bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–07–12
fifty-four papers selected by
Christian Frezza, Universität zu Köln
  1. Universal cell embedding provides a foundation model for cell biology.
  2. Diet-microbiome synergy underlies obesity-associated immunotherapy efficacy.
  3. Dynamic control of nucleotide metabolism in physiology and disease.
  4. Mitochondria setting the stage for ferroptosis.
  5. Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.
  6. Aneuploidy selects for the acquisition of driver genes in breast cancer.
  7. Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
  8. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  9. Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
  10. Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
  11. Bridging omics and physiology to build multimodal clocks of human aging.
  12. Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
  13. L-2-Hydroxyglutarate sensitizes ferroptosis through ATF3/CHAC1-mediated glutathione degradation in hepatocellular carcinoma.
  14. Control theory analysis of dynamic metabolic response elucidates mitochondrial-cytoplasmic coupling and nutrient partitioning.
  15. The PRECISE European initiative for cancer-vulnerability mapping and prediction.
  16. Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
  17. Jack-of-a-new-trade: Itaconate targets the PPP/G6PD to control lung cancer.
  18. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  19. Constitutive DUSP2 expression enhances lymphoid cell proliferation by activating CDK1 and promotes lymphomagenesis.
  20. Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
  21. Mitochondria produce lactate to vent redox pressure.
  22. A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
  23. The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate.
  24. PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
  25. A scalable deep-learning framework for cancer detection using cell-free DNA shallow whole-genome sequencing.
  26. N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
  27. Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
  28. Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.
  29. Microbiota and immunotherapy: The birth of a new paradigm?
  30. Context-dependent selection sculpts mutational landscapes in the normal lung.
  31. A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
  32. Evolving patterns of co-mutations from tumor initiation to metastatic progression.
  33. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  34. Multi-Tissue Metabolomic Signatures of Five Longevity Interventions Converge on Ergothioneine and Lipid Remodeling in Male UM-HET3 Mice.
  35. Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
  36. Sequential infection reprograms the immune landscape to shape future responses.
  37. Senescent cells accumulate lipid droplets.
  38. A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration.
  39. Reinke Crystals are Immunoreactive for Purine-Synthesising Metabolic Enzymes.
  40. Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
  41. Investigating the determinants of immunotherapy response in the primary tumour of clear cell renal cell carcinoma (RCC).
  42. Spatial ecology of breast cancer reveals co-evolution of proliferative and dormant niches.
  43. SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.
  44. ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
  45. De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
  46. Tissue mechanopathology of cancer.
  47. Genetic drivers of etiologic heterogeneity in thyroid cancer.
  48. An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma.
  49. Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC.
  50. B cell-intrinsic IRF8 transcriptionally reprograms antigen presentation to sustain CD8⁺ T cell antitumor immunity.
  51. Multiscale metabolic mapping of lung tissue via coregistered mass spectrometry and nonlinear optical imaging.
  52. The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity.
  53. Profiling of terminating ribosomes reveals translational control at stop codons.
  54. Ancient feeding-related neuropeptides regulate alloparenting in ants.
  1. Nature. 2026 Jul 08.
    Universal cell embedding provides a foundation model for cell biology.
    Tabula Sapiens Consortium
      Developing a universal representation space for cells that encompasses the tremendous molecular diversity of cell types across species would be transformative for cell biology. Recent work using single-cell transcriptomic approaches to create molecular definitions of cell types in the form of cell atlases has provided the necessary data for such an endeavour1-3. Here we present the universal cell embedding (UCE) foundation model. UCE was trained on a large corpus of cell data using self-supervision, creating a unified biological latent space that can represent cells across diverse tissues and species. This latent space captures important biological variation despite the presence of experimental noise. UCE's universality means that new cells can be embedded with no data labelling, model training or fine-tuning. We used UCE to create the Integrated Mega-scale Atlas, embedding 36 million cells, with more than 1,000 uniquely named cell types, from hundreds of experiments, dozens of tissues and eight species. We gain insights into the organization of cell types and tissues within the space. UCE's embedding space exhibits emergent behaviour, identifying biology that it was never trained for, such as identifying developmental lineages and embedding data from species that were not included in the training set. Overall, by enabling a universal representation for every cell state and type, UCE is a valuable tool for analysis, annotation and hypothesis generation over single-cell data.
    DOI:  https://doi.org/10.1038/s41586-026-10689-z
  2. Nature. 2026 Jul 08.
    Diet-microbiome synergy underlies obesity-associated immunotherapy efficacy.
    Lysanne Desharnais, Anikka Swaby, Meriem Messaoudene, Samuel Doré, Miranda W Yu, Benoit Fiset, Valérie Breton, Mayra Ponce, Yongjia Hu, Liam Wilson, Mark Sorin, Ye Wang, Ken Dewar, Michael Pollak, Arielle Elkrief, Bertrand Routy, Logan A Walsh, Daniela F Quail.
      Physiological host factors, such as the gut microbiome and obesity, independently influence anti-tumour immunity and responses to immune checkpoint inhibitors (ICIs)1, with high body mass index (BMI) having an unexpected link with greater ICI efficacy2-6. However, how these factors interact across diverse dietary contexts remains unclear. Here, using 12 mouse diet models that reflect a spectrum of obesity biology, we characterize diet-driven metabolic, immune and gut microbiota features associated with ICI sensitivity. We find that obesity-associated ICI responses are poorly correlated with metabolic dysfunction and are instead dependent on the diet-gut axis. Obesogenic diets promote a robust and persistent gut microbial ecosystem that is capable of restoring ICI sensitivity following a short-term diet switch or fecal microbiota transplants (FMTs) from non-responder models. Monocolonization of germ-free mice with favourable bacteria such as Lactobacillus johnsonii, together with an obesogenic diet, synergistically promotes tumour regression through an enrichment of microbiota-derived aromatic amino acid metabolites. Moreover, human-to-mouse FMT from donors with a high BMI enhanced ICI efficacy compared with donors with a normal BMI, and an obesogenic diet restored sensitivity following FMT from a non-responder patient. Our study provides insight on epidemiological associations between BMI and ICI efficacy, and suggests that immunomodulatory synergy between diet and the gut microbiota could be leveraged to improve ICI outcomes and FMT interventions.
    DOI:  https://doi.org/10.1038/s41586-026-10750-x
  3. Nat Cell Biol. 2026 Jul 08.
    Dynamic control of nucleotide metabolism in physiology and disease.
    Dohun Kim, Gerta Hoxhaj.
      Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02004-9
  4. Trends Endocrinol Metab. 2026 Jul 07. pii: S1043-2760(26)00150-5. [Epub ahead of print]
    Mitochondria setting the stage for ferroptosis.
    Sofia Ahola.
      Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron-sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.
    Keywords:  coenzyme Q; ferroptosis; iron–sulfur cluster; lipid peroxidation; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2026.06.006
  5. J Bioenerg Biomembr. 2026 Jul 06. pii: 36. [Epub ahead of print]58(1):
    Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.
    Derek C Lee, Tomas Duraj, Christos Chinopoulos, Thomas N Seyfried.
      ATP is the primary energy currency required by living organisms. Mitochondrial oxidative phosphorylation (OxPhos) produces most of the ATP in quiescent and differentiated cells. OxPhos interruption results in analogous bioenergetic adaptations across divergent evolutionary taxa, yet this adaptation is poorly recognized. Oxygen availability is a major determinant of the source of ATP generation across most eukaryotic cell types. Acute oxygen deprivation, mitochondrial dysfunction, high energy demand, or other metabolic cues can shift relative ATP production from OxPhos to high-throughput fermentation via substrate-level phosphorylations (SLPs). Glucose-derived lactate and glutamine-derived succinate are biomarkers of cytosolic and mitochondrial SLP, respectively. The extracellular accumulation of these metabolites is observed in a broad range of biological systems, including unicellular bacteria and yeast to more complex mammalian cells, including those of the immune system, retina, and muscle. Unsurprisingly, many cancer cells accumulate excess lactate and succinate due to chronic OxPhos insufficiency. This review links ostensibly unique cases of metabolic disruption to the accumulation of lactate and succinate as biomarkers of compensatory fermentative metabolism through cytosolic and mitochondrial SLP. Fundamental principles of cellular energy and environmental adaptation are reviewed that span a broad range of biological complexity.
    Keywords:  ATP; Fermentation; Lactate; Substrate-level phosphorylation; Succinate
    DOI:  https://doi.org/10.1007/s10863-026-10117-x
  6. Nature. 2026 Jul 08.
    Aneuploidy selects for the acquisition of driver genes in breast cancer.
    Khalid N Al-Zahrani, Ellen R Langille, Jocelyn Nurtanto, Andreea Obersterescu, Katie Teng, Christopher Lowden, Julien Dessapt, Cynthia H Chiu, Lauren V Caldwell, David P Cook, Miguel A Pérez-Castro, Jacob M Berman, Ricky Tsai, Alexander T Bahcheli, Geraldine Mbamalu, Shifei Wu, Masahiro Narimatsu, Adele G Lopes, Iosifina Fotiadou, Kin Chan, Linkang Zhang, K W Annie Bang, Michael J Parsons, Larissa Mourao, E Idil Temel, Liddy McCulla, Palavalasa Sravya, Li Zhang, Peter Sajjakulnukit, Costas A Lyssiotis, Alexander D Borowsky, Colinda L G J Scheele, Daniel R Wahl, Hartland W Jackson, Katherine S Stewart, Elaine Fuchs, Sean E Egan, Miguel Angel Pujana, Jüri Reimand, Jeffrey L Wrana, Daniel Schramek.
      Chromosome instability is highly prevalent in cancer and drives large-scale chromosomal imbalances, known as aneuploidies1-4. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here we established a CRISPR knockout- and activation-linked assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immunocompetent mouse models of cancer. We developed a compendium of the ten most frequent human chromosome-arm-level alterations in basal-like breast cancer (BLBC), a disease type that is driven by large copy-number alterations (CNAs)5-8. Using CRISPR-KOALA, we screened the mouse orthologues of 3,752 genes on these arms and identified 90 cancer driver genes, the function of the vast majority of which is unknown. These genes drive distinct signalling pathways including MAPK, HIPPO and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for CNAs in Trp53-mutant BLBC mouse models. Mechanistically, we identify that PLGRKT is a potent oncogene that lies on chromosome 9p and show that its tumour-promoting activity is associated with highly stress-resistant mitochondria and an increased ability to detoxify reactive oxygen species. Together, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogeneous biological processes.
    DOI:  https://doi.org/10.1038/s41586-026-10752-9
  7. Nat Metab. 2026 Jul 08.
    Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
    Ankur Garg, Brandon R Desousa, Raju Roy, Amy Flis, Skyler Y Blume, Yohei Abe, Arthur A Melo, Ryan R Cupo, Gabriela Grigorean, Daniel R Southworth, James Shorter, Isha H Jain.
      Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.
    DOI:  https://doi.org/10.1038/s42255-026-01566-0
  8. Aging (Albany NY). 2026 Jul 06. 18(1): 787-812
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy
    DOI:  https://doi.org/10.18632/aging.206395
  9. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123
    Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
    Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.
      Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
    Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance
    DOI:  https://doi.org/10.1073/pnas.2529208123
  10. Annu Rev Genet. 2026 Jul 09.
    Mitochondrial DNA Inheritance and Germline Purifying Selection: Insights From Drosophila.
    Zhe Chen, Hong Xu.
      The mitochondrial genome resides in a highly mutagenic environment and is typically maternally inherited with little recombination, features that should render mitochondrial DNA (mtDNA) prone to the accumulation of deleterious variants. Contrary to this expectation, mtDNA integrity is remarkably well-preserved over evolution. Purifying selection in the female germline that limits transmission of deleterious mtDNA mutations has been documented in various animal models and in humans. Here, we synthesize the literature, with an emphasis on insights from Drosophila, revealing that replication competition-the preferential propagation of healthy genomes over deleterious ones-is the main mechanism driving mtDNA purifying selection in the germline. We highlight developmentally orchestrated mitochondrial processes that couple genome function to replication, enabling selection based on the bioenergetic performance of individual genomes during oogenesis. Finally, we discuss how replication competition can generate genetic conflicts, particularly through the emergence of selfish mtDNA, and how such conflicts may have shaped mtDNA evolution and features of mitochondrial genetics, including maternal inheritance and the mitochondrial bottleneck.
    DOI:  https://doi.org/10.1146/annurev-genet-011626-033825
  11. Cell. 2026 Jul 09. pii: S0092-8674(26)00705-1. [Epub ahead of print]189(14): 4190-4192
    Bridging omics and physiology to build multimodal clocks of human aging.
    Seda Koyuncu, Dunja Petrovic, David Vilchez.
      Human aging is a heterogeneous, multi-system process that spans molecular, tissue, and physiological decline. In this issue of Cell, Li et al. integrate clinical data, multi-omics, and organ-associated signatures to construct a multi-layer framework for quantifying biological aging across scales.
    DOI:  https://doi.org/10.1016/j.cell.2026.06.018
  12. Cell Death Dis. 2026 Jul 07.
    Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
    Marta Iozzo, Luigi Ippolito, Erica Pranzini, Simone Romagnoli, Giulia Gangarossa, Caterina Grillo, Sara Roccabianca, Giada Sandrini, Matteo Benelli, Giuseppina Comito, Elisa Giannoni, Paola Chiarugi.
      Prostate cancer (PCa) progression is strongly influenced by the metabolites available in the tumor microenvironment (TME), including lactic acid (LA), which is actively imported by PCa cells to boost mitochondrial metabolism and drive de novo collagen synthesis, sustaining increased malignancy. LA exploitation promotes the unbalance of tricarboxylic acid (TCA) cycle intermediates, particularly succinate and fumarate, well-known epigenetic modifiers for histone (de)methylation. Here, we show that the LA-induced increase in succinate levels affects the activating H3K4me3 methylation mark in PCa cells, promoting a pro-invasive phenotype. Notably, pharmacological targeting of H3K4me3 using OICR-9429 reduces LA-enhanced PCa cell invasiveness. Moreover, LA-induced H3K4me3 enrichment regulates the expression of procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1), a key enzyme involved in collagen maturation. Genetic impairment of PLOD1 reduces the LA-driven invasive potential of PCa cells, thereby highlighting PLOD1 as a crucial epigenetically regulated mediator of tumor invasion. Overall, our findings uncover a novel LA-fuelled metabolic-epigenetic axis that promotes the H3K4me3-mediated PLOD1 upregulation, consequently fostering PCa aggressiveness and unveiling a potential therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41419-026-09091-4
  13. Cell Death Dis. 2026 Jul 08.
    L-2-Hydroxyglutarate sensitizes ferroptosis through ATF3/CHAC1-mediated glutathione degradation in hepatocellular carcinoma.
    Caixia Xi, Junfeng Pang, Mohammad Oliaeimotlagh, Rui Mao, Wenbo Zhi, Kimya Jones, Tianxiang Hu, Huidong Shi, Ande Satyanarayana, Anatolij Horuzsko, Chunhong Yan, Nahid F Mivechi, Xingguo Zhu.
      Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and glutathione (GSH) depletion and represents a therapeutic vulnerability in hepatocellular carcinoma (HCC). While canonical ferroptosis regulation centers on cystine uptake and GPX4-mediated GSH utilization, the endogenous metabolic pathways governing ferroptosis sensitivity in liver tumors remain incompletely understood. Here, using a metabolic-scale CRISPR activation screen integrated with transcriptomic and metabolomic analyses, we identify L-2-hydroxyglutarate dehydrogenase (L2HGDH) as a potent antagonist of ferroptosis in HCC. We demonstrate that L2HGDH is frequently suppressed in liver tumors, leading to pathological accumulation of its substrate L-2-hydroxyglutarate (L2HG). Elevated L2HG sensitizes HCC cells to ferroptosis both in vitro and in vivo. Mechanistically, L2HG acts as a metabolic-epigenetic regulator that inhibits 2-oxoglutarate-dependent dioxygenases, induces histone hypermethylation, and remodels chromatin accessibility to activate an ATF3-dependent transcriptional program. This program induces the glutathione-degrading enzyme CHAC1, thereby accelerating GSH degradation to 5-oxoproline and disrupting redox homeostasis. Notably, L2HG-induced ferroptosis occurs independently of impaired cystine uptake, transsulfuration pathway activity, or increased GPX4-mediated GSH utilization, revealing a non-canonical ferroptosis mechanism driven by enhanced GSH catabolism. Consistent with these findings, genetic targeting of L2HGDH suppresses tumor growth, elevates L2HG levels, enhances GSH degradation, and promotes ferroptosis in HCC xenograft models. Collectively, our study identifies the L2HGDH-L2HG axis as a previously unrecognized metabolic checkpoint controlling ferroptosis sensitivity in liver cancer and uncovers glutathione degradation as a therapeutically exploitable vulnerability for ferroptosis-based treatment strategies in HCC.
    DOI:  https://doi.org/10.1038/s41419-026-09052-x
  14. bioRxiv. 2026 Jul 01. pii: 2026.06.28.735091. [Epub ahead of print]
    Control theory analysis of dynamic metabolic response elucidates mitochondrial-cytoplasmic coupling and nutrient partitioning.
    Xingbo Yang, Daniel J Needleman.
      Cells adjust their internal circuits in response to changes in their environment. Hence, exposing cells to changing conditions provides a way to probe the intrinsic dynamics of cellular internal circuits. Metabolic networks are examples of such circuits since metabolic fluxes dynamically adjust when environmental conditions are transiently altered. Most existing theoretical frameworks focus on cellular metabolic steady states and do not consider the dynamics of changes in metabolic fluxes. In this work, we applied transfer function analysis from control theory to analyze the changes of NADH oxidative fluxes in the mitochondria and cytoplasm in mouse oocytes in response to dynamical perturbations of oxygen depletion and recovery. We observed an overshoot of NADH oxidative flux in the cytoplasm upon oxygen recovery which is absent in the mitochondrial NADH oxidative flux. Metabolic perturbation experiments and transfer function analysis indicate that this cytoplasmic NADH overshoot results from the coupling of the mitochondrial and cytoplasmic NADH cycles. The degree of overshoot is determined by competing timescales associated with the exchange rates of lactate and pyruvate with the media and their interconversion rates catalyzed by lactate dehydrogenase. Applying control theory to the data enables the inference of the exchange and conversion rates of pyruvate and lactate, allowing predictions of the contribution of lactate to mitochondrial respiration. Our work indicates that the oocytes maintain a homeostatic respiration rate across nutrient conditions by modulating the contribution of lactate to mitochondrial respiration.
    DOI:  https://doi.org/10.64898/2026.06.28.735091
  15. Nat Genet. 2026 Jul 10.
    The PRECISE European initiative for cancer-vulnerability mapping and prediction.
    PRECISE consortium
      
    DOI:  https://doi.org/10.1038/s41588-026-02658-z
  16. Nat Metab. 2026 Jul 08.
    Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
    Anthony S Grillo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01569-x
  17. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00189-0. [Epub ahead of print]38(7): 1264-1266
    Jack-of-a-new-trade: Itaconate targets the PPP/G6PD to control lung cancer.
    Stefanie K Wculek.
      Itaconate is known as an anti-inflammatory metabolite derived from macrophages that dampens immune responses; however, its role in cancer has emerged to be complex. Mansouri et al.1 report a previously unknown anti-cancer feature of (octyl-) itaconate as an inhibitor of glucose-6-phosphate dehydrogenase (G6PD) in the lung tumor microenvironment (TME) in macrophages and cancer cells.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.004
  18. Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.
    Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle
    DOI:  https://doi.org/10.7554/eLife.107953
  19. Cell Rep. 2026 Jul 10. pii: S2211-1247(26)00730-8. [Epub ahead of print]45(7): 117652
    Constitutive DUSP2 expression enhances lymphoid cell proliferation by activating CDK1 and promotes lymphomagenesis.
    Yu Qian, Jutatip Panaampon, Bjoern Chapuy, Xueyan Zhang, Xiujuan Zhao, Zhe Wang, Pengfei Zhang, Tongchai Payungwong, Aretina Zhang, Qiang Ke, Jing Zhong, Ping Yuan, Lei Zhang, Min Hong, Il-Kyu Choi, Jiankun Guan, Dinis Pedro Calado, Scott Rodig, Olga Pozdnyakova, Klaus Rajewsky, Susana A Godinho, Siwanon Jirawatnotai, Hao Wu, Margaret A Shipp, Stephanie K Dougan, Baochun Zhang.
      DUSP2 is known as a nuclear dual-specificity phosphatase, highly restricted to immune cells. Its expression is induced by antigenic and mitogenic stimuli and has been implicated in immune cell differentiation and functions. However, its role in immune cell mitotic proliferation and hematologic malignancies has not been rigorously examined. Here, we show DUSP2 is highly expressed in human B-cell, T cell, and other hematologic malignancies. Ablating DUSP2 expression in lymphoma cell lines decreases growth and viability. In mice, transgenic Dusp2 expression promotes B-cell and T cell proliferation, and malignant transformation. Mechanistically, DUSP2 promotes cell cycle progression by activating CDK1 through dephosphorylation at inhibitory Tyr15 and Thr14, which is mediated not by its own phosphatase activity, but instead by a structural motif that recruits CDC25 phosphatases. This work reveals an unexpected oncogenic role for DUSP2 in lymphoid malignancies and the function of a structural motif, which represents an appealing target site for therapeutic intervention.
    Keywords:  CDC25; CDK1; CP: Cancer; CP: Immunology; DUSP2, PAC-1; cell cycle; hematologic malignancies; immune cell; lymphomagenesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117652
  20. Neurosci Bull. 2026 Jul 07.
    Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
    Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.
      Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.
    Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING
    DOI:  https://doi.org/10.1007/s12264-026-01657-8
  21. Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]
    Mitochondria produce lactate to vent redox pressure.
    Serwah A Danquah, Lucas B Sullivan.
      Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
    DOI:  https://doi.org/10.1016/j.tem.2026.06.005
  22. Cell Rep. 2026 Jul 04. pii: S2211-1247(26)00681-9. [Epub ahead of print]45(7): 117603
    A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
    Chunyan Wu, Tongtong Wang, Songlin Gong, Jing Zhang, Charlotte G Mann, Min Li, Ziyu Liu, Yizhi Sun, Shenwei Shi, Zhenghong Liu, Katrien De Bock, Miroslav Balaz, John Speakman, Christian Wolfrum.
      Brown adipose tissue (BAT) regulates whole-body energy balance through uncoupling protein 1 (UCP1)-dependent thermogenesis and secretion of metabolic factors. Recent studies suggest UCP1-independent mechanisms contribute to energy balance, with UCP1 being conditionally dispensable. However, how adaptation to UCP1 deficiency is regulated remains unclear. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift toward an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). The Ucp1/Gfral knockout increased food intake to compensate for decreased energy expenditure in AT. Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed. These findings identify a regulatory brown adipocyte subpopulation emerging in response to UCP1 deficiency, representing a compensatory mechanism for maintaining energy homeostasis in mammals.
    Keywords:  CP: metabolism; GDF15; GFRAL; Ucp1 knockout mice; adipose tissue; cold exposure; energy expenditure; single-nucleus RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117603
  23. bioRxiv. 2026 Jun 30. pii: 2026.06.29.733391. [Epub ahead of print]
    The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate.
    Alva G Sainz, Chulhwan S Kwak, Kwang Bog Cho, Sejal A Sripadanna, Brandon H Bergsneider, Zoe Zizzo, Aarooran S Durairaj, Zehui Du, Ian Cooney, Anthony Venida, Nike Bharucha, Ioannis Karakikes, Wah Chiu, Michael Lim, Michael C Bassik, Xinnan Wang.
      BAX macropores in the outer mitochondrial membrane (OMM) are canonical mediators of apoptosis, but whether the same pore structure can drive distinct cell death pathways remains unclear. Here, we identify the OMM protein MIRO1 as a context-specific modulator of BAX activity. Mechanistically, MIRO1 binds BAX via MIRO1's N-terminal domain to promote macropore formation and the release of mitochondrial DNA (mtDNA) into the cytoplasm, triggering the STING-pIRF3 signaling axis. In glioma cells, this pathway sustains GPX4 expression via pIRF3-mediated transcriptional activation and confers ferroptosis resistance while bypassing inflammation. By contrast, in Parkinsonian neurons, the MIRO1-BAX complex promotes mitochondrial-stress-induced apoptosis. Using structure-guided drug discovery, we developed first-in-class small molecules that allosterically disrupt the MIRO1-BAX complex by engaging MIRO1's distal GTPase pocket. These compounds sensitize glioma cells to ferroptosis and protect neurons from apoptosis. Our findings reveal a disease-specific mitochondrial switch for life-death decisions and illuminate the molecular logic by which cells exploit and interpret OMM permeabilization.
    DOI:  https://doi.org/10.64898/2026.06.29.733391
  24. Cell Death Dis. 2026 Jul 10.
    PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
    José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver.
      Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09079-0
  25. Sci Adv. 2026 Jul 10. 12(28): eady9432
    A scalable deep-learning framework for cancer detection using cell-free DNA shallow whole-genome sequencing.
    Haichao Wang, Paulius D Mennea, Grainne McAndrew, Ozge Sonmezler, Dmitry S Shcherbo, Emma-Jane Ditter, Sarah Østrup Jensen, Alessandra I G Buma, Christopher G Smith, Zhao Cheng, Clare Harris, Rosalind J Cutts, Sarah Hrebien, Philip A J Crosbie, Pippa G Corrie, Michel M van den Heuvel, Amit Roshan, Frank McCaughan, Robert C Rintoul, Florian Markowetz, Tommy Kaplan, Wendy N Cooper, Hui Zhao, Nitzan Rosenfeld.
      Cell-free DNA (cfDNA) in body fluids enables noninvasive cancer detection. Multifeature artificial intelligence (AI) can improve sensitivity by integrating diverse biomarkers when cancer signals are sparse. Tumor-informed assays that rely on mutations have limited practicality for early cancer detection. Emerging fragmentomic and epigenetic features underpin tumor-naive approaches to screening for individuals with low tumor burden. Here, we designed UNITE-a universal cfDNA feature ensemble framework that provides scalable cancer detection methods based on "genomic bin-fragment length" matrices derived from shallow whole-genome sequencing (sWGS) data at 0.1× depth. Using sWGS data from 2063 plasma samples (631 controls and 1432 cases from 26 cancer types), we systematically evaluated both XGBoost (UNITE-XGB) and convolutional neural networks (UNITE-CNN) across multiple feature spaces and cancer stages. In stage I-II cancer, UNITE-XGB and UNITE-CNN achieved 31 and 21% sensitivity, respectively, at 95% specificity. These findings provide roadmaps for developing multifeature AI beyond plasma biopsies.
    DOI:  https://doi.org/10.1126/sciadv.ady9432
  26. bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]
    N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
    Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.
      N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.
    DOI:  https://doi.org/10.64898/2026.06.29.735215
  27. Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00708-4. [Epub ahead of print]45(7): 117630
    Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
    Kenkyo Matsuura, Ririko Shinonaga, Mizuki Yamamoto, Yoshiki Yamamoto, Hsin Chen, Ayaka Maeno, Kayo Okuda, Haruki Inoue, Sota Imotani, John Glushka, Koji Miki, Yukako Watanabe, Mamoru Takada, Hironori Kaji, Jun-Ichiro Inoue, Ayuna Hattori, Hiromi Imamura, Takahiro Ito.
      Triple-negative breast cancer (TNBC) lacks effective molecularly targeted therapies. Here, we identify branched-chain amino acid (BCAA) metabolism as a selective vulnerability in human TNBC, particularly in the claudin-low subtype. TNBC cells show greater dependence on BCAAs than other breast cancer subtypes, and intracellular BCAA levels are heterogeneous within tumors in vivo. Cells with high BCAA levels exhibit enhanced sphere formation and cancer stem cell potential in xenograft models. BCAT1, a cytoplasmic BCAA aminotransferase, is upregulated in claudin-low TNBC and enables tumor growth by promoting BCAA production from branched-chain ketoacids. BCAT1 knockdown impairs TNBC growth in vivo, and high BCAT1 expression predicts poor prognosis in patient cohorts. Conversely, BCAA catabolism via the BCKDH complex is suppressed in TNBC, and reactivation of BCKDH by BCKDK knockout blocks clonogenic growth. These findings reveal BCAA metabolic balance as a key regulator of TNBC stemness and malignancy.
    Keywords:  CP: cancer; TNBC; branched-chain amino acid; claudin-low; metabolic vulnerability; metabolite imaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117630
  28. Sci Adv. 2026 Jul 10. 12(28): eaee7678
    Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.
    Nathaniel Hai, Chinmayee Vallabh Prabhu Dessai, Dingcheng Sun, Jianpeng Ao, Pin-Tian Lyu, Yifan Zhu, Ji-Xin Cheng.
      Intracellular chromophores {e.g., NADH [reduced form of nicotinamide adenine dinucleotide (oxidized form)] and FAD (flavin adenine dinucleotide)} play a central role in regulation of cellular metabolism. Although autofluorescence has been extensively used for label-free mapping of chromophores inside a cell, its sensitivity and molecular specificity are constrained by the low quantum yield and the fluorescence spectral overlap. Here, we address these challenges by using a photothermal approach to measure the optical absorption of chromophores rather than its autofluorescence. Our two-photon photothermal (2PPT) microscope exploits localized thermal transients generated through two-photon absorption, enabling detection of chromophore-specific signatures beyond the reach of autofluorescence. We demonstrate submicromolar limits of detection for the metabolic coenzymes NADH and FAD of 0.87 and 0.99 μM, respectively. Such high sensitivity enables differentiating the influence of mitochondrial shapes on metabolism. 2PPT can identify the biomolecular source of contrast from cellular mitochondria in a label-free manner on the basis of spectroscopy. 2PPT microscopy is used to study metabolic alterations of mitochondria in cancer under chemotherapy at the single-organelle level.
    DOI:  https://doi.org/10.1126/sciadv.aee7678
  29. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00233-0. [Epub ahead of print]38(7): 1269-1272
    Microbiota and immunotherapy: The birth of a new paradigm?
    Rachel C Newsome, Christian Jobin.
      Emerging data suggest fecal microbiota transplantation (FMT) may improve cancer patients' responses to immune checkpoint blockade not only by enriching beneficial bacteria but also by depleting harmful taxa. Here, we discuss the "supplementation" and new "depletion" FMT paradigms in cancer management and highlight key knowledge gaps to be addressed to move this field forward.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.007
  30. Res Sq. 2026 Jul 02. pii: rs.3.rs-10195584. [Epub ahead of print]
    Context-dependent selection sculpts mutational landscapes in the normal lung.
    Edward Evans, Ferriol Calvet, Fabio Marongiu, Faiz Jabbar, Elan Eisenmesser, William Hill, Clare Weeden, Oriol Pich, Moumita Ghosh, Robert Keith, York Miller, Daniel Merrick, Clara Troccoli, Andrew Rowan, Takahiro Karasaki, Selvaraju Veeriah, David Moore, Mihaela Angelova, Olivia Lucas, Charlotte Grieco, Lydia Liu, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Nuria Lopez-Bigas, Emilia Lim, Charles Swanton, James DeGregori.
      Just as organismal evolution is driven by environmental changes, somatic evolution is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices, or by extrinsic exposures. We present deep mutational profiling using duplex sequencing of over 370 samples of non-malignant lung tissue from 202 subjects, showing how aging, smoking and different anti-cancer therapies are associated with selection for particular mutations in normal lung tissue. Mutations within known cancer driver genes exhibit selection in the normal tissue that differs from that for lung cancers, with a substantially expanded spectrum of sites under selection. Multiregional profiling of mutational landscapes reveals convergent evolution within each individual's lung. Understanding the forces controlling clonal selection as we age and due to lifetime exposures could be critical for controlling multiple diseases of old age.
    DOI:  https://doi.org/10.21203/rs.3.rs-10195584/v1
  31. Nat Commun. 2026 Jul 08.
    A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
    Qian Zhang, Huimin Zhang, Marscha Hirschi, Sheng Li, Gabriel C Lander, Jie Yang, Xiang-Lei Yang.
      Cellular homeostasis requires tight coordination between metabolic and translational networks. Here we identify a direct molecular link between these processes through a cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) in complex with the NAD⁺-dependent deacetylase SIRT2. This interaction is promoted by the NAD⁺ metabolite ADP-ribose (ADPR), which acts as a molecular bridge between the two enzymes. Within the SIRT2 active site, ADPR engages SerRS residue K414 located in a flexible catalytic-domain loop. Acetylation of K414 is dispensable for binding. Functionally, complex formation inhibits SIRT2 deacetylase activity by blocking substrate access, while SIRT2 association suppresses SerRS aminoacylation activity by preventing tRNA binding. Thus, SerRS and SIRT2 mutually regulate each other, with ADPR enhancing while tRNA attenuating their interaction. Oxidative stress promotes this interaction via a PARP1-dependent pathway, revealing an ADPR-responsive regulatory module that couples metabolic state to translational output. This regulatory module is likely conserved across vertebrates.
    DOI:  https://doi.org/10.1038/s41467-026-75266-4
  32. Nat Genet. 2026 Jul 10.
    Evolving patterns of co-mutations from tumor initiation to metastatic progression.
    Arvind Iyer, Miljan Petrovic, Debora Sesia, Luca Nanni, Marco Mina, Giovanni Ciriello.
      Phenotypically healthy cells frequently harbor somatic variants at cancer-associated genes, indicating that malignant transformation requires the selection of several alterations. Predicting which combinations of mutations, or co-mutations, exhibit oncogenic capacity requires identifying co-mutations that occur more or less frequently than expected. However, statistical frameworks to solve this problem are hampered by tumor heterogeneity and data availability. Here we curated putative oncogenic mutations in >70,000 human tumors from 119 subtypes, and designed a strategy to search for co-mutations based on in silico simulation of mutagenesis (SelectSim). Using this dataset and tool, we discovered and validated co-mutations across independent human cohorts, compared co-mutations across different tumor types and identified potential risk factors of metastatic progression. Notably, across several cohorts of phenotypically normal tissue samples, we show that, unlike individual oncogenic variants, significantly co-occurring mutations are largely cancer-specific and are observed rarely in healthy tissues, providing clues about the paths to tumorigenesis.
    DOI:  https://doi.org/10.1038/s41588-026-02661-4
  33. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  34. bioRxiv. 2026 Jul 02. pii: 2026.06.24.734388. [Epub ahead of print]
    Multi-Tissue Metabolomic Signatures of Five Longevity Interventions Converge on Ergothioneine and Lipid Remodeling in Male UM-HET3 Mice.
    Bretton Badenoch, Oliver Fiehn, Noa Rappaport, Sara Greenfield, Sriram Chandrasekaran, Richard A Miller.
      The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17α-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments. The most influential metabolites - defined as the minimum set explaining 50% of cumulative model gain - differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.
    DOI:  https://doi.org/10.64898/2026.06.24.734388
  35. Aging Cell. 2026 Jul;25(7): e70624
    Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
    Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.
      Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.
    Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control
    DOI:  https://doi.org/10.1111/acel.70624
  36. bioRxiv. 2026 Jul 01. pii: 2026.06.26.734836. [Epub ahead of print]
    Sequential infection reprograms the immune landscape to shape future responses.
    Mengdi Guo, Yanis Hichem Bouzaher, Diala Abd-Rabbo, Rene Quevedo, Heidi J Elsaesser, Wenxi Xu, Melissa Yi Ran Liu, Fauzia N Izzati, M Teresa Ciudad, Matthew Bianca, Zhe Qi Liu, Joao E M de Oliveira, Arthur Mortha, Landon J Edgar, Tracy L McGaha, Tiffany A Reese, David G Brooks.
      Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naïve CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naïve and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.
    DOI:  https://doi.org/10.64898/2026.06.26.734836
  37. Aging (Albany NY). 2026 Jul 01. 18(1): 768-786
    Senescent cells accumulate lipid droplets.
    Noa Rachmian-Cooper, Riva Shmulevich, Hagay Akiva, Sarka Pokorna, Bareket Dassa, Ulysse Cherqui, Sergey Malitsky, Maxim Itkin, Binyamin Amichai Kliger, Inna Goliand, Tomer Meir Salame, Valery Krizhanovsky.
      Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.
    Keywords:  Alzheimer’s disease; aging; lipid droplets; metabolism; senescence
    DOI:  https://doi.org/10.18632/aging.206390
  38. EMBO Rep. 2026 Jul 07.
    A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration.
    Philippe Dehio, Céline Michard, Juan Carlos Yam-Puc, Adrià-Arnau Martí I Líndez, Anett Jandke, Gunhild Unterstab, Lucien Fabre, Loïc Sauteur, Marc Artinger, Daniel F Legler, Michael Sixt, Thorsten Schaefer, Matthias P Wymann, Klaus Okkenhaug, Thierry Soldati, Matthias Mehling, Christoph Hess.
      Amoeboid cell migration is key to efficient T cell immunity. Spatial polarization of organelles within cells, including endo-lysosomes, is a prerequisite of migration. However, how ultrastructural polarization is linked to the signaling requirements governing T cell migration remains unknown. Here we show that signaling molecules generated by endo-lysosome-localized kinases regulate velocity of amoeboid migration. Specifically, imaging of T cells identifies accumulation of endo-lysosomes decorated with the lipid kinases VPS34-PIKfyve at the uropod of polarized cells. Activity of VPS34 and PIKfyve regulates speed, but not directedness, of migrating T cells. Mechanistically, PI(3,5)P2 generated by the sequential action of VPS34 and PIKfyve, mediates Ca2+ efflux from lysosomes via the mucolipin TRP cation channel 1 (TRPML1), thus controlling activity of myosin IIA and hence the generation of propulsive force through retrograde actin flow. The VPS34-PIKfyve kinases also regulate velocity of myeloid cells, as well as of the amoeba Dictyostelium discoideum - establishing the axis as an evolutionarily conserved speed control system of amoeboid cell migration.
    DOI:  https://doi.org/10.1038/s44319-026-00861-x
  39. Andrology. 2026 Jul 06.
    Reinke Crystals are Immunoreactive for Purine-Synthesising Metabolic Enzymes.
    John Woulfe, Trevor A Flood, Sharlene Faulkes, David G Munoz.
       BACKGROUND: Reinke crystals are a defining histological feature of human adult Leydig cells, the testosterone-producing cells of the testis. These structures are present in the cytoplasm and the nucleus and display quantitative alterations in a variety of physiological and pathological contexts. The functional significance and protein composition of Reinke crystals have remained elusive for over a century.
    OBJECTIVES: We sought to explore the protein composition of Reinke crystals.
    MATERIALS AND METHODS: Double labelling immunofluorescence for the purine nucleotide-synthesizing enzymes inosine monophosphate dehydrogenase (IMPDH) and phosphoribosyl pyrophosphate synthetase (PRPS) and confocal microscopic imaging were performed on samples of human Leydig cell tumours and adjacent non-neoplastic testis.
    RESULTS: We demonstrate that Reinke crystals are intensely immunoreactive for IMPDH and PRPS, two key rate-limiting enzymes in the de novo synthesis of purine nucleotides.
    DISCUSSION: IMPDH and PRPS are two of several metabolic enzymes that are capable of forming mesoscale filamentous aggregates as a mechanism to regulate enzyme activity. IMPDH is also able to form crystals in cellulo. Our observations potentially link Reinke crystal formation to purine nucleotide metabolism in Leydig cells.
    CONCLUSION: If confirmed in future studies, this finding may have important implications for understanding metabolic contributions to male reproductive disorders.
    Keywords:  GTP; Leydig cells; Reinke crystals; inosine monophosphate dehydrogenase; nucleotides; phosphoribosyl pyrophosphate synthetase
    DOI:  https://doi.org/10.1111/andr.70302
  40. Cell Calcium. 2026 Jun 18. pii: S0143-4160(26)00054-0. [Epub ahead of print]136 103161
    Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
    Johannes Pfabe, Amanda Cambraia, Prasanna K Dadi, Melanie Cutler, Cristiane Dos Santos, Christopher Acree, Aliyah Habashy, Guy Perkins, Mark H Ellisman, David A Jacobson, Marjan Slak Rupnik, Rafael Arrojo E Drigo.
      Calorie restriction (CR) promotes beta cell longevity by regulating cell identity, organelle and protein homeostasis, and metabolism pathways. CR beta cells have higher cAMP levels and mitochondria with an elevated potential to generate ATP. However, CR beta cells have reduced insulin secretion due to increased peripheral insulin sensitivity. How CR impacts beta cell Ca²⁺ homeostasis to regulate beta cell insulin release remains unknown. We investigated this question using acute pancreatic tissue slices prepared from ad-libitum (AL) or CR mice loaded with a low affinity Ca²⁺ indicator and recorded cytosolic Ca²⁺ gradients with fast confocal imaging. We exposed these slices to increasing glucose concentrations and applied our semi-automatic analysis pipeline to detect thousands of individual beta cells followed by identification of individual Ca²⁺ spiking events. We observed that elevated cAMP in CR beta cells causes fast short-amplitude Ca²⁺ oscillations that potentiate insulin release despite a largely disconnected beta cell network landscape. Using acetylcholine stimulation, we found that faster IP3R-driven Ca²⁺ oscillations linked to higher cytosolic cAMP levels protect beta cells against acute depletion of ER Ca²⁺. Therefore, this study demonstrates that CR promotes beta cell cAMP and ER Ca²⁺ homeostasis to enhance beta cell secretory function.
    Keywords:  Beta cell calcium; Calorie restriction; Endoplasmic reticulum (er)
    DOI:  https://doi.org/10.1016/j.ceca.2026.103161
  41. BMJ Oncol. 2026 ;5(2): e001031
    Investigating the determinants of immunotherapy response in the primary tumour of clear cell renal cell carcinoma (RCC).
    Cerise Tang, Deepak Poduval, Suzanna Lee, Justine Panian, Ava Saidian, Rishabh Rout, David van Dijk, Rana R McKay, David A Braun.
       Objective: Immune checkpoint inhibitors (ICIs) have demonstrated durable clinical benefit in a subset of patients with metastatic renal cell carcinoma (RCC), yet the molecular features that govern therapeutic response within the primary tumour remain poorly defined. This is of particular importance in the current era, where cytoreductive nephrectomy is less commonly performed and many patients with metastatic disease still have the primary RCC tumour in place. To deepen our understanding of ICI response in the primary tumour and to understand the evolution of RCC on ICI, we conducted a comprehensive genomic analysis of paired pretreatment and post-treatment primary RCC tumours treated with ICI.
    Design setting and participants: We performed a multimodal analysis of 46 ICI-treated primary RCC tumour specimens from 33 patients, including 13 matched pretreatment biopsies and post-treatment nephrectomies to investigate the genomic and transcriptomic evolution of tumours exposed to ICI therapy. Seventeen samples were from responders (>30% radiographic shrinkage, n=4 pretreatment, n=13 post-treatment) and 29 samples were from non-responders (<30% shrinkage, n=11 pretreatment, n=18 post-treatment). Whole-exome and RNA-seq were performed at Caris Life Sciences.
    Results: In this limited cohort, pretreatment responder biopsies are enriched for immune-related gene programmes, including B cell and tertiary lymphoid structure signatures. Longitudinal analysis reveals immune pathways decline in responders while non-responders show signatures of T cell exhaustion. However, the small number of patients with paired samples constrains statistical power and limits generalisability.
    Conclusions: Our findings highlight the value of primary tumour profiling in understanding ICI response dynamics in RCC.
    Keywords:  Immunotherapy; Kidney cancer
    DOI:  https://doi.org/10.1136/bmjonc-2025-001031
  42. Genome Med. 2026 Jul 09.
    Spatial ecology of breast cancer reveals co-evolution of proliferative and dormant niches.
    Cenk Celik, William A Weston, Thais de Moraes-Lacerda, Eloise Withnell, Shi Pan, Tooki Chu, John Labbadia, Alexis R Barr, Maria Secrier.
       BACKGROUND: Cancer progression involves not only uncontrolled proliferation but also the strategic entry of tumour cells into reversible (quiescent) or irreversible (senescent) states of cell cycle arrest (G0). These states can give rise to rare persister-like cancer cells that survive hostile tumour microenvironment conditions, facilitating drug resistance, metastasis and disease relapse. Despite their importance, identifying and understanding the mechanisms regulating these cell populations remains challenging.
    METHODS: We leveraged single-cell and spatially profiled primary breast tumours to quantify G0 arrest and proliferation decisions in cancer cells, revealing molecular and spatial features associated with proliferation-G0 dynamics.
    RESULTS: We uncovered a G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity. Spatial analyses revealed distinct ecological niches: G0 cells inhabited protective niches with complement pathway activity proximal to CXCL10+ macrophages and myofibroblastic cancer-associated fibroblasts (CAFs), whereas proliferative zones were associated with CLEC9A+ dendritic cells and PERK signalling, with distinct drug sensitivities.
    CONCLUSIONS: Our findings highlight key principles underpinning G0-proliferation dynamics and niche specialisation in breast cancer, offering novel insights into the spatial drivers of tumour heterogeneity and evolution.
    Keywords:  Breast cancer; G0 persister cells; Quiescence; Spatial transcriptomics; Tumour dormancy; Tumour microenvironment
    DOI:  https://doi.org/10.1186/s13073-026-01711-0
  43. bioRxiv. 2026 Jun 29. pii: 2026.06.24.734337. [Epub ahead of print]
    SIRT5-dependent regulation of ASL controls arginine metabolism and T cell function.
    Kim Han, Rachael J Klein, Kaiyuan Wu, Anna Chiara Russo, Allison M Meadows, Thomas C Recupero, Rahul Sharma, Anand K Gupta, Nathan T Brandes, Benjamin Schwarz, Michael N Sack.
      NAD⁺ supplementation blunts Th1 and Th17 inflammation, in part, through arginine metabolism-dependent regulation of mitochondrial energetics, redox balance and signal transduction. Whether the NAD + -dependent sirtuin deacylases contribute to this regulation is unknown. Here, we show that both SIRT1 and SIRT5 transcript levels are induced in CD4 + T cells in human participants following oral supplementation of the NAD + precursor nicotinamide riboside (NR). Among the sirtuin family members, SIRT5 rather than SIRT1 emerged as the predominant regulator of arginine and fumarate metabolism. Genetic depletion or pharmacologic inhibition of SIRT5 attenuated NR-mediated increases in arginine and fumarate and abolished the anti-inflammatory -effects of NR on Th1 and Th17 cytokine production. In contrast, the responses to exogenous arginine or citrulline supplementation were preserved, indicating that SIRT5 functions upstream of arginine biosynthesis. Metabolomic profiling further demonstrated that SIRT5 is required for NR-induced remodeling of the arginine biosynthetic pathway. Mechanistically, SIRT5 physically interacted with arginosuccinate lyase (ASL), promoted ASL-dependent arginine accumulation, and regulated ASL post-translational acylation, including glutarylation and malonylation. Loss of SIRT5 disrupted NR-mediated redox homeostasis, antioxidant gene expression, and cytokine suppression. Collectively, these findings identify SIRT5 as a critical mediator of NAD⁺ precursor-induced metabolic remodeling that links ASL-dependent arginine metabolism to redox balance and effector function in human CD4⁺ T cells.
    DOI:  https://doi.org/10.64898/2026.06.24.734337
  44. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615
    ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
    Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.
      Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.
    Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117615
  45. EMBO Rep. 2026 Jul 07.
    De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
    Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.
      Postnatal maturation of the mammalian heart requires a vast increase in respiratory enzymes. The mitochondria-specific lipid cardiolipin (CL) is essential for respiratory chain integrity but has no defined function in heart maturation. Here, we determined how the two steps of CL biogenesis, de novo synthesis and acyl chain remodeling, affect the maturation of cardiac mitochondria in mice. Cardiomyocyte-restricted deletion of the CL synthase Crls1 in late gestation does not affect CL levels at birth but blocks the increase in the tissue concentration of CL observed during normal postnatal maturation. Deletion of Crls1 prevents the postnatal rise in cristae density and in the intramitochondrial concentration of respiratory proteins. This inhibits cardiac development, precipitates heart failure, and causes death by the age of 2 weeks. In contrast, ablation of CL remodeling by cardiomyocyte-restricted deletion of Tafazzin does not disrupt mitochondrial maturation or cardiac development, although it has a similar effect on the CL concentration and profoundly alters the CL species composition. Our data show that CL synthesis, but not CL remodeling, controls expression of the respiratory chain by a mechanism independent of the CL concentration.
    DOI:  https://doi.org/10.1038/s44319-026-00864-8
  46. Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00230-3. [Epub ahead of print]61(7): 1392-1406
    Tissue mechanopathology of cancer.
    Johanna Ivaska, Sarah Sale, Alpha S Yap.
      Cancers are complex cellular communities comprising tumor cells and their microenvironment. Recent advances in cancer biology have emerged from efforts to analyze tumors as tissues, in which emergent properties arise as tumor cells interact with one another, their microenvironment, and the host tissue. In this review, we consider interactions involving mechanical forces and mechanosignaling pathways that detect changes in physical inputs to regulate cellular behavior. This rapidly developing field provides perspectives for understanding cancer biology and tumor interactions with the host ecosystem.
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.006
  47. Nat Commun. 2026 Jul 10.
    Genetic drivers of etiologic heterogeneity in thyroid cancer.
    Yon Ho Jee, Nikita Pozdeyev, Christopher R Gignoux, Samantha White, Bryan R Haugen, Anurag Verma, Raitis Peculis, Vita Rovite, Ashley J Mulford, Alan R Sanders, Cari M Kitahara, Mary Pat Reeve, Peter Kraft, Alicia R Martin.
      Thyroid cancer is the most common endocrine malignancy, yet its biological underpinnings remain incompletely understood. Here we show that common risk alleles for thyroid cancer point to distinct biological pathways underlying disease susceptibility. We perform a multi-ancestry genome-wide association meta-analysis of thyroid cancer (16,167 cases and 2,430,374 controls), identifying 51 independent loci, including 21 not previously reported. By integrating these loci with genetic associations for 151 thyroid-cancer-related traits, we identify pleiotropic mechanistic clusters linked to thyroid function, oncogenic pathways, and mixed physiological function. Two thyroid-specific clusters, associated with thyroid stimulating hormone or thyroid growth and function, are enriched in thyroid tissues. Oncogenic clusters include DNA repair (ATM, CHEK2, TP53) and telomere maintenance (TERT) genes, implicating shared cancer mechanisms. Cluster-specific polygenic scores are associated with thyroid disease, cancer, and metabolic traits across ancestry groups, suggesting distinct genetic subtypes of thyroid cancer risk and supporting pleiotropy-based approaches to genetic risk stratification.
    DOI:  https://doi.org/10.1038/s41467-026-75111-8
  48. Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00721-7. [Epub ahead of print]45(7): 117643
    An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma.
    Weiwei Dai, Ruotong Tian, Ming Whye Chong, Jin Li, Bowen Yin, Zhuoyang Fan, Shasha Bian, Minfeng Shu.
      The glioblastoma microenvironment is highly immunosuppressive and enriched with macrophages, which critically promote tumor progression and confer resistance to current therapies. However, the molecular mechanisms by which glioblastoma cells orchestrate macrophage recruitment through post-transcriptional regulation remain poorly understood. Here, we identify a glioblastoma-intrinsic pathway whereby the m6A RNA modification reader IGF2BP3 couples RNA metabolism with metabolic competition and immune remodeling. Specifically, IGF2BP3 selectively binds and stabilizes m6A-modified transcripts encoding the methionine transporter SLC38A2, thereby enhancing methionine uptake by glioblastoma cells. This metabolic advantage creates a methionine-deprived state in neighboring macrophages, leading to reduced global m6A methylation and increased expression of the chemokine CCL5. Elevated CCL5 subsequently drives further macrophage infiltration, establishing a feedforward loop that amplifies nutrient competition and sustains immunosuppression within the tumor microenvironment. Together, our findings delineate an m6A-dependent metabolic circuit that governs macrophage recruitment in glioblastoma and suggest a therapeutic avenue to reprogram the tumor immune microenvironment.
    Keywords:  CCL5; CP: Cancer; IGF2BP3; SLC38A2; glioblastoma; methionine; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117643
  49. EMBO J. 2026 Jul 10.
    Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC.
    Qin Shen, Chen Mei, Yidan Chen, Qian Zhang, Qingzhe Wu, Xinyuan Yu, Fei Zhang, Shengduo Liu, Chen Chen, Cunqi Ye, Qi Zhang, Xin-Hua Feng, Li Shen, Hai Song, Tingbo Liang, Penghong Song, Bing Xia, Pinglong Xu.
      EGFR hotspot mutations (mEGFR), including primary L858R, exon 19 deletion, and secondary T790M, are pivotal oncogenic drivers in human non-small cell lung cancer (NSCLC). At the same time, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized tumor cell-intrinsic mechanism in which mutant EGFR (mEGFR) exploits innate immune signaling via the cGAS-STING-TBK1 pathway to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly associates with STING signalosomes and phosphorylates STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 and establishing an unexpected kinase loop critical for DNA damage repair. Genetic or pharmacological disruption of mEGFR-STING-TBK1 coupling sensitizes resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin suppressed mEGFR-driven tumors in murine models of spontaneous and immunocompetent NSCLC and in patient-derived organoids. Our findings suggest a new function of cGAS-STING in DNA damage tolerance, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.
    DOI:  https://doi.org/10.1038/s44318-026-00856-3
  50. bioRxiv. 2026 Jul 01. pii: 2026.06.28.735129. [Epub ahead of print]
    B cell-intrinsic IRF8 transcriptionally reprograms antigen presentation to sustain CD8⁺ T cell antitumor immunity.
    Zainab Tiamiyu, Dakota B Poschel, Richa Rashmi, Sergei Bombin, Kendra Fick, Patrick Czabala, Dafeng Yang, Huidong Shi, Keita Saeki, Keiko Ozato, Kebin Liu.
      Interferon regulatory factor 8 (IRF8) is a master transcription factor of myeloid differentiation, but whether IRF8 intrinsically controls B cell function in tumors remains unknown. Using paired single-cell transcriptomic and chromatin accessibility profiling of tumors from wild-type and Irf8-deficient mice, we identify a B cell-intrinsic IRF8 axis regulating antigen presentation and sustaining anti-tumor CD8⁺ T cell immunity. IRF8 establishes conserved chromatin accessibility programs across myeloid cells and plasmablasts centered on antigen processing and MHC class I presentation, but engages distinct motifs by lineage: myeloid cells preferentially utilize ISRE and ETS-composite elements, whereas plasmablasts are selectively enriched for EICE elements, reflecting B lineage-specific IRF8-IRF4 cooperation. Loss of IRF8 disrupts these programs, skews B cells toward plasmablast differentiation and reduces antigen presentation machinery. B cell depletion accelerated tumor growth, while CD40 agonism activated B cells, expanded T cells, and enhanced anti-tumor immunity. B cell-specific IRF8 deletion alone accelerated tumor growth, establishing a cell-intrinsic requirement independent of myeloid IRF8 function. The IRF8-regulated B cell signature was enriched in PD-1 blockade cancer patient responders, and plasmablast abundance correlated with response in pembrolizumab-treated cancer patients. These findings establish IRF8 as a lineage-adapted regulator of antigen presentation and define the IRF8-B cell axis as a determinant of anti-tumor immunity.
    Highlights: IRF8 establishes a conserved chromatin accessibility across tumor-infiltrating myeloid and B cellsMyeloid cells engage ISRE motifs, whereas plasmablasts rely on EICE motifs as IRF8 lineage-specific cis-regulationIRF8 regulates an antigen presentation in B cells to sustain anti-tumor T cell immunityB cell-intrinsic IRF8 transcription signature predicts patient response to PD-1 blockade immunotherapy.
    DOI:  https://doi.org/10.64898/2026.06.28.735129
  51. Sci Adv. 2026 Jul 10. 12(28): eaec3544
    Multiscale metabolic mapping of lung tissue via coregistered mass spectrometry and nonlinear optical imaging.
    Brittney L Gorman, Zhi Li, Gail Deutsch, Heidie L Huyck, Niana Beishembieva, Harsh Bhotika, Heather Olson, Jorge Villazon, Ping Yu, Gloria S Pryhuber, Geremy Clair, Lingyan Shi, Christopher R Anderton.
      The lung is a highly heterogeneous organ that is composed of numerous microanatomical units, each essential for maintaining intricate functions that work in concert. Disruptions in the molecular and cellular mechanisms can cause tissue fibrosis, inflammation, and severe breathing difficulties, which are common characteristics of the disease of prematurity, bronchopulmonary dysplasia (BPD). BPD's molecular changes are not well understood, and this has hindered effective diagnosis and treatment. Here, we present a multimodal imaging workflow for detailed molecular and metabolic characterization of lung tissue at multiple spatial scales. We also developed a hierarchical multimodal registration network for precise coregistration of the data from each modality. Our results show that this approach can reveal previously unknown metabolic changes in distinct functional tissue units affected by disease, including altered lipid distributions, reduced optical redox states, and collagen remodeling. This multimodal approach provided detailed maps of molecular shifts occurring in distinct microanatomical features that, when adopted to interrogate this and other tissue types, has the potential to enable the discovery of new therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.aec3544
  52. Science. 2026 Jul 09. 393(6807): eaea1200
    The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity.
    Xixi Zhang, Sherin Xirenayi, Ye Zhao, Wen Wang, Yuyang Han, Miguel Sobral, Shawn Kang, Chi Zhang, Graham L Barlow, Jason Pyrdol, Jae-Won Cho, Kun Huang, Xiaohan Ning, Martin Hemberg, Guo-Cheng Yuan, Eliezer M Van Allen, David J Mooney, Kai W Wucherpfennig.
      The cancer-immunity cycle requires cross-presenting type I conventional dendritic cells (cDC1s) that induce T cell-mediated immunity, but therapeutic strategies for enhancing intratumoral cDC1 function are currently inadequate. We found the epigenetic enzyme CARM1 (coactivator-associated arginine methyltransferase 1) to be a selective negative regulator of cancer antigen presentation by cDC1s but not cDC2s. Inactivation of the Carm1 gene promoted cDC1 antigen cross-presentation, activation, and accumulation in tumors, and a CARM1 inhibitor enhanced cDC1-mediated priming of T cells by means of a cancer neoantigen vaccine. CARM1 inhibition increased chromatin accessibility at BATF3-Jun and RelA sites that are critical for cDC1 function and activation. Transforming growth factor-β regulated Carm1 expression, which suggests that CARM1 inactivation enhanced intratumoral cDC1 function without altering cDC1 homeostasis. These studies identify CARM1 as a potential therapeutic target for enhancing the antitumor function of mouse and human cDC1s.
    DOI:  https://doi.org/10.1126/science.aea1200
  53. Elife. 2026 07 07. pii: RP109257. [Epub ahead of print]14
    Profiling of terminating ribosomes reveals translational control at stop codons.
    Longfei Jia, Yuanhui Mao, Saori Uematsu, Xinyi Ashley Liu, Leiming Dong, Leonardo Henrique França de Lima, Shu-Bing Qian.
      Accurate termination of protein synthesis is paramount for the integrity of the cellular proteome, yet the dynamics and fidelity of ribosome termination remain poorly understood. Here, we establish a profiling strategy to capture terminating ribosomes in mammalian cells and reveal a substantial heterogeneity in ribosome pausing at individual stop codons. We identify a sequence motif upstream of the stop codon that promotes termination pausing, a finding supported by massively parallel reporter assays. Unexpectedly, reduced termination pausing increases the likelihood of stop codon slippage, giving rise to proteins with heterogeneous C-terminal extensions. Mechanistically, we show that sequence-dependent termination pausing is consistent with post-decoding mRNA scanning by the 3' end of 18 S rRNA. We further uncover tissue-specific patterns of termination pausing that correlate with the stoichiometry of Rps26, which potentially modulates mRNA:rRNA interactions. Together, these results suggest termination pausing as a distinct translational signature shaped by mRNA sequence contexts, ribosome heterogeneity, and cell type-specific translational control.
    Keywords:  biochemistry; chemical biology; human; ribosome; stop codon; translation
    DOI:  https://doi.org/10.7554/eLife.109257
  54. Nature. 2026 Jul 08.
    Ancient feeding-related neuropeptides regulate alloparenting in ants.
    Alexander Paul, Tomas Kay, Ivan Lacroix, Vikram Chandra, Asaf Gal, Patrick K Piekarski, Stephany Valdés-Rodríguez, Amelia L Ritger, Katelyn S Lee, Kip D Lacy, Daniel J C Kronauer.
      Alloparental care and division of labour are hallmarks of insect societies1. Social insect workers typically care for brood within the nest when they are young and transition to foraging outside the nest as they age2-5. This provides a powerful paradigm to study the neural basis of parenting and age-related behavioural change. Although previous work has interrogated aspects of these dynamics6-14, the underlying neural and molecular mechanisms remain poorly understood. Here, using an unbiased pharmacological screen of neuropeptides, we show that two ancestral regulators of feeding, neuropeptide F (NPF) and allatostatin A (AstA), modulate brood-care behaviour in the clonal raider ant. Through functional manipulations, we show that NPF increases brood-care behaviour, whereas AstA has the opposite effect. Furthermore, we find that the levels of NPF and AstA in the brain change naturally as ants age, suggesting that these changes underlie the age-related changes in brood-care behaviour. Finally, we show that, as in solitary species15,16, NPF and AstA remain sensitive to nutritional state, and nutritional state affects brood-care behaviour accordingly. Our results reveal that evolution has co-opted molecular mechanisms that regulated feeding ancestrally to enable cooperative brood care and age-associated division of labour.
    DOI:  https://doi.org/10.1038/s41586-026-10747-6
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