlo Fiore Viscomi, Jerome Gilleron, Anja Zeigerer, Bert Blaauw, Maria Rohm.
      Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.
    Keywords:  Cancer; Lipidomics; Metabolism; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/JCI194687
  10. Nat Metab. 2026 May 13.
    When calcium calls the shots in FAD-dependent respiration.
    Pablo Hernansanz-Agustín.
      
    DOI:  https://doi.org/10.1038/s42255-026-01516-w
  11. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  12. J Clin Invest. 2026 May 15. pii: e206031. [Epub ahead of print]136(10):
    Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.
    Kerui Huang, Norbert Perrimon, Marcus D Goncalves.
      Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.
    DOI:  https://doi.org/10.1172/JCI206031
  13. Nat Metab. 2026 May 14.
    Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.
    Maria M Trętowicz, Angelique M L Scantlebery, Bauke V Schomakers, Kaan D Eroğlu, Michel van Weeghel, Vera Spek, Kasper T Vinten, Luc Legon, Evrim Coskun, Fernando Millan-Domingo, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera, Silvia Montoro-García, Clara Noguera-Navarro, André B P van Kuilenburg, Sofia Moco, Juliette C van Hattum, Harald T Jørstad, Mohammed Benali, Jantine van der Helder, Esmee J M Biersteker, Maheswary Muniandy, Kirsi H Pietiläinen, Eija Pirinen, P Eline Slagboom, Marian Beekman, Joris Deelen, Rubén Zapata-Pérez, Peter J M Weijs, Michael Tieland, Georges E Janssens, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) levels in blood and tissues are widely proposed to decline with age, yet evidence in human blood is inconsistent. Using a rigorously validated ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry system that accounts for real-world analytical variability, we quantify NAD+ across seven independent human cohorts. We find that whole-blood NAD+ levels remain remarkably stable with age and across lifestyle interventions, but change in response to nicotinamide riboside supplementation, as expected. Our results challenge the utility of blood NAD+ levels as a biomarker of ageing or lifestyle factors.
    DOI:  https://doi.org/10.1038/s42255-026-01537-5
  14. EMBO Rep. 2026 May 14.
    In the absence of mitochondrial fusion unequal segregation of mitochondria drives mtDNA loss.
    Lisa Dengler, Francesco Padovani, Bianca Lemke, Rebecca Brugger, Alissa Benedikt, Benedikt Westermann, Boris Maček, Kurt M Schmoller, Jennifer C Ewald.
      Mitochondrial biogenesis and inheritance must be tightly coordinated with cell division to maintain mitochondrial function and cell survival. The dynamics of the mitochondrial network, including fusion and fission, are essential for mitochondrial inheritance and quality control. In budding yeast, simultaneous inhibition of both processes compromises mitochondrial DNA (mtDNA) integrity, increasing the frequency of petite cells. Loss of fusion alone completely eliminates mtDNA. Although this has been known for decades, why mtDNA is lost remained unclear. Here, we examine the effects of impaired mitochondrial fusion by depleting the mitofusin Fzo1. By analyzing over thirty thousand single cells across their cell cycles, we show that Fzo1-depletion induces rapid mitochondrial fragmentation and loss of membrane potential, followed by progressive declines in mtDNA content and growth rate. During division, Fzo1-depleted daughters inherit disproportionately large mitochondrial amounts, leaving mothers with too little. This imbalance, combined with an inability to upregulate compensatory mtDNA synthesis, drives rapid mtDNA loss. Our results reveal how fusion defects cause mtDNA loss and mitochondrial dysfunction, which might have implications for diseases linked to impaired fusion.
    DOI:  https://doi.org/10.1038/s44319-026-00794-5
  15. Nat Commun. 2026 May 14.
    m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation.
    Yucheng Wang, Alice A Daddi, Amir Hosseini, Kazuki Kato, Ehsan Khalili, Håvard T Lindholm, Mengjie Li, Yadong Wang, David C Michael, Catherine A O'Brien, Daniel D De Carvalho, Jan Rehwinkel, Parinaz Mehdipour.
      How cancer cells evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts remains unclear. In cancer, endogenous REs that escape epigenetic silencing are transcribed and can form double-stranded RNA (dsRNA), which activates innate immune responses through viral mimicry. However, RNA-level mechanisms can limit this effect. Here we show that the m6A RNA methyltransferase METTL3 acts as a key regulator of this suppression in colorectal cancer (CRC). Targeting METTL3 increases the accumulation of dsRNAs derived from both pre-existing and newly transcribed REs, amplifying immunostimulatory signalling and activating cell-intrinsic anti-tumour immunity. CRCs display variable sensitivity to METTL3 inhibition: tumours with high basal dsRNA and RNA methylation respond to METTL3 blockade alone, whereas those with low RNA methylation require combination therapy. Co-treatment with DNA methyltransferase inhibitors (DNMTis) restores immune activation in resistant tumours. Together, our findings identify METTL3 as an RNA-level immune checkpoint and suggest combined METTL3 and DNMT inhibition as a therapeutic strategy in CRC.
    DOI:  https://doi.org/10.1038/s41467-026-73211-z
  16. Nat Cell Biol. 2026 May 12.
    RNA imbalance as a hallmark of cellular ageing.
    Ping Sun, Benjamin A Miller, Aaron P Sakai, Kevin Rhine.
      Major advances over the past few decades have highlighted the complex regulation of RNA from transcription to nuclear export and from translation to decay. Despite the emerging cellular landscape of malleable and multifunctional RNA molecules, the role of RNA dysregulation in ageing, one of the most fundamental processes of human biology, is underappreciated. Here we focus on ageing-linked dysregulation of the mRNA life cycle. We summarize how RNA metabolism steadily deviates throughout ageing and senescence: in transcription, aged cells bias shorter genes at the expense of complex transcripts; in splicing, ageing-linked alternative exon usage is common; in translation, ribosomal collisions on mRNAs decouple transcriptional output from protein production; and in decay, aberrant RNAs accumulate due to poor degradation activity. We close by discussing how ageing-linked dysregulation of RNA biology can drive cellular stress and thus serve as a therapeutic target to reverse disease.
    DOI:  https://doi.org/10.1038/s41556-026-01946-4
  17. Nat Commun. 2026 May 13.
    Mechano-metabolic feedback connects tissue fluidity to mitochondrial DNA-dependent immunity in breast cancer.
    Andrea Palamidessi, Emanuela Frittoli, Monica Corada, Emanuele Martini, Leonardo Barzaghi, Chiara Milanese, Galina V Beznoussenko, Alessandro Lazzarin, Edoardo N Bellini, Alexander A Mironov, Zeno Lavagnino, Serena Magni, Sara Barozzi, Dario Parazzoli, Laura Tizzoni, Valentina Dall'Olio, Valeria Cancila, Patrizia Romani, Melody Di Bona, Renata Zobalova, Stepana Boukalova, Mattia Rediti, Pier G Mastroberardino, Jiri Neuzil, Marco Foiani, Sirio Dupont, Claudio Tripodo, Giorgio Scita.
      Why some tumors respond to immunotherapy ("hot" tumors) while others remain resistant ("cold" tumors) is a central challenge in oncology. Elevated RAB5A-dependent endocytosis drives tissue fluidization during the transition to invasive breast carcinoma, but its immunological consequences are unclear. Here we show that RAB5A-driven fluidization induces a mechano-metabolic stress response that disrupts the AMPK-AKAP1-DRP1 mitochondrial fission pathway, causing mitochondrial elongation. RAB5A vesicles interact with hyperfused mitochondria and promote BAX/BAK-dependent pore formation, leading to limited mitochondrial outer membrane permeabilization. This sub-lethal event is amplified by palmitoylated GASDERMIN A oligomerization on mitochondria, establishing a positive feedback loop. The resulting release of mitochondrial DNA activates the cGAS-STING innate immune pathway and drives a hyperinflammatory state. Consequently, RAB5A-expressing tumors in immunocompetent mice grow more slowly, show increased immune infiltration, and display enhanced sensitivity to immune-checkpoint blockade in a BAX/BAK-, cGAS/STING-, and mtDNA-dependent manner. These findings connect mechanical stress, mitochondrial dynamics, and innate immunity, revealing strategies to potentiate antitumor immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-026-71795-0
  18. Trends Cell Biol. 2026 May 12. pii: S0962-8924(26)00066-8. [Epub ahead of print]
    AMPK: a master regulator of mitochondrial quality and quantity.
    Reuben J Shaw, Ian G Ganley, Julien Prudent, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) may have arisen soon after the endosymbiosis event that generated eukaryotes, perhaps to allow the archaeal host to communicate its requirements for ATP to the bacterial endosymbionts that became mitochondria. Consistent with this, AMPK is now known to regulate most aspects of the mitochondrial life cycle. It drives fragmentation of the network by promoting fission and inhibiting fusion, increasing mitochondrial number while allowing isolation of dysfunctional fragments from the network. It promotes the biogenesis of new mitochondrial components while also regulating mitophagy, promoting the degradation of dysfunctional mitochondria and inhibiting the removal of functional mitochondria. We will discuss these new findings and propose that the regulation of mitochondria was an ancient function of AMPK originating in the early eukaryote.
    Keywords:  endosymbiosis; mitochondrial biogenesis; mitochondrial fission; mitochondrial fusion; mitophagy; origin of eukaryotes
    DOI:  https://doi.org/10.1016/j.tcb.2026.04.008
  19. Nat Aging. 2026 May 13.
    Urinary detection of therapy-induced senescence and fibrosis using an injectable albumin-based nanoprobe.
    Muhamad Hartono, Jianfeng Ge, Mary Denholm, Matthew G Ellis, Joaquín Araos Henríquez, Andrew G Baker, Robert C Rintoul, Tijmen Euser, Ljiljana Fruk, Daniel Muñoz-Espín.
      Cellular senescence is a hallmark of age-related disorders, including cancer, in which senescence contributes to tumor progression and treatment resistance. Targeting senescent cells therapeutically requires noninvasive methods to longitudinally monitor senescence burden. Here, we present an injectable nanoprobe for noninvasive detection of therapy-induced senescence in lung cancer and pulmonary fibrosis via urine testing. Using human biopsy samples, clinical transcriptomic datasets and mouse models, we identify matrix metalloproteinase-7 (MMP-7) as a specific biomarker of senescence in lung cancer and bleomycin-induced fibrosis. We develop ALBANC, a nanoprobe composed of human serum albumin linked to gold nanoclusters (AuNCs) through MMP-7-cleavable peptide linkers. MMP-7-mediated cleavage releases AuNCs that are renally excreted, enabling rapid and sensitive colorimetric urine detection via a nanoparticle growth-based assay, enabling longitudinal tracking of cisplatin-induced senescence and senolysis in mouse lung tumors and fibrosis. This approach offers a noninvasive and sensitive precision tool for monitoring senescence burden in lung cancer.
    DOI:  https://doi.org/10.1038/s43587-026-01116-z
  20. Trends Cancer. 2026 May 14. pii: S2405-8033(26)00083-X. [Epub ahead of print]
    Amino acid metabolism at the senescence-cancer interface.
    Giulia Lori, Caterina Mancini, Erica Pranzini, Francesca Magherini, Maria L Taddei.
      Amino acid (AA) metabolism plays a fundamental role in the regulation of cellular senescence. Through profound AA metabolic reprogramming, senescent stromal cells can sustain tumor progression, metastatic dissemination, and the establishment of an immunoevasive microenvironment. Conversely, alterations in AA availability within the tumor microenvironment can enforce tumor-suppressive senescence in malignant cells. In this review, we discuss how senescence-driven rewiring of AA metabolism shapes tumor-stroma interactions and immune responses. We propose that AA-targeted interventions may represent an effective therapeutic strategy to simultaneously mitigate the detrimental effects of stromal senescence while inducing tumor-suppressive senescence in cancer cells.
    Keywords:  amino acid metabolism; cellular senescence; immunoevasion; metastatic colonization; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.04.007
  21. bioRxiv. 2026 Feb 24. pii: 2026.02.23.707530. [Epub ahead of print]
    A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.
    Melanie Key, Steven Joseph, Zhicheng Dou.
      Intracellular pathogens must coordinate their metabolism with nutrient supplies from the host cell, yet the specific metabolites and transport pathways that sustain parasite bioenergetics remain incompletely defined. In the apicomplexan parasite Toxoplasma gondii , infection increases host glycolytic flux and elevates cytosolic lactate and pyruvate, suggesting that these intermediates are co-opted as carbon and energy sources. Here, we show that T. gondii imports host-derived lactate and pyruvate across both the parasitophorous vacuole membrane and the parasite plasma membrane to maintain mitochondrial function, extracellular survival, and acute virulence. Using a hexokinase knockout (Δ hk ) to abolish endogenous pyruvate production, we find that parasites preserve basal oxygen consumption but become strictly dependent on exogenous monocarboxylates to stimulate mitochondrial respiration. By disrupting the parasite formate-nitrite transporters TgFNT1-3, we identify TgFNT1 and TgFNT2 as the principal monocarboxylate transporters required for lactate- and pyruvate-driven respiratory responses. Furthermore, genetic ablation of TgGRA17, a parasitophorous vacuole pore protein, compromises the growth advantage conferred by elevated exogenous lactate, implicating this pore as the entry route for host-derived monocarboxylates into the vacuole. Conversely, host cells lacking the monocarboxylate exporter MCT1 accumulate cytosolic lactate/pyruvate and enhance parasite growth, linking host monocarboxylate export to parasite fitness. When both endogenous pyruvate production and exogenous uptake are disrupted, parasites display severely reduced mitochondrial basal respiratory capacity, membrane potential, ATP levels, extracellular survival, and virulence in mice. Collectively, these findings define a dual-step pyruvate acquisition pathway in T. gondii and reveal host monocarboxylates as critical fuels that buffer parasite bioenergetic stress during infection.
    Significance Statement: Intracellular parasites rely on host nutrients to power their metabolism, yet the routes by which these metabolites cross the membranes between host cytosol and parasite mitochondria are not well defined. Here, we show that Toxoplasma gondii exploits host glycolysis by importing lactate and pyruvate to sustain mitochondrial function and virulence. We identify a two-step pathway in which these monocarboxylates cross the parasitophorous vacuole via the pore GRA17 and then enter the parasite through the formate-nitrite transporters TgFNT1/2. Blocking both endogenous glycolysis and this exogenous pyruvate supply disables parasite mitochondrial fitness, extracellular survival, and virulence. These findings reveal a fundamental strategy of metabolic plasticity in apicomplexan parasites using a multi-membrane nutrient gateway that couples host glycolysis to parasite bioenergetics.
    DOI:  https://doi.org/10.64898/2026.02.23.707530
  22. Trends Biochem Sci. 2026 May 14. pii: S0968-0004(26)00109-X. [Epub ahead of print]
    Post-translational modifications as key regulators of proline metabolism.
    Nina Durand, Arnould Savouré, Sandrine Lebreton.
      Post-translational modifications (PTMs) are emerging as crucial regulators of proline metabolism, a pathway central to redox homeostasis, stress adaptation, and disease progression conserved across species. Beyond transcriptional regulation, PTMs such as phosphorylation, acetylation, and ubiquitination fine-tune the activity, stability, and localization of proline metabolic enzymes, including those involved in its biosynthesis and catabolism. Advances in proteomics and structural biology now provide insights into how these reversible modifications modulate enzyme oligomerization and metabolic flux, with involvement in plant stress tolerance and cancer cell survival. Here, we synthesize recent observations across kingdoms, discuss how PTMs integrate into metabolic control, and highlight future directions for exploiting PTM-based regulation in agriculture and human health.
    Keywords:  cancer metabolism; evolutionary conservation; post-translational modifications; proline metabolism; redox regulation; stress adaptation
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.009
  23. EMBO J. 2026 May 13.
    NAD+ supply and redox state limit developmental speed in the Drosophila eye.
    Nisha Veits, Yuting Guo, Jingjing He, Khalil Mazouni, Ivan Nemazanyy, Martin Bres, Cara Picciotto, Claire Mestdagh, Yan Yan, Francois Schweisguth.
      The cellular and biochemical processes that define the speed at which embryos develop, tissues form, and cells differentiate remain largely unknown. Using the speed of progression of a differentiation front in the developing Drosophila eye to measure developmental speed, we identified genetic perturbations that slowed the progression of this front. Inhibiting the electron transport chain (ETC), and more generally energy production in mitochondria, resulted in reduced developmental speed. Defective ETC activity led to increased NADH/NAD+ ratio, whereas ATP levels remained constant due to a compensatory increase in glycolysis. Targeted perturbations showed that the metabolic state of the cells ahead of and/or at the differentiation front determined its speed. Genetic and diet-based perturbations of NAD+ metabolism indicated that developmental speed was limited by NAD+ availability. Thus, developmental speed appeared constrained by the cellular redox state and the demand for NAD+ in the developing Drosophila eye. Our findings therefore show that the NADH/NAD+ ratio is key to regulating developmental speed and highlight the importance of NAD+ availability for this regulation in Drosophila.
    DOI:  https://doi.org/10.1038/s44318-026-00801-4
  24. J Clin Pharmacol. 2026 May;66(5): e70209
    170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
    Volkmar Weissig.
      One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.
    Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases
    DOI:  https://doi.org/10.1002/jcph.70209
  25. EXO. 2026 ;pii: 202605. [Epub ahead of print]1(1):
    Heme, copper, and a new way to kill cancer cells.
    Xi Zhao, Li Zhuang, Boyi Gan.
      Heme homeostasis influences mitochondrial metabolism and leukemia stem cell biology in acute myeloid leukemia. Lewis et al. uncover a surprising metabolic vulnerability in acute myeloid leukemia: suppression of heme biosynthesis primes leukemic cells for cuproptosis, a form of copper-dependent cell death. By linking heme depletion to mitochondrial cytochrome c oxidase (Complex IV) dysfunction, copper accumulation, and cuproptosis, the study integrates transcriptional regulation, mitochondrial metabolism, and metal homeostasis into a unified framework for selective cancer cell killing.
    Keywords:  BTB and CNC homology 1; Heme; acute myeloid leukemia; copper; cuproptosis
    DOI:  https://doi.org/10.70401/EXO.2026.0004
  26. Genome Res. 2026 May 15. pii: gr.281376.125. [Epub ahead of print]
    Evidence for negative selection against somatic mutations induced in normal fibroblasts by N-ethyl-N-nitrosourea.
    Ronald Cutler, Johanna Heid, Shixiang Sun, Moonsook Lee, Alex Maslov, Lei Zhang, Simone Sidoli, Xiao Dong, Jan Vijg.
      Mutations accumulate with age in most human tissues. While some undergo clonal expansion and contribute to disease, the mutational burden tolerated by a normal cell without functional decline remains unknown. Here, we repeatedly treat proliferating human primary fibroblasts with the point mutagen N-ethyl-N-nitrosourea, and analyze mutation burden by single-cell whole-genome sequencing. Mutation burden increases linearly to ~56,000 single-nucleotide variants per cell, with only a modest reduction in growth rate. We detect negative selection against potentially deleterious coding and noncoding variants, including mutations affecting pathways important for cell growth and maintenance. These findings suggest that selective depletion of harmful variants helps proliferating cells maintain function despite an extreme mutation burden. Because most adult tissues are largely nondividing and cannot remove damaging mutations through a growth disadvantage, somatic mutations that accumulate during aging may have pronounced functional consequences in vivo.
    DOI:  https://doi.org/10.1101/gr.281376.125
  27. J Biol Chem. 2026 May 14. pii: S0021-9258(26)02022-3. [Epub ahead of print] 113150
    Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells.
    Chengmeng Jin, Siying Zeng, Hao Wu, Xun Hu.
      Intracellular lactic acidosis, a metabolic state newly defined in this study, is characterized by a coupled increase in intracellular lactate and proton concentrations, resulting in higher levels inside cancer cells than outside. This finding expands the Warburg paradigm: lactic acidosis is not merely extracellular but intracellular, reshaping metabolism through direct biochemical mechanisms. Acidic pH and elevated lactate jointly suppress glycolysis by inhibiting HK, PFK1 and GAPDH, enforcing a low-flux, energy-efficient state. Meanwhile, pyruvate enters the TCA cycle through a pyruvate - lactate -export - reimport - lactate - pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly. Lactic acidosis also reprograms anaplerosis by promoting lactate-derived oxaloacetate formation and reducing glutamine dependence. Together, these findings establish lactic acidosis as an active regulator of cancer metabolism, revealing a distinct metabolic state. This coupled lactate-proton state drives coordinated metabolic reprogramming across glycolysis and mitochondrial metabolism. representing a fundamental tumor adaptation that may be exploited to disrupt cancer metabolic resilience.
    Keywords:  TCA cycle; Warburg effect; glycolysis; lactic acidosis; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.113150
  28. Crit Rev Oncol Hematol. 2026 May 14. pii: S1040-8428(26)00261-1. [Epub ahead of print] 105374
    The cGAS-STING Pathway in the Tumor Immune Microenvironment: Multidimensional Regulation and Therapeutic Implications.
    Siyu Wu, Boyan Tian, Yahui Sun, Chang Sun, Bowen Sui.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a prominent target in cancer immunotherapy. The highly heterogeneous and dynamically plastic nature of the tumor immune microenvironment (TIME) dictates the outcomes of immunotherapeutic interventions. Although the cGAS-STING pathway has been extensively studied in tumor immunity, current reviews predominantly focus on canonical linear signaling or cell-autonomous functions within isolated immune or tumor cell types, thereby failing to establish an integrated mechanistic framework that accounts for coordinated crosstalk among malignant, immune, and stromal compartments. Here, we move beyond the conventional paradigm of ligand-dependent, cell-intrinsic STING activation and instead adopt a systems-level perspective grounded in spatiotemporal context and dynamic regulation. We systematically delineate how cGAS-STING activity exerts context-dependent, non-cell-autonomous effects across the multicellular TIME network-functioning not as a generic immune amplifier, but as a regulatory axis that orchestrates immune-ecological reconfiguration of the microenvironment. Accordingly, we argue that next-generation therapeutic strategies should transition from indiscriminate pathway activation toward precision-targeted intervention and microenvironmental reprogramming-thereby enabling rational design of more effective and durable cancer immunotherapies.
    Keywords:  Immune cells; Immunotherapy; Stromal cells; Tumor immune microenvironment; cGAS-STING pathway
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105374
  29. Nat Chem Biol. 2026 May 14.
    Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
    Yanghao Zhong, Ayse Z Sahan, Zhengyao Shao, Qian-Yi Zhang, Xin Zhou, Jack G Haggett, Keiichi Koshizuka, Samuel A Myers, J Silvio Gutkind, Jin Zhang.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient sensor that integrates diverse inputs to regulate protein translation and cell growth. While mTORC1 is activated on the lysosome in the classical model, it has become increasingly clear that this multifaceted signaling complex is active at various subcellular locations, such as the nucleus. However, what specific functions mTORC1 serves at these locations and how its signaling is compartmentalized are unclear. To interrogate subcellular pools of mTORC1, we developed TerminaTOR, a genetically encodable inhibitor of mTORC1 that can be targeted to specific subcellular locations. When TerminaTOR is directed to the lysosome, it inhibits canonical lysosomal mTORC1 and induces autophagy. Furthermore, TerminaTOR targeted to the nucleus specifically inhibits nuclear mTORC1, uncovering noncanonical roles of nuclear mTORC1 in regulating the transcription of CCAAT motif-containing genes. Thus, mTORC1 exhibits functional spatial compartmentalization and TerminaTOR serves as a powerful tool for unraveling spatially regulated functions of mTORC1 across different scales.
    DOI:  https://doi.org/10.1038/s41589-026-02188-z
  30. Oncogenesis. 2026 May 15. pii: 22. [Epub ahead of print]15(1):
    Metabolic vulnerabilities and therapeutic opportunities in diffuse large B-cell lymphoma.
    Marie Anne-Catherine Neumann, Christian Frezza.
      Diffuse large B cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma (NHL), exhibits considerable biological heterogeneity. While its classification has traditionally relied on genetic and transcriptomic features, emerging evidence points to distinct metabolic subtypes that may represent novel therapeutic vulnerabilities. Intriguingly, current chemoimmunotherapy regimens exert profound but non-specific effects on tumour metabolism, inadvertently exploiting metabolic dependencies yet without precision. Novel inhibitors targeting glucose, amino acid, lipid, and mitochondrial metabolism demonstrate selective cytotoxicity in metabolically defined lymphoma subsets. This review investigates how standard therapies exploit DLBCL metabolism and examines heterogeneity across subtypes, and evaluates targeted metabolic therapies. We discuss emerging combination strategies with current therapeutic regimes and immunotherapy. Particular focus is given to the metabolic interactions between tumour cells and immune effectors, including CAR T cells and bispecific antibodies. We highlight the importance of translational research to validate metabolic subtypes through metabolomic profiling, identify predictive biomarkers, and develop rational combinations. Moving beyond empiric therapy towards strategic metabolic targeting offers an opportunity to enhance outcomes for patients with this aggressive and diverse lymphoma.
    DOI:  https://doi.org/10.1038/s41389-026-00629-x
  31. Int J Mol Sci. 2026 Apr 29. pii: 3971. [Epub ahead of print]27(9):
    Beyond Correlation: Constraint Architecture Explains Proteome-Metabolome Decoupling.
    Kyung-Hee Kim, Byong Chul Yoo.
      Multi-omics technologies enable parallel quantification of proteomic and metabolomic layers, yet enzyme abundance often shows weak or nonlinear correspondence under diverse biological conditions. This apparent discordance has been attributed to both technical limitations-such as dynamic range compression in LC-MS/MS, metabolite derivatization artifacts, and missing values in proteomic measurements-as well as intrinsic biological properties of metabolic network architecture. While technical factors contribute to cross-omic mismatch, accumulating evidence suggests that constraint-driven network behavior plays a major role in shaping this decoupling. Enzyme abundance constrains catalytic capacity; however, realized flux is selected within this capacity under distributed flux control, as formalized by flux control coefficients in metabolic control analysis, and is further modulated by enzyme kinetics (e.g., km and Vmax), post-translational modifications, substrate availability, and thermodynamic constraints. Metabolite pools, in turn, reflect the physicochemical state of the system, while specific metabolites can also act as regulatory effectors that modulate enzymatic activity and cellular signaling. Because metabolic networks are underdetermined, multiple flux configurations can satisfy identical protein abundance and metabolite concentration data. Static cross-layer correlation is therefore insufficient for mechanistic inference. We synthesize biological mechanisms-including post-translational regulation, allostery, thermodynamic buffering, spatial compartmentalization, feedback amplification, and redox gating-that weaken linear abundance-metabolite expectations. We further outline a constraint-based interpretation framework in which proteomics imposes capacity bounds, metabolomics informs reaction directionality and metabolite pool constraints, and flux-informed approaches reduce solution degeneracy by providing additional information on pathway activity. Moving beyond correlation requires integrating perturbation, temporal resolution, and constraint-aware modeling. Proteome-metabolome discordance should therefore be interpreted not as inconsistency, but as indicative of constraint-driven state selection within high-dimensional biochemical systems.
    Keywords:  constraint-based modeling; fluxomics; metabolic flux; metabolomics; proteomics; redox metabolism; systems biology; thermodynamics
    DOI:  https://doi.org/10.3390/ijms27093971
  32. Bioessays. 2026 May;48(5): e70146
    Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
    Yi Sheng, Zachary Markovich, Sung Min Han, Rui Xiao.
      Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age-related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPRMT) and integrated stress response (ISR) are discussed, including their tissue-specific as well as non-cell-autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context-dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.
    Keywords:  aging; integrated stress response; mitochondria ROS; mitochondrial dynamics; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1002/bies.70146
  33. Nat Rev Cancer. 2026 May 14.
    Stem cells as an essential mediator of the exercise-tumorigenesis link.
    Xueqian Zhuang, Emily S Wong, Tuomas Tammela, Lee W Jones.
      Aerobic exercise has a profound influence on host physiology and cancer risk, yet the mechanisms of how these are linked remain incompletely understood. Since adult stem cells (ASCs) respond to shifts in organismal (host) physiology and are also likely the cancer cells of origin, ASC function could act as an essential mediator of the link between aerobic exercise and cancer incidence. We therefore hypothesize that exercise-induced alterations in host physiology lead to sculpting of distal tissue microenvironments to augment the regenerative capacity of ASCs whilst simultaneously activating highly conserved cell-intrinsic and cell-extrinsic processes that suppress pro-tumorigenic phenotypes. In this Perspective, we dissect this hypothesis by first examining how exercise regulates host physiology through alterations in the systemic milieu and then focus on how these changes shape distant tissue landscapes in which ASCs reside. We then discuss the effects of exercise on ASC function and speculate on the cell-intrinsic and cell-extrinsic mechanisms that may explain the apparent paradox of exercise-induced enhanced stemness in the context of tumour suppression. A better understanding of how exercise-sensing pathways regulate ASC function to maintain or restore tissue homeostasis will have implications for cancer prevention as well as for other age-related conditions in which ASC degradation is complicit.
    DOI:  https://doi.org/10.1038/s41568-026-00933-z
  34. Elife. 2026 May 15. pii: RP102680. [Epub ahead of print]13
    The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells.
    Guillaume Lefrançois, Emilie Lavallée, Marie-Camille Rowell, Véronique Bourdeau, Farzaneh Mohebali, Thierry Bertomeu, Ana Maria Duman, Maya Nikolova, Mike Tyers, Simon-Pierre Gravel, Andreea R Schmitzer, Gerardo Ferbeyre.
      Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD+/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.
    Keywords:  ATP5I; F1ATPase; NAD metabolism; biguanides; biochemistry; chemical biology; human; mitochondria; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.102680
  35. Cell Death Discov. 2026 May 12.
    Epitranscriptomic control of cancer: the emerging roles of m⁵C and ac⁴C RNA modifications.
    Xian Zhong, Jianmei Mao, Jiawei Zhang.
      Cytidine RNA modifications have emerged as key regulators of tumor cancer biology, linking transcriptional control to metabolic adaptation and immune evasion. Among them, 5-methylcytidine (m⁵C) and N⁴-acetylcytidine (ac⁴C) represent dynamic and functionally complementary epitranscriptomic marks that operate through distinct regulatory layers. m⁵C, catalyzed by the NSUN family methyltransferases, primarily stabilizes pro-tumorigenic transcripts, enhances glycolysis, and suppresses antitumor immunity through modulation of cytokine and checkpoint pathways. In parallel, ac⁴C, mediated by the acetyltransferase NAT10, fine-tunes translational efficiency and proteostasis, enabling tumor cells to adapt to metabolic and therapeutic stress. Together, these modifications cooperatively remodel the tumor immune microenvironment by driving macrophage polarization, T-cell exhaustion, and attenuation of interferon signaling, establishing a durable immunosuppressive niche. Notably, pharmacologic or genetic inhibition of m⁵C- and ac⁴C-modifying enzymes reverses malignant phenotypes and restores sensitivity to immune checkpoint and metabolic therapies. Elucidating this two-layer cytidine epitranscriptomic architecture unveils new epigenetic dimensions of tumor plasticity and offers promising avenues for precision RNA-targeted oncology.
    DOI:  https://doi.org/10.1038/s41420-026-03135-6
  36. Pharmacol Res. 2026 May 11. pii: S1043-6618(26)00158-1. [Epub ahead of print] 108243
    Mitochondria and Qi: Merging Eastern and Western Medicine.
    Wanqing Xie, Deborah G Murdock, Douglas C Wallace.
      Since the discovery of mitochondrial DNA (mtDNA) diseases almost 40 years ago, large numbers of diseases have been linked to mutations in both mtDNA and nuclear DNA (nDNA) genes that perturb the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS). Mitochondrial dysfunction is being implicated not only in rare primary mitochondrial diseases but also a wide range of common diseases, yet the availability of effective mitochondrial therapies remains limited. One potential source of mitochondrial therapeutic approaches is Traditional Chinese Medicine (TCM). TCM emphasizes the health-preservation philosophy and practical experience centered around the concept of "Qi", or vital force, and has generated Qi-oriented therapies over the past several thousand years. We propose that various properties and functions attributed to Qi may be explained by modulation of mitochondrial bioenergetics, the interplay between OXPHOS and fatty acid oxidation versus glycolysis and the pentose phosphate pathway (PPP), and the mitochondrial regulation of the immune system through mitochondrial reactive oxygen species (mROS). Hence, TCM therapeutics may provide approaches for treating the increasing spectrum of mitochondria associated diseases.
    Keywords:  Mitochondria; Qi; TCM; energy; mtDNA; therapy
    DOI:  https://doi.org/10.1016/j.phrs.2026.108243
  37. Nat Cell Biol. 2026 May;28(5): 841
    Tracking the fates of cystine in tumours.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-026-01967-z
  38. Nat Rev Genet. 2026 May 14.
    Time matters: circadian genetics and the molecular logic of human health and disease.
    Tia Tyrsett Kuo, Jiarui Wang, Steve A Kay.
      Time is an essential but often underappreciated determinant of human physiology and disease. The circadian clock, a genetic timing system, orchestrates transcriptional and signalling networks across tissues to maintain homeostasis. Recent discoveries have refined our understanding of this system, from a linear transcription-translation feedback loop to a distributed, dynamically coupled network that integrates environmental cues and physiological processes. Genetic variation in core circadian genes and circadian misalignment are now recognized as key modifiers of disease risk, progression and therapeutic response. As precision medicine begins to embrace temporal biology, defining how the circadian clock operates in health and disease has become increasingly important. This Review synthesizes recent advances in circadian genetics and molecular mechanisms, emphasizing their physiological, pathological and therapeutic implications, and outlines future priorities: resolving the composition of the molecular clock, developing disease-specific models, and expanding the chemical toolbox to modulate and interrogate circadian pathways.
    DOI:  https://doi.org/10.1038/s41576-026-00962-2
  39. NPJ Aging. 2026 May 12.
    Aging dictates tumor-specific genomic alterations across cancer types.
    Isabella N Grabski, Jaime L Schneider, Sara Hanahan, Arvind Ravi, Justin F Gainor, Kevin M Haigis, Rafael A Irizarry, Marcia C Haigis.
      Cancer risk increases exponentially with age. As the world's population grows older, the absolute number of cancer diagnoses and cancer-related deaths continues to rise globally, despite declines in age-adjusted cancer mortality in many high-income countries. However, there is still little known about how molecular features of tumors differ according to patient age and how these genomic alterations may impact the treatment of patients of advanced age compared to younger patients who are diagnosed with malignancy. In this study, we survey the largest clinically- and genomically-annotated database available and identify age-associated mutations across distinct cancer types, defined as genes whose mutation rates in cross-sectional cancer populations differ by age. By interrogating paired clinical and genomic data from the AACR Project GENIE database across brain, breast, colorectum, lung, pancreas, and skin cancers, we identified somatic mutations in tumors with distinct age-dependent patterns. We also uncovered age-specific associations in the co-mutation patterns among these genes, demonstrating relationships among mutations that strengthen or weaken with age, as well as connections between age-specific mutation patterns and environmental covariates. Finally, in an exploratory analysis, we observed age-associated trends between PTPRT mutations in lung cancer and clinical response to immune checkpoint inhibitors, highlighting the possibility that certain genomic alterations may differentially associate with outcomes across patient age groups.
    DOI:  https://doi.org/10.1038/s41514-026-00392-8
  40. Nat Commun. 2026 May 15.
    α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
    Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-κB-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-Syn-induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.
    DOI:  https://doi.org/10.1038/s41467-026-73136-7
  41. Bioscience. 2026 May;76(5): 417-428
    Biology Needs Philosophy, But What Philosophy?
    James DiFrisco, Steven Hecht Orzack.
      Philosophy of biology has the potential to contribute to biology by improving scientific reasoning. However, this potential is largely unrealized because of the lack of awareness by most biologists of what philosophy can offer, because of deficits of biological expertise among most philosophers, and because of adherence to disciplinary norms in philosophy that render much work in philosophy of biology irrelevant to biologists. We believe that philosophy of biology will contribute little to biology without a change of practice. We provide guidelines ("comments" sensu Slobodkin 1975, "commandments" sensu Kornberg 2000, 2003, Francis et al. 2007) for how biologists can better engage with philosophy and for how philosophers can better engage with biology so as to create a "philosophical biology" that improves our biological understanding.
    Keywords:  cell biology; evolutionary biology; philosophical biology; philosophy of biology; theoretical biology
    DOI:  https://doi.org/10.1093/biosci/biag016
  42. Am J Physiol Regul Integr Comp Physiol. 2026 May 13.
    Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.
    Miriam Zerrouk, Luca J Delfinis, Christopher G R Perry, Olasunkanmi A J Adegoke.
      Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue and skeletal muscle. Tumor tissue at 4 weeks exhibited higher BCAA levels and elevated branched-chain α-ketoacid dehydrogenase (BCKD) activity compared to samples collected at 2 weeks. At 4 weeks, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to control. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.
    Keywords:  Amino acid transporters; branched-chain amino acids; branched-chain α-keto acids; cancer cachexia; tissue metabolism
    DOI:  https://doi.org/10.1152/ajpregu.00320.2025
  43. Cell Stem Cell. 2026 May 11. pii: S1934-5909(26)00153-0. [Epub ahead of print]
    A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression.
    Xue Han, Kexin Wang, Weiwei Ma, Songqi Zhu, Jingjing Guan, Xiaobin Tian, Zhuangzhuang Zhao, Linjia Jiang.
      Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic stem cells (LSCs) in acute myeloid leukemia (AML) exhibit elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis, compared with blast cells and normal hematopoietic stem cells (HSCs). Deletion of Hmgcs2 in AML cells markedly decreases BHB levels, disrupts LSC function, and impairs leukemia progression in both mouse and human AML models while largely sparing normal hematopoiesis. Mechanistically, BHB suppresses ferroptosis by limiting pro-ferroptotic phospholipid remodeling through epigenetic regulation of fatty acid desaturase 2 (FADS2). Together, these findings identify autonomous ketogenesis as a critical metabolic program that protects LSCs from ferroptotic cell death and sustains leukemia progression.
    Keywords:  AML; BHB; FAO; HMGCS2; LSCs; acute myeloid leukemia; fatty acid oxidation; ferroptosis; ketogenesis; leukemic stem cells; lipid peroxidation; phospholipid remodeling; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.stem.2026.04.013
  44. Nat Rev Genet. 2026 May 11.
    Evolutionary genetics of ageing.
    Handan Melike Dönertaş, Linda Partridge.
      Modern humans now routinely survive to advanced ages, in far greater proportions than ancestral populations, and thus experience the consequences of molecular pathways optimized for youth yet still active in old age. Natural selection weakens over the course of adulthood, creating a selection 'shadow' in which deleterious late-acting mutations accumulate and alleles with early-life benefits persist despite late-life costs. An evolutionary lens helps us to understand puzzling patterns - from conserved longevity pathways spanning the tree of life to a 100-fold variation in maximum lifespan across vertebrates - and explains why age-related diseases share genetic architectures. Advances in comparative genomics, large-scale human genetic studies and multi-omics ageing biomarkers now enable rigorous testing of evolutionary predictions. This Review integrates evolutionary genetics with molecular mechanisms to clarify why ageing evolves, how it varies across species and individuals, and how these insights can guide healthspan extension.
    DOI:  https://doi.org/10.1038/s41576-026-00959-x
  45. Nat Commun. 2026 May 12.
    Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa.
    Linghui Kong, Jiajian Liang, Dan Liu, Shanshan Jia, Hui Gu, Yiwen He, Wenting Luo, Songying Cao, Yizhang Dong, Chao Yang, Minghui Liao, Guojia Wan, Bo Du, Dongxue Ding, Wei Ma, Xiaowei Wei, Anhua Wu, Zhengwei Yuan.
      Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-13C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-026-72988-3
  46. Cell. 2026 May 08. pii: S0092-8674(26)00458-7. [Epub ahead of print]
    AI-predicted spatial transcriptomics unlocks breast cancer biomarkers from pathology.
    Eldad D Shulman, Emma M Campagnolo, Roshan Lodha, Youngmin Chung, Amos Stemmer, Thomas Cantore, Beibei Ru, Tian-Gen Chang, Sumona Biswas, Saugato Rahman Dhruba, Sumeet Patiyal, Sushant Patkar, Andrew Wang, Ranjan K Barman, Chuhan Wang, Rohit Paul, Sarath Chandra Kalisetty, Tom Hu, MacLean P Nasrallah, Ellis Patrick, Jean Yang, Yuan Yuan, Karine Sargsyan, Amy Plotkin, Padma Sheila Rajagopal, Stephen-John Sammut, Stanley Lipkowitz, Peng Jiang, Carlos Caldas, Simon R V Knott, Kenneth Aldape, Joo Sang Lee, Danh-Tai Hoang, Eytan Ruppin.
      Spatial transcriptomics (ST) assays are transforming our understanding of tumor heterogeneity, but their high cost limits their application in large-scale biomarker discovery. Here, we present "Path2Space," a deep-learning model that predicts spatial gene expression directly from histopathology slides. Trained on extensive breast cancer ST data, Path2Space robustly predicts the spatial expression of thousands of genes, outperforming 21 established methods. Charting the tumor microenvironment (TME) of 976 breast cancer TCGA (The Cancer Genome Atlas) tumors, it accurately infers cell-type abundances and identifies three spatially defined breast cancer subgroups with distinct survival outcomes. Notably, the derived low-cost spatial TME landscapes enable more accurate predictions of patient response to chemotherapy and trastuzumab compared with costly conventional bulk-sequencing-based biomarkers. Path2Space thus offers a scalable, fast, and cost-effective alternative to molecular assays. It opens avenues for large cohort treatment biomarker discovery and translationally relevant insights into tumor biology, with potential applicability across many cancer indications.
    Keywords:  HER2; artificial intelligence; breast cancer; deep learning; digital pathology; histopathology; spatial biomarkers; spatial transcriptomics; treatment response prediction; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2026.04.023
  47. Nature. 2026 May 13.
    Ecotypes of triple-negative breast cancer in response to chemotherapy.
    Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Aatish Thennavan, Jianzhuo Li, Emi Sei, Tuan Tran, Min Hu, Mitchell Rao, Chenling Tang, Siyuan He, Anna Casasent, Elizabeth Ravenberg, Gaiane Margishvili Rauch, Alyson R Clayborn, Debu Tripathy, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin.
      Triple-negative breast cancer (TNBC) is an aggressive subtype that is frequently treated with chemotherapy, but only half of the patients respond well and have good clinical outcome1,2. Here we leveraged pretreatment tissue samples from treatment-naive patients with TNBC who received neoadjuvant chemotherapy and performed single-cell transcriptomic analysis of 427,857 cells from 101 patients and spatial transcriptomic analysis of 44 patients. We classified TNBC tumours into 4 patient-level subtypes (archetypes) using the cancer-cell gene expression and identified 13 metaprograms that reflect intra-tumoural heterogeneity at the single-cell level. The TNBC tumour microenvironment consisted of 49 immune and stromal cell states, many of which were reprogrammed relative to normal breast tissues. Furthermore, we identified eight distinct cellular communities (ecotypes) on the basis of the co-occurrences of cancer cells and tumour microenvironment cell types, and their spatial organization in tissues. In contrast to previous studies on T cells, our data show the importance of macrophage subtypes and cancer-cell metaprograms for interferon signalling, human leukocyte antigen expression and cell cycle activity that are associated with a good response to neoadjuvant chemotherapy. Collectively, this study provides new insights into the biology of untreated TNBC tumours and their association with chemotherapy response.
    DOI:  https://doi.org/10.1038/s41586-026-10469-9
  48. Trends Endocrinol Metab. 2026 May 14. pii: S1043-2760(26)00118-9. [Epub ahead of print]
    Harnessing a snake metabolite to control food intake.
    Adèle Buckenmeyer, Nabil Nasri, Daniela Cota.
      Many diverse signals regulate feeding behavior. In Nature Metabolism, Xiao et al. describe the discovery of a new appetite-suppressant metabolite found in pythons, which is also conserved in humans. This research broadens our understanding of postprandial physiology and raises new questions related to metabolic pathology and therapy.
    Keywords:  food intake; gut microbiota; hypothalamus; metabolite; python
    DOI:  https://doi.org/10.1016/j.tem.2026.04.013
  49. Nat Cell Biol. 2026 May 14.
    Tissue rigidity phase transition shapes morphogen gradients.
    Camilla Autorino, Diana Khoromskaia, Louise Harari, Elisa Floris, Harry Booth, Cristina Pallares-Cartes, Vesta Petrasiunaite, Michael Dorrity, Bernat Corominas-Murtra, Zena Hadjivasiliou, Nicoletta I Petridou.
      During development, local mechanochemical cues within the cell microenvironment are translated into signalling pathways that drive cell fate decisions. Yet, as cells differentiate collectively, how global tissue-level properties shape these instructive cues remains unclear. Here we show that a tissue-scale rigidity transition guides patterning by tuning the length scales and timescales of morphogen signalling. By combining rigidity percolation theory, reaction-diffusion modelling, quantitative imaging and optogenetics in zebrafish, we uncover dynamical global tissue rigidity patterns that actively shape the Nodal morphogen gradient by locally changing its concentration and accelerating its signalling activity. In this self-generated mechanism, Nodal, besides instructing meso-endoderm fate specification, increases cell-cell adhesion strength via regulating planar cell polarity genes. Once the adhesion strength reaches a critical point, it triggers a rigidity transition which, in turn, induces the collapse of tissue porosity. The abrupt tissue reorganization negatively feeds back on Nodal signalling, impacting both its length scales, by restricting Nodal diffusivity, and its timescales, by speeding up the expression of its antagonist Lefty, thereby ensuring timely signal termination and robust patterning. Overall, we uncover a multiscale regulatory mechanism by which positional information and tissue material properties dynamically tune one another.
    DOI:  https://doi.org/10.1038/s41556-026-01954-4
  50. bioRxiv. 2026 Feb 26. pii: 2026.02.25.707973. [Epub ahead of print]
    Sphingolipid regulation by yeast Mdm1 supports adaptive remodeling of the methionine transporter Mup1.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Scott Miller, Anne Ostermeyer-Fay, Daniel Canals, Xun Bao, Jing Li, Hanaa Hariri.
      Membrane lipid composition influences endocytic remodeling of nutrient transporters, yet how lipid metabolism is spatially coordinated to support sustained adaptation to nutrient limitations remains unclear. Here, we investigated whether the ER-vacuole tether Mdm1 links sphingolipid homeostasis to regulation of the high-affinity methionine permease Mup1 in budding yeast. To test this, we examined Mup1 trafficking, amino acid homeostasis, and sphingolipid composition in mdm1 Δ cells during starvation. We found that loss of Mdm1 causes persistent retention of Mup1 at the plasma membrane, accompanied by reduced intracellular methionine and broad amino acid depletion. Lipidomic analyses revealed decreased sphingoid bases and altered ceramide composition in mdm1 Δ cells. Importantly, supplementation with the sphingolipid precursor phytosphingosine restored sphingolipid pools, rescued Mup1 endocytosis, and improved amino acid homeostasis. Consistent with a chronic amino acid restriction-like state, mdm1 Δ cells exhibited extended chronological lifespan. Together, these findings identify Mdm1 as a spatial organizer of sphingolipid metabolism required for adaptive endocytic remodeling of Mup1, thereby linking ER-vacuole contact site function to plasma membrane proteostasis and metabolic adaptation.
    DOI:  https://doi.org/10.64898/2026.02.25.707973
  51. Nature. 2026 May 13.
    Sleep chart of biological ageing clocks in middle and late life.
    MULTI Consortium
      Optimal sleep has a vital role in promoting healthy ageing and enhancing longevity. Here we propose Sleep Chart to assess the relationship between self-reported sleep duration and 23 biological ageing clocks derived from in vivo imaging1, plasma proteomics2 and metabolomics3. First, a systemic, U-shaped pattern emerges between sleep duration and biological age gaps across nine brain and body systems and three omics technologies. The sample-specific lowest biological age gaps are achieved between 6.4 and 7.8 h of sleep duration, varying by organ and sex in the UK Biobank (aged 37-84 years). Furthermore, short (<6 h) and long (>8 h) sleep duration, compared with a normal sleep duration (6-8 h), are associated with increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time-to-incident survival predictions, such as depression and diabetes. Finally, the pathways by which long and short sleep duration are associated with late-life depression differ: ageing clocks may partially mediate the pathway for long sleep duration, while short sleep duration shows a more direct link. Although Mendelian randomization does not provide strong evidence that disease causally affects sleep, it cannot completely exclude such reverse causality. Our findings suggest a cross-organ, multi-omics U-shaped relationship between sleep duration and biological ageing clocks, highlighting the potential of sleep optimization to promote healthy ageing, lower disease risk and extend longevity.
    DOI:  https://doi.org/10.1038/s41586-026-10524-5
  52. Nat Aging. 2026 May 14.
    Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
    David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.
      Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.
    DOI:  https://doi.org/10.1038/s43587-026-01120-3
  53. Diabetes. 2026 May 13. pii: db250781. [Epub ahead of print]
    Nicotinic Acetylcholine Receptor Signaling Activates Beige Adipocytes and Mediates Systemic Metabolism.
    Shanshan Liu, Kezhou Zhu, Wenwen Zhang, Tong Pan, Martin O'Brien, Ichitaro Abe, Lily Dale, Justin Piejak, Nadia Houssein, Biyang Zhang, Matthew Fein, Shingo Kajimura, Raymond Yung, X Z Shawn Xu, Jun Wu.
       ARTICLE HIGHLIGHTS: Beige-adipocyte activity, mediated by CHRNA2, significantly influences adipose function and systemic metabolism. The CHRNB2 subunit forms a functional receptor with CHRNA2 and is essential for the response to nicotinic acetylcholine receptor agonists in beige adipocytes. Deletion of Chrnb2 in mice compromises the adaptive response to cold in subcutaneous adipose tissue and renders exacerbated metabolic dysfunction due to diet-induced obesity. This cholinergic signaling within subcutaneous adipose tissue declines with aging. CHRNB2 partial agonists, a family of drugs clinically used for smoking cessation, activate both murine and human beige adipocytes.
    DOI:  https://doi.org/10.2337/db25-0781
  54. Ageing Res Rev. 2026 May 14. pii: S1568-1637(26)00168-6. [Epub ahead of print] 103176
    Decoding Human Longevity: Genetic and Molecular Insights from Accelerated to Successful Ageing.
    Monica Cattaneo, Sara Carnevali, Paolo Madeddu, Annibale A Puca.
      Ageing is an inevitable, yet highly heterogeneous process shaped by genetic, epigenetic, and environmental influences. While most individuals experience progressive functional decline, a minority exhibits accelerated degeneration due to rare pathogenic mutations, whereas others achieve exceptional healthy longevity. This continuum-from progeroid syndromes to centenarians-provides a unique framework to examine how deleterious and protective genetic variants differentially modulate conserved biological pathways. Genetic models of accelerated ageing reveal mechanisms driving premature functional deterioration, whereas studies of exceptionally long-lived individuals highlight variants associated with resilience, stress adaptation, and preserved homeostasis. Together, these extremes define a genetic dichotomy that informs, but does not deterministically predict, ageing trajectories. This review critically highlights current evidence on genetic factors and molecular mechanisms that regulate human ageing across this spectrum. Beyond established hallmarks such as cellular senescence and chronic inflammation, we discuss emerging pathways implicated in successful ageing, including hypoxic adaptation, transcriptional and chromatin regulation, autophagy, and metabolic reprogramming. We further evaluate epigenetic clocks as quantitative tools for assessing biological ageing, emphasising their strengths, limitations, and context dependence. Throughout, we distinguish between genetic associations, mechanistic findings, and preclinical evidence, explicitly addressing gaps, biases, and translational uncertainty. This synthesis was conducted using a qualitative narrative review approach integrating human genetic data, mechanistic studies, and translational evidence across models of accelerated and successful ageing.
    Keywords:  Ageing; Longevity; centenarian alleles; genetic dichotomy
    DOI:  https://doi.org/10.1016/j.arr.2026.103176
  55. Curr Opin Struct Biol. 2026 May 14. pii: S0959-440X(26)00069-2. [Epub ahead of print]98 103287
    Recent advances in integrative cryoEM/ET toward visualizing the molecular sociology of cellular organelles.
    Jingwei Xu.
      Advances in cryo-electron microscopy and tomography (cryoEM/ET) allow us to visualize cellular ultrastructure at molecular resolution in a near-native state. By bridging the resolution between cell and structural biology, in situ cryoEM/ET unravels unprecedented molecular details of macromolecular complexes, as well as their spatial organization, within intact cells and organelles. Beyond structural determination, emerging image processing pipelines combine subtomogram averaging with contextual, quantitative, and multimodal analyses to reveal how molecules are coordinated in cellular space - what might be termed the "molecular sociology" of cells. Here, we review recent progress in specific cellular organelles, highlight key conceptual trends, and discuss current limitations and future perspectives for integrative in situ structural biology.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103287
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