bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–06–28
sixty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Host metabolism can produce many indoles and phenols independently of the microbiome.
  2. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  3. Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
  4. Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
  5. Proteolytic coordination of the OXPHOS Life Cycle.
  6. The metabolic basis of regulated cell death.
  7. Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
  8. How long-term dietary cholesterol can slow down its own clearance by liver cells.
  9. Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.
  10. Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
  11. De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
  12. Assembly of the catalytic module and the rotor of human ATP synthase.
  13. Three decades of cancer genetics.
  14. Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.
  15. Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
  16. Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
  17. Molecular architecture of the human citrate synthase-malate dehydrogenase 2 metabolon.
  18. Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.
  19. Mapping and engineering the human cell-cell interactome.
  20. FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
  21. Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA.
  22. Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
  23. Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.
  24. Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
  25. Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
  26. Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
  27. A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
  28. Phosphatidylserine and RhoB connect PI4P and PA metabolism to maintain plasma membrane identity.
  29. Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
  30. NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma.
  31. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  32. mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.
  33. Mediator subunit MED4 enforces metastatic dormancy in breast cancer.
  34. Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
  35. An immunological panacea for cancer-related cachexia.
  36. Mitochondrial stress response drives microglial senescence.
  37. Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
  38. Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.
  39. Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.
  40. Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2.
  41. Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
  42. A ratiometric fluorescent reporter of mitochondrial sodium.
  43. Chronic stress unleashes an intratumor phage-fibroblast-B cell circuit to promote tumor growth.
  44. Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
  45. Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state differentiation.
  46. A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
  47. Somatic mutations impose an entropic upper bound on human lifespan.
  48. Lactate as a Chemical Modification on Proteins and Metabolites.
  49. Meta-analysis of DNA methylation aging signatures in 17 human tissues.
  50. MitoCatch directs mitochondria delivery and prevents cell degeneration.
  51. Metabolic control of RNA splicing by polyamines.
  52. The Heterogeneity of B Cells Potentially Contributes to Metastasis of Clear Cell Renal Cell Carcinomas.
  53. Persistence of memory: lifespan dynamics of the human antiviral antibody reactome.
  54. Cellular assembly and functional resilience of the mammalian RNA exosome.
  55. Amino acid sensing and signaling in plants.
  56. Excessive vascular integrity restricts anti-tumor immunity.
  57. The multifaceted inducers of cellular senescence.
  58. Age-dependent epigenetic control of flavonoid metabolism underlies chemical defenses in ancient Ginkgo biloba.
  59. Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
  60. Intratumoral B cells under stress.
  61. The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.
  1. Nat Metab. 2026 Jun 23.
    Host metabolism can produce many indoles and phenols independently of the microbiome.
    Jenna E AbuSalim, Kellen Olszewski, Salma Youssef, Sarah J Mitchell, Craig J Hunter, Jessica Little, Ashley Sidebottom, Jacob A Boyer, Steve D Knutson, Laith Z Samarah, Michael R MacArthur, Alessa L Henneberg, Rolf-Peter Ryseck, Christiane A Opitz, David W C MacMillan, Mohamed S Donia, Eric G Pamer, Sabrina Imam, Christopher J Lehmann, Olatoyosi Odenike, Joshua D Rabinowitz.
      Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown because they have important physiological impacts, with indoles agonizing aryl hydrocarbon receptor signalling and phenols being associated with healthy body weight. Although there is a growing body of research on which bacteria produce these metabolites, the host contribution to their circulating pools has not been characterized. Here, through stable isotope tracing in cell culture, mice and rats, we show that mammalian cells can make aryl-pyruvates, aryl-lactates, aryl-acetates and aryl-carboxylic acids independently of the microbiome. We demonstrate that circulating levels of these metabolites in mice and human patients are robust to perturbations of the microbiome. By contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol and p-cresol. Overall, these results suggest that host metabolism is a major contributor to circulating indole and phenol metabolite pools.
    DOI:  https://doi.org/10.1038/s42255-026-01550-8
  2. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  3. Nature. 2026 Jun 24.
    Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
    Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Priyadarshini Jaishankar, Pusu Yang, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Linmeng Han, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, Philip L S M Gordts, Adam R Renslo, Peng Zhao, Amit R Majithia, Alan R Saltiel.
      Metabolism of the hepatic low-density lipoprotein receptor (LDLR) is a key determinant of cholesterol homeostasis1,2. The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined3-6. Here we identify a new pathway regulated by Ral GTPases that links extracellular cholesterol signals to the intracellular trafficking machinery controlling LDLR turnover. Chronic dietary cholesterol activates the Ral proteins by increasing RAS activity, routing LDLR to lysosomes for degradation and inhibiting its recycling independently of transcriptional regulation or PCSK9. Constitutive activation of Ral via RalGAPB deletion or overexpression of constitutively active Ral mutants in hepatocytes reduces LDLR levels and impairs cholesterol clearance. Ral engages the endocytic RalBP1-REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA). Ral activation directs CTSA towards lysosomes for maturation while limiting its secretion, further promoting LDLR degradation in lysosomes. Genetic variants in this pathway significantly associate with altered cholesterol in humans. Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease.
    DOI:  https://doi.org/10.1038/s41586-026-10697-z
  4. Nat Commun. 2026 Jun 23. pii: 5563. [Epub ahead of print]17(1):
    Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry.
    Laura Pérez Pañeda, Jelena Misic, Tereza Kadavá, Nils-Göran Larsson, Albert J R Heck.
      Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F1-TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.
    DOI:  https://doi.org/10.1038/s41467-026-74730-5
  5. Biochem J. 2026 Jul 08. 483(7): 1253-1280
    Proteolytic coordination of the OXPHOS Life Cycle.
    Nataliia Nechytailo, Karolina Szczepanowska.
      The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.
    Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover
    DOI:  https://doi.org/10.1042/BCJ20250120
  6. Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]
    The metabolic basis of regulated cell death.
    Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.001
  7. bioRxiv. 2026 Jun 12. pii: 2026.06.11.731694. [Epub ahead of print]
    Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
    Andrea L Cote, Claire L McIntyre, Joshua A Acklin, Lillian R Delacruz, Yunping Qiu, Irwin J Kurland, Alison E Ringel.
      Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8 + T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.
    DOI:  https://doi.org/10.64898/2026.06.11.731694
  8. Nature. 2026 Jun 25.
    How long-term dietary cholesterol can slow down its own clearance by liver cells.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-01899-6
  9. Trends Cancer. 2026 Jun 20. pii: S2405-8033(26)00126-3. [Epub ahead of print]
    Horizontal mitochondrial transfer and the tug-of-war between cancer cells and immune cells.
    Jaromir Novak, Denisa Hortova, Berwini Endaya, Magdalena Krulova, Michael V Berridge, Jiri Neuzil.
      Horizontal mitochondrial transfer (HMT) is an emerging field of cell biology. Since its discovery, HMT has been extensively studied in the context of cancer due to the essential role of mitochondria in fueling the proliferation of tumor cells. The role of HMT in cancer, however, reaches far beyond a simple mechanism of organelle acquisition. Indeed, several recent studies have demonstrated HMT from cancer to immune cells and vice versa, with a profound impact on antitumor immune responses and potentially on immunotherapy efficacy. In this opinion article, we propose that HMT should receive attention as another modulatable mechanism of the functional tug-of-war between cancer and immune cells, further contributing to the complexity of the tumor microenvironment and likely sculpting the outcome of competition between the two teams of cells.
    Keywords:  horizontal mitochondrial transfer; immunotherapy; tumor-infiltrating lymphocytes; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.trecan.2026.05.008
  10. bioRxiv. 2026 Jun 10. pii: 2026.06.06.727699. [Epub ahead of print]
    Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
    Kyoungmin Kim, Tanvi Shankar, Yaqi Gao, Ian K Williamson, Nathaniel Snyder, Evan P Kransdorf, Ralph DeBerardinis, Heinrich Taegtmeyer, Brandon Faubert, Anja Karlstaedt.
       Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits α-ketoglutarate dehydrogenase (α-KGDH) and is associated with reduced cardiac contractile function.
    Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress.
    Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation.
    Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress and provide evidence that reductive-citrate formation may induce epigenetic modifications in the heart.
    DOI:  https://doi.org/10.64898/2026.06.06.727699
  11. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00665-0. [Epub ahead of print]45(7): 117587
    De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity.
    Julia L Weber, Tien Bui, Keomonyroth Nuon, Adam J Fike, Sophia M Crocker, Kristen N Bricker, Anju Maharjan, Wujuan Zhang, Aaron R Goldman, Sathi Babu Chodisetti, Ziaur S M Rahman.
      Whether and how pyrimidine metabolites promote systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in systemic lupus erythematosus (SLE)-prone B cells. Temporal inhibition of pyrimidine synthesis dampens SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC), and antibody responses. Uridine monophosphate synthase (UMPS) conditional deletion, however, reveals a B cell-intrinsic requirement of de novo pyrimidine synthesis in foreign antigen-driven and SLE-prone GC, PC, and antibody responses and kidney immune complex deposition. Metabolomics, mitochondrial stress test, metabolic flow cytometry, glycolytic rate assay, and RNA sequencing highlight the importance of pyrimidine synthesis in promoting aerobic glycolysis and oxidative phosphorylation in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator, cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promote pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.
    Keywords:  CAD; CP: Immunology; UMPS; autoantibody; autoimmunity; germinal center; mTORC1; plasma cell; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117587
  12. EMBO J. 2026 Jun 26.
    Assembly of the catalytic module and the rotor of human ATP synthase.
    Jiuya He, Joe Carroll, Shujing Ding, Jiao Li, Ian M Fearnley, John E Walker.
      Human ATP synthase is a molecular rotary machine bound in inner mitochondrial membranes, built from twenty-eight subunits of seventeen kinds, two encoded in mitochondrial DNA, the remainder in nuclear genes. The machine consists of a rotor and an interacting stator. Turning of the rotor driven by a transmembrane proton motive force effects a cycle of structural changes in the catalytic part of the stator, producing three ATP molecules per rotation. Here, to establish how the stator and rotor are assembled, we deleted subunits and known assembly factors from human cells, purified and accumulated assembly intermediate complexes, and characterized them by gel analysis and mass spectrometry, allowing us to propose pathways of assembly of the rotor and the catalytic F1-module of the stator. These observations provide opportunities for further development by structural analysis of the accumulated intermediates. The compositions of the various assembly intermediates support the view that ATP synthase arose via independent evolution of its three constituent structural components, the catalytic F1-module, the peripheral stalk module, and the membrane-associated Fo-module.
    DOI:  https://doi.org/10.1038/s44318-026-00842-9
  13. Nat Genet. 2026 Jun 26.
    Three decades of cancer genetics.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41588-026-02657-0
  14. Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00658-3. [Epub ahead of print]45(7): 117580
    Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.
    Valentino Sudaryo, Dayanne R Carvalho, Jacqueline A Carozza, Xujun Cao, Courtney Kernick, Anthony F Cordova, J Michelle Lee, Theodore L Roth, Lingyin Li.
      STING (stimulator of interferon genes) agonists are promising innate immune therapies and can be synergized with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. How STING agonists such as cGAMP and its analogs enter and induce STING activation and toxicity in T cells is unclear despite known transporters for other cell types. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter in activated primary mouse and human T cells. T cells upregulate this transporter upon activation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity, suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.
    Keywords:  ADU-S100; CP: immunology; CP: molecular biology; LRRC8A; LRRC8C; SLC7A1; STING; T cells; VRAC; arginine; cGAMP; extracellular cGAMP; toxicity
    DOI:  https://doi.org/10.1016/j.celrep.2026.117580
  15. Nat Commun. 2026 Jun 25.
    Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
    Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.
      Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.
    DOI:  https://doi.org/10.1038/s41467-026-74315-2
  16. bioRxiv. 2026 Jun 09. pii: 2026.06.05.730515. [Epub ahead of print]
    Revealing the spatiotemporal dynamics of methionine metabolism with a genetically encoded single-fluorophore biosensor.
    Katarina A Cohen, Arnav Jhawar, Gilberto Garcia, Naiara Goni, Megan Chen, Athena Alcala, Ryo Higuchi-Sanabria, Danielle L Schmitt.
      Methionine is an essential amino acid, used for protein synthesis, redox homeostasis, and methylation reactions throughout the cell. However, the compartmentalized dynamics of methionine have remained elusive, due to a lack of available tools to measure methionine with high spatial and temporal resolution. To address this limitation, we have developed a single fluorescent protein-based methionine optical reporter (Meteor) which reports subcellular changes in methionine with high dynamic range. Using Meteor, we demonstrate the subcellular uptake of methionine in multiple cell lines into several locations, including the mitochondrial matrix. Furthermore, we use Meteor to illuminate the dynamics of the methionine cycle in the cytoplasm and nucleus, finding cancer cells can rapidly increase methionine from metabolic precursors in both locations. Finally, demonstrated that Meteor can be used to visualize methionine dynamics in vivo using Caenorhabditis elegans . Thus, we have developed a new tool to measure methionine dynamics across scales with high dynamic range and spatiotemporal resolution.
    DOI:  https://doi.org/10.64898/2026.06.05.730515
  17. Acta Crystallogr D Struct Biol. 2026 Jul 01.
    Molecular architecture of the human citrate synthase-malate dehydrogenase 2 metabolon.
    Angela J Kayll, Umanga Rupakheti, Renee St John, Gabriel Rementeria, Joseph J Provost, Christopher E Berndsen.
      Metabolons are transient biomolecular complexes that enhance the efficiency of metabolic pathways through substrate channeling. These complexes are difficult to study because of their transient nature, thus limiting our understanding of how they are formed and regulated. The citric acid cycle is proposed to contain many such complexes, although few have been characterized structurally. Here, we provide direct structural evidence for the complex of human citrate synthase (hCS) and human mitochondrial malate dehydrogenase 2 (hMDH2), which is part of the larger proposed citric acid cycle metabolon. Our structural model supports previous cross-linking studies and suggests that hMDH2 can interact with each subunit of the hCS dimer, forming up to a hexameric complex. However, this complex appears to be transient, as titration of hMDH2 into hCS in activity assays does not saturate. We further show that the interaction site with hCS is nonspecific, as hCS could also stimulate oxaloacetate formation by cytosolic and plant MDH enzymes. This structural model will provide a basis for understanding the structure and regulation of the broader citric acid cycle metabolon.
    Keywords:  SAXS; citrate synthase; malate dehydrogenase; metabolons
    DOI:  https://doi.org/10.1107/S2059798326005802
  18. J Immunol. 2026 Jun 07. pii: vkag147. [Epub ahead of print]215(6):
    Mechanisms and functions of intercellular mitochondria transfer to and from macrophages.
    Wentong Jia, Jonathan R Brestoff.
      Cell-to-cell communication is essential for maintaining homeostasis and coordinating complex biological processes in multicellular organisms. Classically, cells communicate using secreted peptides and metabolites and through cell contact-dependent signaling. Emerging studies over the past 20 years indicate that many cell types, including innate immune cells such as macrophages, participate in a process called intercellular mitochondria transfer, in which macrophages either donate their own mitochondria to other cells or accept mitochondria originating from another cell type. This raises the intriguing possibility that macrophages use mitochondria transfer as a mechanism of cell-to-cell communication. In this review, we describe the distinct mechanisms and functional roles of mitochondria transfer in macrophages across different organ systems and highlight how this biology contributes to health maintenance and disease pathogenesis.
    Keywords:  acceptor; cell-to-cell communication; donor; intercellular mitochondria transfer; macrophage
    DOI:  https://doi.org/10.1093/jimmun/vkag147
  19. Nat Biotechnol. 2026 Jun 23.
    Mapping and engineering the human cell-cell interactome.
    Dino Di Carlo, Leonardo Morsut, Megan L McCain, Heather J Wright, Mohamad Abedi, Sean A Yamada-Hunter, Jason Z Zhang, Keriann Backus, Eunji Chung, Yingxiao Wang, Thomas A Rando, Long Cai, Matt Thomson, Michael B Elowitz, John K Lee, Owen Witte.
      Efforts to systematically understand how cell interactions tune tissue-level function have motivated transformative advances in single-cell transcriptomics and spatial profiling. Although these technologies can measure molecular states in individual cells and their spatial mapping within tissues, they also reveal that there exists a fundamental knowledge gap of how cells influence each other in context. In this Perspective, we propose an initiative to map and engineer the human cell-cell interactome: a functional atlas of how all major human cell types communicate. We highlight how recent innovations can make this vision achievable. As a first moonshot, we propose the 'Billion Cell×Cell Project', which systematically characterizes the outcomes of defined cell-cell dyads across diverse cell types and conditions. We envision this multistage initiative will produce progressively deeper insights and unlock additional avenues for therapeutic discovery. We call on the scientific community to join us in building the tools, datasets and models that will decode and rewrite the language of life between cells.
    DOI:  https://doi.org/10.1038/s41587-026-03177-2
  20. Sci Adv. 2026 Jun 26. 12(26): eaec8143
    FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
    Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.
      Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8143
  21. Cell Rep. 2026 Jun 24. pii: S2211-1247(26)00604-2. [Epub ahead of print]45(7): 117526
    Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA.
    Tanzina Tanu, Anna M Cox, Jennifer A Karlow, Priyanka Sharma, Kaiwen Sun, Xueyang He, Swathy Babu, Madeline K Roelofs, Ethan Jeon, Jiajia Chen, Constance Wu, Jared Brown, Nelson B Barrientos, Andrew S McCallion, Kevin M Brown, Stephen J Chanock, David Liu, Tongwu Zhang, Kathleen H Burns, Paul L Boutz, Megan L Insco.
      Endogenous retroviral (ERV) RNA is highly expressed in cancer, suggesting a selective advantage. We identify recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance factor lost in 30% of all cancers. We show that Z18 truncating mutations are oncogenic and that Z18 plays an evolutionarily conserved role in the nuclear surveillance of oncogenic ERV RNA. In zebrafish, Z18 truncation accelerates melanoma onset and selectively increases ERV RNA. Human cancer cell lines and patient tumors with Z18 mutations also upregulate ERV RNA. In engineered human melanoma cells, Z18 truncation enhances ERV RNA accumulation more than heterozygous Z18 loss, consistent with dominant-negative activity. Truncated Z18 directly stabilizes and relocalizes ERV RNA to the cytoplasm. ERV RNA expression accelerates melanoma and is required for Z18 truncation-mediated melanoma onset in zebrafish. Growth of human melanoma cells similarly depends on Z18-regulated ERV RNA. Together, these findings support Z18-regulated ERV RNA as a driver of oncogenesis.
    Keywords:  CP: cancer; CP: molecular biology; ERV RNA; NEXT complex; endogenous retroviral RNA; melanoma; nuclear RNA surveillance; nuclear exosome targeting complex; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117526
  22. bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]
    Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
    Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.
      Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.
    DOI:  https://doi.org/10.64898/2026.06.09.730804
  23. Int Rev Immunol. 2026 Jun 27. 1-18
    Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.
    Yaru Liu, Wei Du, Weimin Deng.
      Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8+ T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8+ T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8+ T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8+ T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8+ T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.
    Keywords:  CD8+ T cells; Cancer immunotherapy; epigenetics; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1080/08830185.2026.2687543
  24. Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00288-6. [Epub ahead of print]
    Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
    Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang.
      Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.
    Keywords:  cancer-associated fibroblasts; stroma; stroma-targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.001
  25. Nat Commun. 2026 Jun 21.
    Mitochondrial DNA heteroplasmy drives cortical neuronal disturbances in human organoids harbouring the common m.3243A>G mutation.
    Denisa Hathazi, Camilla Lyons, Daniel Lagos, Oliver Podmanicky, Mariana Zarate-Mendez, Yu Nie, Juliane S Müller, Kieren S J Allinson, Huw Naylor, Majlinda Lako, Ibrahim Elsharkawi, Irena Muffels, Eva Morava, Tamas Kozicz, Patrick Chinnery, András Lakatos, Rita Horvath.
      Mitochondrial diseases frequently affect the brain leading to severe and disabling neurological symptoms. The heteroplasmic m.3243 A > G mutation in MT-TL1, encoding mt-tRNALeu, is responsible for ~80% of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which is one of the most characteristic mitochondrial syndromes, leading to disability and early death. There are no animal models harbouring this mutation to provide precise mechanistic insights informing therapeutic interventions. Here, we generate a human iPSC-derived cerebral organoid slice model that recapitulates cortical architecture and mitochondrial pathology. Using biological assays and single-cell RNA sequencing, we uncover heteroplasmy-dependent transcriptional shifts and changes in key cellular processes in cortical neurons. Organoids with high heteroplasmy show a predominant impairment of deep-layer neurons triggered by mitochondrial stress, leading to axonal degeneration and apoptosis, similar to brain autopsy of a MELAS patient. Our findings provide insights into the vulnerability of long-range projection neurons in mitochondrial diseases, advancing our understanding of disease mechanisms with a view to potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-026-74103-y
  26. Cell Death Dis. 2026 Jun 25.
    Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.
    Lauren Brakefield-Laird, Amit Budhraja, Peter M Hall, Dixie Brewington, Jamila Moore, Josi Lott, Yonghui Ni, Dennis Voronin, Oliver Grant-Chapman, Tresor O Mukiza, Tristen Wright, Yong-Dong Wang, Sandi Radko-Juettner, Shondra M Pruett-Miller, Stanley Pounds, Peter Vogel, Joseph T Opferman.
      MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.
    DOI:  https://doi.org/10.1038/s41419-026-09037-w
  27. Biochim Biophys Acta Mol Cell Res. 2026 Jun 24. pii: S0167-4889(26)00076-5. [Epub ahead of print]1873(6): 120178
    A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
    Marcelo Mesa Costa-Lima, Fernando Gomes, Thaynara Roberta Damaceno, Mário H Barros.
      The hotdog-fold acyl-CoA thioesterases (ACOTs) are enzymes typically related to lipid metabolism and are widely spread across the tree of life, but many members of this group are poorly characterized. In this work, through in silico analyzes we identified the MICOS-associated mitochondrial proteins of unknown function Mrx3 and Fmp10 as two putative ACOTs in Saccharomyces cerevisiae with structural homology to the mammalian thioesterases Them4 and Them5, which possess a conserved motif that is catalytic toward thioester hydrolysis. Lipidomics analyses revealed that the mrx3Δ and fmp10Δ mutants have lower free fatty acid (FFA) levels with concomitant accumulation of storage lipids, besides a decreased pool of cardiolipin species. During our functional investigation, we observed that the absence of either protein partially restores respiratory capacity in the leu5Δ strain, whose mutation has been previously linked to very slow respiratory growth due to severe Coenzyme A (CoA) depletion in the mitochondrial matrix. We verified that the respiratory defect of the leu5Δ mutant is also related to a defect in the respiratory chain given the low NADH-dependent oxygen consumption rate and is specifically linked to defective Complex IV activity. The strain's growth defect was exacerbated by deletion of the glycine transporter HEM25 and was ameliorated by either δ-aminolevulinic acid (ALA, a heme precursor) or iron supplementation. These results may indicate that the leu5Δ strain has a subtle heme deficiency. We propose a model in which Mrx3 and Fmp10 control the mitochondrial acyl-CoA/CoA ratio through a thioesterase activity, which finely modulates the mitochondrial membrane lipidome, with a concomitant effect in heme biosynthesis. In the leu5Δ mutant, there is a disturbed metabolic homeostasis. Deleting these hotdog-fold proteins cause increased acyl-CoA levels and partially restores metabolic balance, potentially by repartitioning carbon flux through the tricarboxylic acid (TCA) cycle to replenish succinyl-CoA using the limited available CoA pool, which may be sufficient to restore heme biosynthesis. This mechanism highlights the critical role of CoA compartmentalization and the underlying connection of distinct metabolic pathways.
    Keywords:  Coenzyme A (CoA) transport; Heme biosynthesis; Mitochondrial lipid metabolism; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120178
  28. J Cell Biol. 2026 Aug 03. pii: e202509213. [Epub ahead of print]225(8):
    Phosphatidylserine and RhoB connect PI4P and PA metabolism to maintain plasma membrane identity.
    Shiying Huang, Yeun Ju Kim, Xiaofu Cao, Timothy W Bumpus, Mira Sohn, Matthew Tyler Menold, Ryan K Dale, Jin Joo Kang, Saori Uematsu, Shagun Gupta, Shu-Bing Qian, Haiyuan Yu, Tamas Balla, Jeremy M Baskin.
      Proper functions of cellular organelles require tight control of membrane phospholipid composition, yet the mechanisms by which lipid imbalances are sensed and corrected remain largely unknown. Here, we present evidence of an unexpected metabolic connection between plasma membrane (PM) phosphoinositide metabolism and two key anionic lipids, phosphatidylserine (PS) and phosphatidic acid (PA). Prolonged depletion of PM phosphatidylinositol 4-phosphate (PI4P) by pharmacological inhibition of PI 4-kinase IIIα (PI4KIIIα/PI4KA) increases phospholipase D (PLD) activity and PA levels in the PM. Using lipidomics, RNA-seq, and proximity proteomics, we find that PI4P loss induces a concomitant decrease in PS, activating a reciprocal relationship between PS synthesis and PLD-mediated PA generation. These changes also drive transcriptional and translational upregulation of the small GTPase RhoB, which enhances PLD-mediated PA synthesis and actin cytoskeletal remodeling. Because reduced PI4KA activity underlies numerous hereditary diseases, our studies reveal how perturbation of PM phosphoinositide synthesis triggers an integrated response that maintains the anionic character and structural integrity of the PM.
    DOI:  https://doi.org/10.1083/jcb.202509213
  29. Nat Cell Biol. 2026 Jun 26.
    Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
      
    DOI:  https://doi.org/10.1038/s41556-026-02008-5
  30. Cell Signal. 2026 Jun 22. pii: S0898-6568(26)00341-4. [Epub ahead of print] 112686
    NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma.
    Xin Sun, Qirui Zhou, Yayun Wu, Weiwei Qian, Jiaxing Ma, Tao Zhang.
      This study aimed to define the functional role of the HIF-1α target gene NDUFA4L2 in clear cell renal cell carcinoma (ccRCC), specifically its regulation of mitochondrial function and the ferroptosis cell death pathway. Through TCGA data analysis and in vitro and in vivo models, we confirmed that HIF-1α induces NDUFA4L2 expression and mitochondrial localization. Using shRNA-mediated knockdown combined with rescue experiments employing the ferroptosis inhibitor ferrostatin-1 and the mitochondrial antioxidant mitoTEMPO, we demonstrated that silencing NDUFA4L2 triggered mitochondrial lipid peroxidation, altered mitochondrial ultrastructure, and suppressed proliferation via a mitochondria-associated ferroptotic mechanism. Mechanistically, NDUFA4L2 functioned parallel to Lactate Dehydrogenase B (LDHB); their genetic or pharmacological co-inhibition synergistically enhanced ferroptosis and suppressed cell viability in vitro and tumor growth in vivo, associated with elevated ferroptosis markers (PTGS2, 4-HNE). Furthermore, NDUFA4L2 knockdown sensitized tumors to radiotherapy by amplifying ferroptotic cell death. In conclusion, NDUFA4L2 is a critical suppressor of mitochondria-associated ferroptosis in ccRCC, acting cooperatively with LDHB to maintain redox homeostasis, and targeting the NDUFA4L2/LDHB axis represents a promising therapeutic strategy, particularly in combination with radiotherapy.
    Keywords:  Clear cell renal cell carcinoma (ccRCC); Ferroptosis; Lipid peroxidation; Mitochondria; NDUFA4L2
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112686
  31. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
  32. EMBO J. 2026 Jun 22.
    mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.
    Nora S Siefert, Andrea Zanotti, Anastasija Paneva, Martin Schneider, Dominic Helm, Wilhelm Palm.
      Acidification of lysosomes, endosomes and the Golgi underpins organelle-specific functions within the endomembrane system. This process is driven by vacuolar-type H + -ATPases (V-ATPases), proton pumps that reversibly assemble from peripheral V1 and membrane-integral Vo domains to regulate organelle pH. In yeast, V1-Vo assembly at the vacuole is mediated by the RAVE complex, but V-ATPase assembly in mammalian cells remains less well understood. Here, we systematically characterize physiological roles of the mammalian RAVE complex, composed of the subunits Dmxl1 or Dmxl2, Wdr7 and Rogdi. Under basal conditions, mRAVE broadly promotes V-ATPase assembly and luminal acidification of endomembrane organelles. Upon mTORC1 inactivation, mRAVE is recruited to lysosomes and required for the resulting increase in V-ATPase assembly and catabolic activity. Loss of mRAVE disrupts organelle acidification, leading to suppression of lysosomal catabolism, accumulation of dysfunctional lysosomes and lysosomal exocytosis. Restoring lysosomal pH rescues basal function in mRAVE-deficient cells but not the mTORC1-regulated increase in catabolic activity. Thus, mRAVE is an essential V-ATPase assembly factor that couples acidification to organelle function and nutrient signaling.
    DOI:  https://doi.org/10.1038/s44318-026-00838-5
  33. Nat Cell Biol. 2026 Jun 22.
    Mediator subunit MED4 enforces metastatic dormancy in breast cancer.
    Seongyeon S Bae, Hsiang-Hsi Ling, Jiankang Zhang, Yi Chen, Hong Chen, Dhiraj Kumar, Ajay K Saw, Kunal Rai, Aaron D Viny, Ronald A DePinho, Filippo G Giancotti.
      Long-term survival in breast cancer is often limited by metastatic recurrence arising from disseminated cancer cells that persist in a dormant state. The mechanisms that enable these dormant cells to survive and subsequently reawaken remain incompletely understood. Here an unbiased genome-scale genetic screen identified Med4 as a cancer cell-intrinsic gatekeeper in metastatic reactivation. Correspondingly, MED4 haploinsufficiency was found to be prevalent in metastatic breast cancer and associated with poorer clinical outcomes. Syngeneic mouse metastasis models revealed that MED4 enforces metastatic dormancy. Mechanistically, and unexpectedly given the canonical role of the Mediator complex in transcriptional activation, MED4 suppresses enhancer priming (H3K4me1) and activation (H3K27ac). Loss of a single Med4 allele disrupts enhancer poise, leading to extracellular matrix remodelling and integrin-mediated mechanotransduction programmes that ultimately drive metastatic outgrowth. Together, these findings establish MED4 as a key regulator of breast cancer cell dormancy and nominate MED4 haploinsufficiency as a potential predictive biomarker for patients at high risk of metastatic relapse.
    DOI:  https://doi.org/10.1038/s41556-026-01984-y
  34. Nat Commun. 2026 Jun 24. pii: 5564. [Epub ahead of print]17(1):
    Pseudouridine synthase PUS1 and initiation factor mtIF2 are human mitoribosomal small subunit assembly factors.
    Vivek Singh, Dmitrii Shiriaev, Lorina Bilalli, Anas Khawaja, Joanna Rorbach.
      Assembly of the mitochondrial ribosome (mitoribosome) is a crucial step in mitochondrial gene expression. This process facilitates mitochondrial translation, which produces essential subunits of the oxidative phosphorylation machinery-the cell's primary energy-producing machinery. Disruptions in mitoribosome assembly can lead to severe human diseases. Given its fundamental importance, detailed structural analysis of mitoribosome assembly pathways is essential for advancing our understanding of mitochondrial function in both health and disease. In this study, we characterize twelve distinct assembly states of the mitoribosomal small subunit (mtSSU) isolated from human cells. Our findings reveal the intricate details of the final maturation stages of the mtSSU platform, decoding center, and the 3'-end of 12S rRNA. This process is governed by coordinated actions of assembly factors that ensure precise, stepwise rRNA folding and the integration of mitoribosomal proteins into the developing subunit. Our approach identifies pseudouridine synthase PUS1 and initiation factor mtIF2 as assembly factors, expanding their known roles beyond mt-tRNA maturation and translation, respectively. In addition, the identified assembly intermediates provide insight into the modular nature of mtSSU biogenesis in mitochondria and further link late-stage assembly to the acquisition of translational competence.
    DOI:  https://doi.org/10.1038/s41467-026-74700-x
  35. Trends Cancer. 2026 Jun 24. pii: S2405-8033(26)00133-0. [Epub ahead of print]
    An immunological panacea for cancer-related cachexia.
    Jingyu Xue, Tianyi Lu, Kailin Yang, Alexander Birbrair, Shengtao Zhou.
      Cancer cachexia, responsible for up to 30% of cancer deaths, has transitioned conceptually from a mere nutritional deficit into a highly coordinated, multi-organ immunometabolic network that systematically dismantles host homeostasis. This review synthesizes the paradigm-shifting discoveries that position the immune system as the central conductor of tissue wasting. We delineate how redundant inflammatory cascades, neuro-immune circuits, and local cellular plasticity converge to drive muscle and adipose catabolism. Furthermore, we dissect the metabolic competition for nutrients between tumor cells and host immunity, which accelerates structural degradation. Finally, we highlight how single-cell multiomics, spatial transcriptomics, and artificial intelligence are redefining clinical stratification, shifting the therapeutic horizon toward individualized, multi-node immunometabolic interventions, thereby providing a theoretical framework for the management of cachectic wasting syndrome.
    Keywords:  cachexia; cytokines; immune cells; immune metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2026.06.005
  36. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
  37. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731205. [Epub ahead of print]
    Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
    Austin K Murchison, Julia C Heiby, Hansen Tao, Matthew J Matrongolo, Alessandro Ori, Monther Abu-Remaileh.
      Zinc is an essential structural and enzymatic cofactor for roughly 10% of proteins, including transcription factors, metabolic enzymes, and cytoskeletal components. It also supports critical functions across organelles such as gene regulation in the nucleus, protein folding in the endoplasmic reticulum, and energy production and antioxidant defense in mitochondria. Despite these indispensable roles, the cellular mechanism that recycles zinc to maintain homeostasis during zinc deficiency remains poorly understood. Here, we identify a biphasic response to zinc limitation, which involves the rapid degradation of the zinc-storing metallothionein followed by the degradation, in an autophagy-dependent manner, of other zinc-binding proteins. We show that metallothionein is rapidly imported into the mitochondria to be degraded by the mitoprotease LONP1. Zinc starvation leads to severe mitochondrial dysfunction and metallothionein degradation allows local zinc release to alleviate nutrient stress. Our results reveal a non-canonical, mitochondria-mediated degradation pathway for a nutrient-storing protein that mobilizes zinc locally to maintain metabolic homeostasis and establish mitochondria as active hubs for nutrient recycling.
    DOI:  https://doi.org/10.64898/2026.06.09.731205
  38. Cell Death Dis. 2026 Jun 25.
    Targeting mitochondrial α-ketoglutarate sequestration disables dual oncogenic drivers and metabolic adaptability in pancreatic ductal adenocarcinoma.
    Yeting Xu, Hongjiang Guo, Shengxi Li, Yucheng Wang, Yinghao Cao, Lin Wang, Qiuxia Chen, Ziyi Qin, Jiaxing Qiu, Yuhan Liu, Yunfan Li, Jiaming Zou, Yingying Wang, Kaihan Zhang, Rui Ju, Lei Guo.
      Pancreatic ductal adenocarcinoma (PDAC) exhibits hyperactive mitochondrial metabolism, yet how this rewiring spatially restricts the availability of metabolites for oncogenic signaling and drives systemic metabolic dysregulation in PDAC remains unknown. Here, we identify enhanced mitochondrial α-ketoglutarate (α-KG) sequestration as a key metabolic vulnerability in PDAC. Using multi-omics, preclinical models, and clinical correlation analyses, we identified elevated mitochondrial metabolic gene expression in PDAC. Moreover, higher expression of dihydrolipoamide succinyltransferase (DLST) correlates with poorer PDAC prognosis, suggesting the role of mitochondrial α-KG sequestration in PDAC progression. Targeting mitochondrial respiration with the complex I inhibitor carboxyamidotriazole orotate (CTO) redirected α-KG flux from mitochondrial sequestration, and increased α-KG-dependent m6A demethylation of MYC mRNA and HIF-1α hydroxylation. Combining CTO or α-KG dehydrogenase complex inhibitor devimistat with an α-KG analog (dimethyl α-KG) amplified c-Myc/HIF-1α suppression. Consequently, prolonged CTO exposure downregulated multiple metabolic pathways (glycolysis, pentose phosphate pathway, fatty acid synthesis) regulated by c-Myc/HIF-1α, and significantly delayed PDAC progression in vitro and in vivo. Our work first identify a novel mechanism whereby mitochondrial metabolism drives systemic metabolic dysregulation in PDAC through the sequestration of α-KG, and establishes "redirecting α-KG flux from mitochondrial sequestration" as a strategy to disable PDAC's metabolic adaptability. The orotate salt form of carboxyamidotriazole effectively disrupts mitochondrial α-KG sequestration to suppresses PDAC growth at a dose equivalent to the clinically tested level.
    DOI:  https://doi.org/10.1038/s41419-026-09016-1
  39. Elife. 2026 Jun 25. pii: RP107596. [Epub ahead of print]14
    Mycobacterium tuberculosis partitions the Krebs cycle under iron starvation.
    Agnese Serafini, Acely Garza-Garcia, Davide Sorze, Luiz Pedro Sorio de Carvalho, Riccardo Manganelli.
      In this study, we investigated how iron limitation alters central metabolism in Mycobacterium tuberculosis using metabolomics and stable isotope tracing. Our findings reveal a well-orchestrated metabolic programme to enable Krebs cycle activity despite the inefficient action of its iron-dependent enzymes. Under such conditions, carbon flux through the oxidative branch of the Krebs cycle is stalled, resulting in the accumulation of metabolites that are partially secreted. As a result, carbon flux from glycolysis is partially diverted to the reductive branch of the Krebs cycle to support the production of oxaloacetate and malate through the activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase. Both branches terminate with the synthesis of malate, which is secreted. This unprecedented split of the Krebs cycle and malate secretion in a bacterial pathogen facilitates the continuous flow of carbon through the core of carbon metabolism, overcoming the metabolic stalling triggered by iron starvation.
    Keywords:  Mycobacterium tuberculosis; central carbon metabolism; infectious disease; iron starvation; isotope tracing; microbiology; nutritional immunity
    DOI:  https://doi.org/10.7554/eLife.107596
  40. Br J Cancer. 2026 Jun 26.
    Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2.
    Ke Zheng, Keqiang Rao, Xiaoxu Lu, Miaomiao Yang, Hui Wu, Zhilong Ai, Jing He.
       BACKGROUND: Ten-eleven translocation 2 (TET2) is initially identified as a mammalian DNA dioxygenase to orchestrate expression of numerous genes and diverse interplays of physiological and pathological processes. Beyond its canonical role, the moonlight functions of TET2 have been gradually uncovered.
    METHODS: RNA-seq, qPCR and western blot are employed to validate expression of genes. ChIP and RIP analyses are conducted to test the enrichment of genes. Stable isotope labelled glucose is utilized to analyze the metabolic flux. Xenograft analysis is performed to explore growth of tumour in vivo.
    RESULTS: TET2 binds to and oxidizes mRNA 5-methylcytosine (m5C) of the transcription factors ATF3 and ATF4, thereby enhancing mRNAs degradation. Deficiency of TET2 rewires de novo serine synthesis and the viability of hepatocellular carcinoma (HCC) cells. Both ATF3 and ATF4 are required to sustain transcription of de novo serine synthesis enzymes and the associated metabolic reprogramming under TET2 loss. Ultimately, ATF3 collaborates with ATF4 to contribute to growth of tumours lack of TET2. Deficiency of TET2 sensitizes HCC tumours to serine restriction.
    CONCLUSIONS: Our findings not only elucidate a heretofore unrecognized mechanism of transcriptional suppression of de novo serine synthesis enzymes, but also propose a targetable vulnerability of HCC tumours.
    DOI:  https://doi.org/10.1038/s41416-026-03526-7
  41. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731211. [Epub ahead of print]
    Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
    Bo J Price, Sai Sangeetha Balasubramaniam, Adam L Hughes.
      Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.
    DOI:  https://doi.org/10.64898/2026.06.09.731211
  42. Nat Chem Biol. 2026 Jun 22.
    A ratiometric fluorescent reporter of mitochondrial sodium.
    Koushambi Mitra, Soyoung Kim, Daphne Oettinger, Sanjeev Uthishtran, Qian Zhao, Aneesh Tazhe Veetil, Joseph R Ramirez, Hening Lin, Senthil Arumugam, Yamuna Krishnan.
      Cells cope with salt stress, hypoxia or elevated cytosolic Ca2+ by regulating their mitochondrial Na+ levels. The discovery of the mitochondrial Na+/Ca2+ exchanger and its disease relevance has revealed the need to map mitochondrial Na+ in situ. Here we describe a ratiometric fluorescent reporter for Na+, denoted MitRatiNa, that reports mitochondrial Na+ levels independent of membrane potential and in diverse cell lines. Na+ in individual mitochondria varies greatly and, depending on cell type, can be as low as 1-5 mM or as high as 40 mM on average. We demonstrate that mitochondrial Na+ increases during cytosolic Ca2+ elevation, inhibition of glycolysis or respiration. Mitochondria in skin fibroblasts from healthy humans show a high Na+ population that disappears in fibroblasts of persons with mitochondrial diseases. The newfound ability to map absolute Na+ at the resolution of single mitochondria enables the dissection of regulatory mechanisms for mitochondrial Ca2+ and Na+ and potential identification of new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41589-026-02253-7
  43. Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00291-6. [Epub ahead of print]
    Chronic stress unleashes an intratumor phage-fibroblast-B cell circuit to promote tumor growth.
    Hilal Bashir, Katherine Z Sanidad, Purnima Ravisankar, Kelly M Banks, Avipsa Bose, Shui Yu, Joshua J C McGrath, Hannah C Carrow, Taeyul K Kim, Chloe A Troxell, Julia A Brown, Lucy R Hart, Jeremy Goc, Mikala Egeblad, Jayanta Chaudhuri, Han Sang Kim, Patrick C Wilson, David C Lyden, Irina R Matei, Naohiro Inohara, Gregory F Sonnenberg, Melody Y Zeng.
      Chronic stress disrupts the gut microbiota in patients with cancer; however, how stress-induced microbiota perturbations impact anti-tumor immunity remains unclear. Here, we show that the gut microbiota is required for chronic stress-induced glucocorticoid production, which impairs antigen-specific germinal center B cell responses. In mouse models of colorectal cancer or melanoma, chronic stress promotes translocation of a gut pathobiont, Enterococcus gallinarum (Eg), to tumors. Within tumors, Eg phage DNA induces glucocorticoid production by cancer-associated fibroblasts (CAFs) via TLR9, which suppresses anti-tumor B cell responses through the glucocorticoid receptor. Targeting intratumoral TLR9 or Eg significantly lowers intratumor glucocorticoid levels and reverses the tumor-promoting effects of chronic stress. Extending these findings to human cancer, we identify lytic phages in a Klebsiella pneumoniae isolate from human colorectal tumors that promote tumor growth and detect phage DNA in human brain tumors. Together, our study reveals a chronic stress-induced intratumor phage-CAF-B cell circuit that weakens anti-tumor immunity.
    Keywords:  B cells; anti-tumor immunity; bacteriophages; cancer immunotherapies; colorectal cancer; gut microbiota; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.004
  44. Nature. 2026 Jul;655(8121): 45-46
    Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
    Amaia Zabala-Letona, Arkaitz Carracedo.
      
    Keywords:  Biochemistry; Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-026-01802-3
  45. Nat Genet. 2026 Jun 22.
    Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state differentiation.
    Masashi Nomura, Ramya Raviram, Joshua S Schiffman, Lillian Bussema, Vivian Lu, Noelle Wheeler, John J Y Lee, Yilin Fan, Mian Hua Zheng, Florian Ruiz, Husain Danish, Sorcha Kellett, Labeeba Nusrat, Ronan Chaligne, Jason T Huse, W K Alfred Yung, Shota Tanaka, Nobuhito Saito, Sunit Das, Catherine Potenski, Dan A Landau, Mario L Suvà.
      The progression of isocitrate dehydrogenase-mutant glioma (IDH-G) from slow-growing tumor to fatal disease is associated with transcriptional and DNA methylation changes that remain poorly understood. Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus DNA methylation, single-nucleus RNA sequencing and bulk exome sequencing. We show that IDH-G progression is associated with an increase in malignant stem-like states, decreased differentiation and methylation loss, which marks tumors with worse clinical outcome. Methylation loss was uniformly observed across malignant cells within individual tumors, suggesting that it may underlie rather than result from the increase in stem-like states. Analysis of cell-state heritability and plasticity using high-resolution phylogenetic trees links DNA methylation loss to alterations in glioma cell-state encoding and heritability. Our study offers insights into how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.
    DOI:  https://doi.org/10.1038/s41588-026-02642-7
  46. Mol Cell. 2026 Jun 26. pii: S1097-2765(26)00389-8. [Epub ahead of print]
    A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.
    Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong.
      How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.
    Keywords:  Drosophila; OXPHOS; mitochondria; mitochondrial protease; respiration complex
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.018
  47. NPJ Aging. 2026 Jun 25.
    Somatic mutations impose an entropic upper bound on human lifespan.
    Evgeniy Efimov, Vlad Fedotov, Leonid Malaev, Ekaterina E Khrameeva, Dmitrii Kriukov.
      Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations. Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 1759 years to 156 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline. Multi-organ integration predicts median lifespans of 146-194 years-approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.
    DOI:  https://doi.org/10.1038/s41514-026-00421-6
  48. Annu Rev Biochem. 2026 Jun;95(1): 525-547
    Lactate as a Chemical Modification on Proteins and Metabolites.
    Shuke Xiao, Andrew L Markhard, Jonathan Z Long.
      Lactate's role in biochemistry and physiology has attracted considerable biochemical interest for over a century. Beyond its classical description as a glycolytic byproduct, lactate is now recognized as a central energy metabolite, a redox shuttle, and a signaling molecule. Modern advances in mass spectrometry have uncovered yet another dimension of lactate biology: lactate as a chemical modification on proteins and metabolites. Covalent conjugation of lactate to the ε-amine of a protein lysine side chain generates a posttranslational modification (lysine lactylation); in a related reaction on metabolites, conjugation of lactate to the α-amine of free amino acids produces a class of bioactive lactate-modified amino acids (the N-lactoyl amino acids). These lactate modifications represent a fundamental mechanism by which transient increases in glycolytic flux are translated into durable downstream effectors. Here, we review the detection, regulation, and function of these lactate-derived modifications in cellular and organismal homeostasis.
    Keywords:  N-lactoyl amino acids; covalent; glycolysis; lactate; lactylation
    DOI:  https://doi.org/10.1146/annurev-biochem-051024-015746
  49. Nat Aging. 2026 Jun 26.
    Meta-analysis of DNA methylation aging signatures in 17 human tissues.
    Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, Robin Grolaux, Bernadette Jones-Freeman, Severine Lamon, Mandhri Abeysooriya, Itamar Levinger, Carlie Bauer, Adam P Sharples, Aino Heikkinen, Elina Sillanpaa, Miina Ollikainen, Cassandra Smith, James R Broatch, Navabeh Zarekookandeh, Linn Gillberg, Ida Blom, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev, Matthew Taper, Cassandra Malecki, Sean Lal, Nathalie Saurat, Steve Horvath, Andrew Teschendorff, Nir Eynon.
      Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.
    DOI:  https://doi.org/10.1038/s43587-026-01164-5
  50. Cell Res. 2026 Jun 25.
    MitoCatch directs mitochondria delivery and prevents cell degeneration.
    Ana Paula Mendonça, Luca Scorrano.
      
    DOI:  https://doi.org/10.1038/s41422-026-01274-0
  51. Trends Biochem Sci. 2026 Jun 26. pii: S0968-0004(26)00177-5. [Epub ahead of print]
    Metabolic control of RNA splicing by polyamines.
    Sebastian J Hofer, Ghada Alsaleh, Anna Katharina Simon.
      Polyamines are ancient metabolites that support growth, translation, and autophagy. Zabala-Letona et al. reveal a new mode of action-'metabolic shielding'-in which polyamines protect phosphorylation motifs in spliceosomal factors. This work links polyamines, for the first time, to alternative splicing, raising new questions for cancer, aging, and beyond.
    Keywords:  aging; autophagy; cancer; metabolism; spermidine
    DOI:  https://doi.org/10.1016/j.tibs.2026.06.001
  52. Cancer Invest. 2026 Jun 21. 1-14
    The Heterogeneity of B Cells Potentially Contributes to Metastasis of Clear Cell Renal Cell Carcinomas.
    Yuanhong Chen, Chun Guo, Shaoang Huang, Caixia Ling, Wenxian Lin, Zhengfang Liang, Jingjie Zhao, Lingzhang Meng, Yulian Tang, Kun Ye.
       BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits extensive immune infiltration, yet the influence of immunological heterogeneity on clinical outcomes remains poorly elucidated.
    OBJECTIVES: Addressing the formidable challenge of metastasis suppression in ccRCC treatment.
    METHODS: Use scRNA-seq analysis and immunofluorescent imaging to categorize B cells into sub-clusters based on distinct gene expression profiles.
    RESULTS: Identify two significant B cell subpopulations, B cell (HLA-DRA) and B cell (FKBP11); show the upregulation of six genes (DERL3, FKBP11, MZB1, TNFSF13B, MYO9B, and ACAP1) in infiltrating B lymphocytes associated with poor prognosis of ccRCC; find that B cell (HLA-DRA) displays a noteworthy association with ccRCC metastasis and demonstrates relevance to tumor immunity across diverse cancers.
    CONCLUSIONS: The heterogeneity within B-cell subpopulations may substantially contribute to the metastatic potential of clear cell renal cell carcinoma. The findings provide insights into targeted interventions and improved clinical outcomes.
    Keywords:  B cells; Heterogeneity; Immunofluorescent; Metastasis; Renal cell carcinoma; scRAN-seq
    DOI:  https://doi.org/10.1080/07357907.2026.2675653
  53. Nat Commun. 2026 Jun 22.
    Persistence of memory: lifespan dynamics of the human antiviral antibody reactome.
    Moriah M Mitchell, Tomasz Kula, Jennifer L Remmel, Siyang Xia, Ellen L Shrock, Yumei Leng, H Benjamin Larman, Yu Chen, Mikael Knip, Marianna Cortese, Michael J Mina, Alberto Ascherio, Stephen J Elledge.
      The human antiviral antibody reactome provides a cumulative molecular record of immune exposures. Using high-resolution VirScan profiling, we compared epitope-level antibody responses across early childhood and adulthood. Infants are born with maternal IgG antibodies, but these antibodies decay rapidly and are replaced by endogenous responses to ~22 new viral exposures within three years. Pediatric antibody reactivities remain highly dynamic until about age 7 and are broad in epitope specificity but largely short-lived. In contrast, adult reactomes are remarkably stable and individualized, enabling accurate longitudinal donor identification (Immunoprint, > 99.99% accuracy). Stability varies by viral family, with Pneumoviridae and Picornaviridae persisting more robustly than Coronaviridae or Orthomyxoviridae. Across ages, immunodominant epitopes and initial binding strength predict response persistence. Longitudinal profiling highlights biological and epidemiological drivers of reactome change. This population-level, age-stratified atlas informs our understanding of immune memory and development with applications to vaccine design, surveillance, and precision public health.
    DOI:  https://doi.org/10.1038/s41467-026-74680-y
  54. EMBO J. 2026 Jun 25.
    Cellular assembly and functional resilience of the mammalian RNA exosome.
    Tsimafei Navalayeu, Nikolaus Beer, Monika Bebjaková, Robert W Kalis, Ulrich Hohmann, Karel Stejskal, Gabriela Krššáková, Nina Fasching, Veronika A Herzog, Niko Popitsch, Elisabeth Roitinger, Clemens Plaschka, Johannes Zuber, Stefan L Ameres.
      Most eukaryotic proteins assemble into multisubunit complexes that coordinate essential cellular functions, yet the principles governing their assembly and proteostatic control remain largely undefined. Here, we systematically dissect the cellular assembly and functional organization of the RNA exosome, an essential ribonucleolytic complex, using an inducible dual-guide CRISPR/Cas9 system in mouse embryonic stem cells. We reveal a sequential assembly pathway where Exosc2, Exosc4, and Exosc7 initiate complex formation, facilitating the incorporation of barrel and cap subunits in a defined hierarchy. Unlike other structural subunits, the terminally incorporated cap subunit Exosc1 is dispensable for cell viability, revealing a modular, functionally resilient architecture. We demonstrate that orphan subunits are selectively degraded via the ubiquitin-proteasome system, enforcing stringent quality control over RNA exosome biogenesis. These findings define an assembly logic of of the mammalian exosome and uncover previously unrecognized plasticity in the composition and function of this essential ribonucleolytic complex.
    DOI:  https://doi.org/10.1038/s44318-026-00824-x
  55. Curr Opin Plant Biol. 2026 Jun 25. pii: S1369-5266(26)00065-8. [Epub ahead of print]92 102922
    Amino acid sensing and signaling in plants.
    Shivsam Bady, Björn Heinemann, Tatjana M Hildebrandt.
      Amino acids are central metabolic intermediates but they can also serve as metabolic signals conveying information on nutrient status, developmental state, and environmental conditions. This review summarizes current concepts and emerging mechanisms of amino acid sensing and signaling in plants. Recent progress has expanded our understanding of glutamate receptor-like channels (GLRs), which couple amino acid perception to Ca2+ signaling during root growth, wound responses and immunity. Plant-specific upstream regulators of the target of rapamycin (TOR) kinase complex have been identified that link amino acid sensing to growth control. New findings provide insight into tissue-specific functions of TOR as well as its integration with hormone signaling and amino acid metabolism. In addition, we discuss cysteine-dependent protein persulfidation as a post-translational modification integrating sulfur metabolism and redox regulation. Despite recent progress, mechanistic knowledge on amino acid signaling processes in plants is far from complete and the distinct metabolic context of autotrophy suggests that additional, potentially plant-specific sensing principles remain to be uncovered.
    DOI:  https://doi.org/10.1016/j.pbi.2026.102922
  56. Cell. 2026 Jun 25. pii: S0092-8674(26)00634-3. [Epub ahead of print]189(13): 3842-3844
    Excessive vascular integrity restricts anti-tumor immunity.
    Rosa Trotta, Linsha Ma, Massimiliano Mazzone.
      Vessel normalization aims to correct the abnormal vasculature in the tumor to improve drug delivery and immune control. In this issue of Cell, Wang et al. identify an immune-excluding vasculature in small-cell lung cancer, where excessive vessel integrity drives immune desertification, and propose "reverse normalization" to restore immune access and overcome immunotherapy resistance.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.034
  57. Aging (Albany NY). 2026 Jun 22. 18(1): 719-732
    The multifaceted inducers of cellular senescence.
    Hilah Gal, Valery Krizhanovsky.
      Cellular senescence is a stable form of cell-cycle arrest induced by diverse intrinsic and extrinsic stimuli. While senescence contributes to tumor suppression, wound repair, and placental and embryonic development, the chronic accumulation of senescent cells promotes tissue dysfunction, chronic inflammation, tumorigenesis, and age-related diseases. This review provides a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarizes the molecular mechanisms through which they trigger the senescence program. Although these stimuli differ widely, many converge to core effector pathways, resulting in a stable growth arrest. Understanding the varied stimuli and their underlying mechanisms of senescence induction is crucial for revealing the heterogeneity of senescent cells and developing interventions that modulate senescence during aging and disease.
    Keywords:  aging; cell senescence
    DOI:  https://doi.org/10.18632/aging.206391
  58. Plant Cell. 2026 Jun 27. pii: koag199. [Epub ahead of print]
    Age-dependent epigenetic control of flavonoid metabolism underlies chemical defenses in ancient Ginkgo biloba.
    Jinkai Lu, Yanbing Jiang, Bang Chang, Tongfei Wang, Shixiong Ren, Xi Zhang, Qingjie Wang, Jiawen Cui, Zhaogeng Lu, Sian Liu, Yadi Chen, Chunxiang Fu, Yingfang Zhu, Biao Jin, Jinxing Lin, Peng Liu, Richard A Dixon, Li Wang.
      Ancient trees such as Ginkgo biloba exhibit remarkable longevity and sustained physiological vigor despite millennia of environmental stress, yet how aging reprograms their secondary metabolism and chemical defense remains unclear. Here, we investigated age-related epigenetic and metabolic changes across G. biloba individuals aged 1-1,070 years. We identified DEFICIENS AGAMOUS-LIKE 1 (GbDAL1) as a central age-associated regulator of flavonol metabolism. GbDAL1 expression rises progressively with age but is significantly reduced in juvenilized branches; this shift is driven by reduced expression of the DNA methyltransferase chromomethylase2 (GbCMT2), leading to promoter hypomethylation. Restoring GbCMT2 activity reinstates promoter DNA methylation and suppresses GbDAL1 transcription. Functionally, GbDAL1 negatively regulates flavonol biosynthesis by directly repressing the flavonol synthase (GbFLS) gene and inhibiting the transcriptional activity of GbMYBF1, thereby attenuating expression of flavonol pathway genes. Although total flavonol biosynthesis declines with age, metabolite profiling revealed marked accumulation of methylated and prenylated flavonols in ancient trees, suggesting an adaptive metabolic shift toward more stable defensive metabolites. These metabolites, together with diverse terpenoids, phenols and alkaloids, accumulate in the heartwood to form a persistent chemical barrier that supports long-term defense. Collectively, our findings reveal an epigenetically mediated age-metabolite regulatory axis in G. biloba, uncovering a molecular mechanism that links aging to secondary metabolic reprogramming and may contribute to the exceptional longevity and resilience of perennial plants.
    Keywords:   Ginkgo biloba ; DNA methylation; GbDAL1; ancient trees; flavonols
    DOI:  https://doi.org/10.1093/plcell/koag199
  59. Trends Immunol. 2026 Jun 25. pii: S1471-4906(26)00137-7. [Epub ahead of print]
    Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
    Amélie E Bura, Andrea Rolong, Christophe Paget, Maxime Guéguinou.
      Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.
    Keywords:  T cells; cancer; immune checkpoint blockade; immunometabolism; mitochondrial calcium signaling; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.it.2026.05.012
  60. Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00260-6. [Epub ahead of print]
    Intratumoral B cells under stress.
    Ziv Shulman.
      In this issue of Cancer Cell, Bashir et al. show that stress-induced corticosterone suppresses germinal center B cell responses and impairs anti-tumor immunity. Their study identifies gut microbiota-derived phage DNA as a key trigger of TLR9 activation and corticosterone secretion by cancer-associated fibroblasts, revealing an intricate bacteria-driven immune-suppression mechanism.
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.015
  61. Adv Exp Med Biol. 2026 ;1514 207-253
    The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.
    Toni K Träger, Fotis L Kyrilis, Greg Kafetzopoulos, Christian Tüting, Panagiotis L Kastritis.
      The ancient pyruvate dehydrogenase complex (PDHc) performs the "link reaction" of cellular respiration-a discovery from the 1930s that was central in the award of the 1953 Nobel Prize in Physiology and Medicine to Krebs and Lipmann. Fast forward to 2024, PDHc emerges with roles in Alzheimer's, cancer, and neurodegeneration, as well as in obesity and aging processes. Due to these recent reports, structural analysis of PDHc, a 10-megadalton enzymatic complex, comes into focus-only now this analysis begins to unveil an enormous and challenging molecular complexity. Cutting-edge techniques and methods, such as cryo-electron microscopy (cryo-EM), cross-linking (XL) and mass spectrometry (MS), advanced molecular and biochemical analysis, and computational structural biology, powered by artificial intelligence (AI), converge to systematically probe the mechanistic details governing PDHc function. This chapter collects and updates the knowledge in PDHc structure and function and pinpoints unresolved questions, with the hope of not waiting another 90 years for their answer.
    Keywords:  Acetyl-CoA; Citric acid cycle; Enzyme regulation; Glycolysis; Histone acetylation; Keto acid dehydrogenase complex family; Krebs cycle; Metabolic diseases; Metabolon; Mitochondria; Mitochondrial pyruvate carrier; Nuclear function; Pyruvate oxidation regulation; Respirasome; Structural biology; TCA cycle
    DOI:  https://doi.org/10.1007/978-3-032-26629-3_9
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