bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–08–30
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
  2. All-optical multimodal mapping of single-cell-type-specific metabolic activities via REDCAT.
  3. SGLT2 inhibitors activate pantothenate kinase in the human heart.
  4. The hallmarks of protein and amino acid restriction in aging and longevity.
  5. Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
  6. Systematic multivariate analysis of chromatin complex dependencies reveals Set1C/COMPASS as a melanoma-enriched epigenetic vulnerability.
  7. Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.
  8. Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.
  9. An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation.
  10. Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.
  11. Transferable genetic toolsets for nonmodel gut Clostridia enable in vivo reversible control of metabolite production.
  12. Determinants of mutation susceptibility along the genome are largely invariant across human tissues.
  13. Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
  14. Nuclear CGAS promotes cancer dissemination.
  15. Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease.
  16. Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
  17. Mitochondria as central regulators of cancer progression and antitumor immunity.
  18. hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
  19. Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
  20. Shiny metal catalysts at the origin of metabolism.
  21. The OmniAge compendium of aging omic biomarkers links mitotic clocks to clonal hematopoiesis and causality.
  22. Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
  23. A developmental biologist's guide to mechanics.
  24. Integrating in situ single-particle cryo-electron microscopy with cryo-electron tomography for high-resolution structural biology in native cellular contexts.
  25. Virtual Cell Challenge 2026: Benchmarking zero-shot generalization across cellular contexts.
  26. cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
  27. A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
  28. The long return on discovery science in cancer therapeutics.
  29. A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
  30. Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
  31. SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation.
  32. Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
  33. SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.
  34. Nuclear mechanobiology: a brief history and five unresolved questions.
  35. Integrative spatial profiling of 3D genome organization and gene expression in tissue.
  36. Pan-tumor spatial transcriptomics reveals conserved properties of tumor organization.
  37. Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
  38. Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging.
  39. Architectural logic of the 3D genome: mechanisms of dysregulation and emerging cancer therapeutics.
  40. Propionic acidemia as a framework for understanding the impact of disturbed propionyl-CoA on histone modifications.
  41. Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
  42. Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
  43. From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
  44. Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
  45. Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling.
  46. Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
  47. Understanding cardiovascular aging as a disorder of mitochondrial network.
  1. Sci Adv. 2026 Aug 28. 12(35): eaeg8792
    Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
    Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.aeg8792
  2. Nat Methods. 2026 Aug 27.
    All-optical multimodal mapping of single-cell-type-specific metabolic activities via REDCAT.
    Yajuan Li, Zhaojun Zhang, Archibald Enninful, Negin Farzad, Presha Rajbhandari, Hua Tian, Jungmin Nam, Xiaoyu Qin, Jorge Villazon, Anthony A Fung, Hongje Jang, Zhiliang Bai, Nancy R Zhang, Brent R Stockwell, Rong Fan, Mina L Xu, Zongming Ma, Lingyan Shi.
      Metabolism is fundamental to cell function, yet its activities vary across tissue environments. Resolving these processes in situ at single-cell resolution is crucial for understanding physiology in health and disease. However, existing methods lack biochemical specificity or direct linkage to cell identity. Here we report a method, Raman Enhanced Delineation of Cell Atlases in Tissues (REDCAT), an all-optical platform integrating Raman scattering microscopy and high-plex immunofluorescence to co-map metabolism and cell types. REDCAT achieves subcellular profiling of protein, lipid, nuclear metabolites and redox metabolism in human tissues. In lymph nodes, it revealed cell-type-specific metabolic specialization. In lymphoma, REDCAT uncovered profound reprogramming and transitional states during tumor transformation. In the liver, it resolved zonation-dependent metabolic gradients. By linking cell identity to spatial metabolic states, REDCAT provides a framework for studying immunity and cancer, offering a path to deciphering the metabolic basis of disease.
    DOI:  https://doi.org/10.1038/s41592-026-03180-0
  3. Science. 2026 08 27. 393(6814): 895-902
    SGLT2 inhibitors activate pantothenate kinase in the human heart.
    Nicholas Forelli, Trace Thome, Deborah M Eaton, Kollin Schultz, Jiten Patel, Caitlyn E Bowman, Ryo Kawakami, Jae Woo Jung, Ivan A Kuznetsov, Kristina Li, Jialiu A Liang, Kirsten Branch, Claire Brady, Kenneth C Bedi, Yijun Yang, Kaustubh Koya, Nesrine Bouhrira, Emily Megill, Daniel S Kantner, Louis G Smith, Cristin F MacIntosh, Kushol Gupta, Gregory R Bowman, Nathaniel W Snyder, Jonathan Edwards, Kenneth B Margulies, Zoltan Arany.
      Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality in heart failure, but their pharmacological target remains unclear. In this study, we showed that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A (CoA) synthesis. Using stable isotope infusions, we established that SGLT2i activate CoA synthesis and broadly stimulate fuel use in human cardiac tissue. We also demonstrated that SGLT2i bind PANK1 at physiological concentrations, directly inducing conformational changes and increasing enzymatic activity. In silico modeling identified the site of SGLT2i binding on PANK1, which was confirmed by amino acid mutagenesis. Finally, we showed that SGLT2i-mediated PANK activation is necessary and sufficient to increase contractility of human cardiomyocytes. In summary, we demonstrate off-target activation of PANK1 and promotion of CoA synthesis by SGLT2i, which may explain their marked clinical benefits.
    DOI:  https://doi.org/10.1126/science.aeh4856
  4. Cell Press Blue. 2026 Aug 17. pii: 100079. [Epub ahead of print]1(5):
    The hallmarks of protein and amino acid restriction in aging and longevity.
    Bailey A Knopf, Dudley W Lamming.
      Despite widespread recommendations for higher protein intake during aging, increasing evidence suggests that dietary protein restriction (PR) promotes metabolic health, healthspan, and lifespan across diverse organisms. Mechanistic studies further demonstrate that restriction of specific amino acids, particularly methionine, isoleucine, and valine, recapitulates many of the benefits of PR, highlighting the specific amino acid composition of the diet as a key determinant of aging. Here, we define the hallmarks of PR through the lens of aging, examining how PR and restriction of specific essential amino acids impact metabolic health, nutrient sensing, senescence, mitochondrial function, and the epigenome. We also discuss the known and unknown roles of non-essential amino acids in healthy aging. Overall, this review provides a comprehensive overview of current knowledge regarding the benefits of PR and amino acid restriction for healthy aging and highlights the therapeutic potential of interventions based on these diets to promote healthspan and longevity.
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100079
  5. Cell Rep. 2026 Aug 27. pii: S2211-1247(26)00951-4. [Epub ahead of print]45(9): 117873
    Prohibitin controls MRS2-Mediated mitochondrial Mg2+ uptake to Shape bioenergetics.
    Soumya Maity, Manigandan Venkatesan, Adhishree Chidambaram, Sukanthathulse Uthayabalan, Louis Tung Faat Lai, Nicholas D Clark, Abhinaya Lakkureddi, Karthik Ramachandran, Kristen Bentz, Ravi Ramalingam, Sanjana Sen, Moeez Akram, Susan T Weintraub, Brij B Singh, David Gius, Joseph A Baur, Arianne L Theiss, Jeffrey Caplan, Doreen Matthies, Peter B Stathopulos, Muniswamy Madesh.
      Mitochondrial magnesium (mMg2+) is essential for cellular metabolism and bioenergetics, yet the mechanisms governing its transport remain poorly understood. Although MRS2 constitutes the pore of the mMg2+ channel, the molecular machinery regulating its function is unknown. Here, unbiased proteomics identified the prohibitin (PHB) complex as a prominent MRS2-interacting partner. Integrated biochemical and functional analyses demonstrate that the conserved coiled-coil domain mediates MRS2 homo-oligomerization, whereas the C-terminal region of MRS2 interacts with PHB1 to promote channel activity. Quantitative calibration of mitochondria-targeted MagFRET sensors revealed maximal mMg2+ uptake (∼15 mM), which was markedly reduced in Phb1-deficient hepatocytes. Complementary loss- and gain-of-function studies establish PHB1 as a positive regulator of MRS2-mediated mMg2+ uptake without affecting MCU-dependent Ca2+ transport. In vivo, hepatic Phb1 deletion attenuated mMg2+ uptake and enhanced cellular bioenergetics. These findings identify PHB1 as an activator of the MRS2, advancing our understanding of mMg2+ uptake machinery and its role in metabolic regulation.
    Keywords:  CP: molecular biology; MCU; MRS2; PHB; bioenergetics; calcium; channel; endoplasmic reticulum; magnesium; metabolism; mitochondria; prohibitin; structure
    DOI:  https://doi.org/10.1016/j.celrep.2026.117873
  6. PLoS Comput Biol. 2026 Aug 27. 22(8): e1014018
    Systematic multivariate analysis of chromatin complex dependencies reveals Set1C/COMPASS as a melanoma-enriched epigenetic vulnerability.
    Luisa Quesada Camacho, Mohammad Fallahi-Sichani.
      Epigenetic dysregulation is a common feature of cancer. It creates vulnerabilities arising from an increased reliance on chromatin-based mechanisms that sustain malignant transcriptional states. While many chromatin regulators are broadly required for cellular viability, others function in a context-dependent manner across distinct oncogenic settings, tissue lineages, and differentiation states. Moreover, chromatin regulators often operate within multi-subunit complexes; thus, epigenetic vulnerabilities emerge from coordinated complex activities. Here, we integrate large-scale genetic dependency maps from human cancer cell lines with curated epigenetic complex annotations to perform a systematic, multivariate analysis of complex-level epigenetic dependencies across cancer lineages. Our analysis reveals that dependencies frequently cluster among functionally related chromatin complexes and that biologically related cancer types (e.g., hematologic malignancies) share similar dependency patterns, consistent with shared underlying epigenetic requirements. Focusing on melanoma, we identify multiple enriched epigenetic complex dependencies, including complexes previously associated with recurrent genetic alterations or melanocyte lineage regulation, as well as a previously unrecognized vulnerability involving the H3K4 methyltransferase complex Set1C/COMPASS. This dependency is not restricted to a specific melanoma differentiation state, but genetic depletion of CXXC1 (a critical complex-specific subunit) suggests that CXXC1-dependent melanoma cells require Set1C/COMPASS activity to maintain global H3K4 trimethylation (H3K4me3) and proliferation. Integrative modeling links Set1C/COMPASS dependency to MYC- and E2F-driven transcriptional programs, which are suppressed upon complex inhibition. Together, this work combines integrative, multivariate analysis of lineage-enriched epigenetic dependencies with genetic perturbation, transcriptional profiling, and single-cell analysis to uncover an enriched epigenetic dependency on Set1C/COMPASS in melanoma cells.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014018
  7. PLoS Biol. 2026 Aug 28. 24(8): e3003649
    Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling.
    Jie Zhang, Qian Shan, Xin Wang, Meijiao Li, Yang Yang, Mei Duan, Ruofeng Tang, Junxiang Zhou, Fengyang Wang, Yuehui Shi, Kai Jiang, Chonglin Yang.
      Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003649
  8. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2601318123
    Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.
    Jing Wang, Zegui Ni, Xinxin Zhang, Linling He, Xinyue Zhang, Xu Cheng, Haimo Wang, Guoying Sun, Zhenwei Lu, Chengxu Liu, Hongjie Qian, Youli Lu, Gangyi Liu, Jingying Jia, Jian Ye, Linzhang Huang, Haobin Ye, Rong Li, Wufan Tao, Peng Li, Tong-Jin Zhao, Xingrong Du.
      Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.
    Keywords:  CORVET/HOPS; T cells; amino acid; integrated stress response; metabolism
    DOI:  https://doi.org/10.1073/pnas.2601318123
  9. Cell Rep. 2026 Aug 27. pii: S2211-1247(26)00980-0. [Epub ahead of print]45(9): 117902
    An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation.
    Jason W Miklas, Katharina Papsdorf, Eric D Sun, Aleksandra Tsenter, Nicole R Haseley, Brandon Ameglio, Uche N Medoh, Daniel Richard, Frank McCarthy, Karen L Artiles, Andy Hims, Aleksandra Levina, Olivia Y Zhou, Joshua E Elias, Monther Abu-Remaileh, Anne Brunet.
      Secreted proteins are essential to modulate homeostasis in the extracellular space and facilitate communication to distal cells or tissues. Yet, the identity and functional importance of extracellular proteins in aging have been understudied. Here we use proximity labeling followed by quantitative proteomics to systematically characterize proteins along the intestinal secretory pathway in C. elegans, focusing on secreted proteins. We identify intestine-secreted proteins that are modulated with age, and validate the secretion of these proteins in vivo. One of these secreted proteins, ACP7, is well conserved in humans, and its overexpression extends lifespan in a secretion-dependent manner. Interestingly, we find that ACP7 acts as a secreted phosphatase in the extracellular space. Finally, we identify additional proteins along the secretory pathway that regulate lifespan. Our systematic characterization of tissue-specific secreted proteins during aging uncovers conserved proteins that impact lifespan and highlights extracellular enzymes associated with lifespan regulation.
    Keywords:  CP: metabolism; aging; intestine; lifespan; phosphatase; proximity labeling; quantitative proteomics; secreted proteins; secretome; secretory vesicle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117902
  10. Physiol Genomics. 2026 Aug 26.
    Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.
    Lingjun Lu, Jordan L Levy, Tracy G Anthony, Ioannis P Androulakis.
      Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semi-mechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.
    Keywords:  Dietary timing; Essential amino acids; circadian entrainement; modeling; nutrient sensing
    DOI:  https://doi.org/10.1152/physiolgenomics.00152.2026
  11. Nat Biotechnol. 2026 Aug 25.
    Transferable genetic toolsets for nonmodel gut Clostridia enable in vivo reversible control of metabolite production.
    Ting-Ting Li, Xi Chen, Fangzhao Wang, Yuelin Angelina Tang, Marissa Sim, Leyi Xiao, Wen-Bing Jin, Huiqing Shi, Jiayan Yoshii Ma, Xiaoyu Yang, Yaping Liu, Matthew T Sorbara, Chun-Jun Guo.
      Gut Clostridia species, including commensal members of the Clostridiaceae and Lachnospiraceae families, maintain microbiota homeostasis and influence human health and disease; however, adequate genetic toolsets to study abundant but nonmodel gut Clostridia are lacking. Here we present a set of transferable and modular genetic toolsets that function broadly across phylogenetically diverse gut Clostridia. We first identify a panel of strong constitutive promoters that drive robust gene expression across diverse clostridial strains. We then develop an inducible promoter system that enables precise, tunable gene regulation and facilitates the implementation of CRISPR-Cas gene-deletion systems. We apply this system for targeted and reversible control of trimethylamine and deoxycholic acid production, two microbiota-derived metabolites implicated in host lipid metabolism and diseases, in mice. This robust genetic toolkit for nonmodel gut Clostridia enables functional studies to causally link microbiota genes to host physiology and disease, paving the way for therapeutic genetic engineering of microbiota.
    DOI:  https://doi.org/10.1038/s41587-026-03269-z
  12. Genome Biol. 2026 Aug 22. pii: 268. [Epub ahead of print]27(1):
    Determinants of mutation susceptibility along the genome are largely invariant across human tissues.
    Corinna Lewis Schmalohr, Yashna Paul, Nina Bundschuh, Andreas Beyer.
       BACKGROUND: The propensity for accumulating somatic mutations varies along the genome, which critically influences somatic mosaicism, tumor evolution and the potential role of somatic mutations in the context of age-associated diseases. Genomic factors contributing to the variability of mutation rates have been established, including, for example, distance from the replication origin, chromatin structure and sequence context. However, their relative importance for explaining variable mutation rates along the genome as well as variable mutation rates between tissues remains elusive.
    RESULTS: Here, we present a modelling strategy that integrates 146 genomic features at different scales to predict susceptibilities for point mutations in 25 human tissues along the genome. These models faithfully predict mutation rates in coding and non-coding parts of the human genome in cancer and healthy tissues, including even unseen tissue types that were not used during the model training. Our work revealed that the dependency of mutation rates on chromatin structure and other genomic features is remarkably invariant across tissues, pointing to fundamental, conserved processes underlying mutagenic processes. Local variability in mutation rates on the scale of a few base pairs is almost exclusively driven by the sequence context, whereas large-scale variability is dominated by chromatin features, gene expression and GC content.
    CONCLUSIONS: Our modelling strategy quantifies the relative contribution of genomic factors to mutation susceptibility, predicting mutational biases at any genomic resolution across human tissues, and provides a basis for better understanding tumor evolution and age-related diseases.
    Keywords:  Chromatin context; Machine learning; Mutation susceptibility; SNVs; Sequence context; Somatic mutations
    DOI:  https://doi.org/10.1186/s13059-026-04245-1
  13. Cell Metab. 2026 Aug 28. pii: S1550-4131(26)00328-1. [Epub ahead of print]
    Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
    Yong Tang, Ziqing Chen, Hirak Sarkar, Yong Wei, Sereno L Lopez-Darwin, Asael Roichman, Ji Woo Park, Qinglan Li, Cao Fang, Zihong Chen, James Gow, Minhong Shen, Jennifer Shi, Lifei Jiang, Richard Klar, Xiang Hang, Janette R Lugo, Christina J DeCoste, Jennifer M Miller, Wei Wang, Peter Romanienko, Alana L Welm, Ileana M Cristea, Liling Wan, Joshua D Rabinowitz, Yibin Kang.
      Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.
    Keywords:  CD8(+) T cells; EVP; MTDH; PPARα; extracellular vesicles and particles; immunotherapy; lipid metabolism; tumor-liver interaction
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.003
  14. Trends Cell Biol. 2026 Aug 25. pii: S0962-8924(26)00160-1. [Epub ahead of print]
    Nuclear CGAS promotes cancer dissemination.
    Jana Klümper, Alexander Schramm, Lorenzo Galluzzi.
      Nuclear CGAS has previously been shown to promote tumor progression by inhibiting DNA repair. Recent data from Zhang et al. demonstrate that, upon phosphorylation by PKCα, CGAS translocates to the nucleus and initiates a CTNNB1-dependent program supporting metastatic dissemination. Thus, nuclear CGAS emerges as a multifaceted driver of cancer progression.
    Keywords:  TRIM33; exclusion; homologous recombination; immune evasion; three Cs; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.004
  15. Nat Rev Mol Cell Biol. 2026 Aug 27.
    Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease.
    Carsten Janke, Anna Akhmanova, Francesca Bartolini, Satish Bodakuntla, Filippo Del Bene, Virginie Hamel, Timothy J Mitchison, Thomas Müller-Reichert, François Nédélec, Eva Nogales, Gaia Pigino, Antonina Roll-Mecak, Giampietro Schiavo, Thomas Surrey, Zdenek Lansky.
      Microtubules are well-researched components of the cytoskeleton, yet we lack a holistic understanding that bridges molecular and cellular details with the broader functions of the microtubule cytoskeleton in development, ageing and disease. For example, how microtubule properties and functions are affected by tubulin post-translational modifications, disease-related mutations or variation of the microtubule lattice remains unexplored. In this Roadmap, we argue that integrating various experimental and theoretical approaches to bridge different spatial and temporal scales will offer new opportunities for gaining insights into essential cellular mechanisms and physiology, eventually revealing how microtubule dysfunction can lead to a broad spectrum of human diseases. Built on the current state of the art in the microtubule field, our Roadmap highlights future opportunities and challenges and proposes ways to tackle them. Given the many fundamental questions remaining to be answered, the microtubule cytoskeleton will continue to inspire scientists as it has been doing for decades.
    DOI:  https://doi.org/10.1038/s41580-026-01011-w
  16. Mol Metab. 2026 Aug 25. pii: S2212-8778(26)00117-1. [Epub ahead of print] 102433
    Mitochondrial NCLX Couples Glucagon- and PDE2A-Dependent Signals to Regulate Hepatic Lipid Metabolism.
    Essam A Assali, Mahmoud Taha, Ahmad Salhab, Johnny Amer, Karthickeyan Chella Krishnan, Marko Kostic, Michaela Veliova, Alexandra J Brownstein, Orian S Shirihai, Rifaat Safadi, Israel Sekler.
      Mitochondrial calcium signaling, particularly its glucagon-mediated oscillatory dynamics, plays a pivotal role in regulating hepatic metabolism and is known to be disrupted in steatotic liver disease. We recently identified the mitochondrial Na+/Ca2+ exchanger NCLX as a key mediator of glucagon-induced mitochondrial calcium oscillations, essential for proper gluconeogenic function. Here, using hepatocyte-specific NCLX knockout (cKO) mice, we demonstrate that NCLX is critical for intrahepatic lipolysis and fatty acid oxidation (FAO); its loss impairs glucagon-stimulated lipid droplet catabolism and blunts FAO. Mechanistically, we find that NCLX deficiency disrupts allosteric activation of lipolytic enzymes and increases CPT1 sensitivity to malonyl-CoA-mediated inhibition, resulting in defective lipolysis and FAO. We further show that glucagon regulates hepatic NCLX via cAMP/PKA-dependent phosphorylation at NCLX Ser258. Notably, PDE2A acts as a negative regulator of this pathway by degrading mitochondrial cAMP. Hepatic mitochondrial PDE2A abundance and cAMP-degrading activity are elevated in HFD, and in vivo BAY 60-7550 treatment suppresses mitochondrial cAMP degradation and augments PKA signaling in steatosic livers. Pharmacologic inhibition of PDE2A with BAY 60-7550 enhances NCLX phosphorylation, restores mitochondrial calcium efflux and oscillations, and stimulates FAO in an NCLX-dependent manner. Importantly, we uncover that cAMP/PKA-dependent phosphorylation of NCLX at Ser258 is suppressed in human steatotic livers, and that pharmacologic inhibition of PDE2A ameliorates hepatic FAO and steatosis in both dietary and genetic MASLD models. Collectively, our findings establish the glucagon-PKA-PDE2A-NCLX signaling axis as a key metabolic rheostat integrating mitochondrial calcium dynamics with lipid homeostasis, providing a promising therapeutic target for MASLD.
    Keywords:  Glucagon signaling; Hepatic steatosis; MASLD (Metabolic dysfunction-associated steatotic liver disease); NCLX; PDE2A (Phosphodiesterase 2A); fatty acid oxidation; lipolysis; mitochondrial bioenergetics; mitochondrial calcium signaling
    DOI:  https://doi.org/10.1016/j.molmet.2026.102433
  17. Trends Endocrinol Metab. 2026 Aug 26. pii: S1043-2760(26)00176-1. [Epub ahead of print]
    Mitochondria as central regulators of cancer progression and antitumor immunity.
    Aurora Gomez-Duran, Inmaculada Martínez-Reyes.
      Mitochondria coordinate metabolic and signaling pathways that influence cancer progression across multiple stages of the disease. Beyond supporting tumor growth, mitochondria contribute to metastatic dissemination and shape interactions between tumor and immune cells through diverse outputs, including metabolite production, redox regulation, and mitochondrial genome dynamics. In this review, we discuss how mitochondrial functions sustain cancer cell proliferation, regulate pathways that facilitate metastatic progression, and influence antitumor immunity. We further highlight emerging roles for mitochondrial DNA variation, intercellular mitochondrial transfer, and mitochondrial dysfunction in immune cell exhaustion and senescence. Finally, we discuss how these advances are revealing therapeutic opportunities to target mitochondrial pathways and enhance the efficacy of current cancer immunotherapies.
    Keywords:  antitumor immunity; cancer metabolism; metastasis; mitochondria; mitochondrial genetics
    DOI:  https://doi.org/10.1016/j.tem.2026.07.005
  18. Nucleic Acids Res. 2026 Aug 24. pii: gkag832. [Epub ahead of print]54(16):
    hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
    Valentina Pecoraro, EunBin Kong, Puneet Sharma, Yulia Gonskikh, Marek Żywicki, Fabian Nagelreiter, Markus Schosserer, Katrin Freiburghaus, Jean-Marc Nuoffer, Johannes Grillari, Norbert Polacek.
      Cells adapt to metabolic stress by orchestrating gene expression to mitigate cellular damage, sustain homeostasis, and promote survival. Within this framework, translational control provides a rapid and efficient layer of regulation. Non-coding RNAs have recently emerged as effective modulators of translation, partly by targeting the ribosome. The contribution of ribosome-associated non-coding RNAs (rancRNAs) to translation regulation, however, remains largely unexplored in human cells. Here, we identified the human Y3 (hY3) RNA as a rancRNA that inhibits protein synthesis and attenuates cellular metabolism. hY3 function was particularly critical under nutrient deprivation, where it promoted adaptive stress responses. In this context, depletion of hY3 disrupted the delicate balance between survival and apoptosis by reducing the expression of pro-survival factors and impairing the activation of the integrated stress response (ISR). Loss of hY3 reduced starvation-dependent phosphorylation of eukaryotic translation initiation factor 2α, thereby attenuating ISR signalling, which results in non-physiologically elevated global translation rates during nutrient deprivation. Together, our findings establish hY3 as a ribosome-bound regulator of translation and stress responses, positioning it as a determinant of cell fate under metabolic stress.
    DOI:  https://doi.org/10.1093/nar/gkag832
  19. Dev Cell. 2026 Aug 28. pii: S1534-5807(26)00290-X. [Epub ahead of print]
    Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
    Matej Durik, Mona Karout, Daniel Sampaio Gonçalves, Tania Knauer-Meyer, Coralie Spiegelhalter, Nadia Messaddeq, Marco Seehawer, Pauline Stephan, Dmitry V Bulavin, Yann Herault, Lars Zender, William M Keyes.
      Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here, we identify that senescent cells dispose of large fragments through cell-to-cell adhesion, which we term "senescent-cell adhesion fragments" (SCAFs). Found in many senescent states, including human and mouse cells, and mouse tissues, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreases SCAF formation but induces senescent-cell death, due to an inability to shed damaged mitochondria. Live imaging and proteomics show that SCAFs ultimately rupture, releasing a complex proteome, including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Immunostaining also reveals amyloid-like material in senescent cells that can be externalized through fragmentation. Altogether, these findings identify a feature that facilitates senescent cell survival but also externally deposits damaged intracellular contents, with implications for cancer and neurodegeneration.
    Keywords:  DAMPs; aging; amyloid; cancer; cell-cell adhesion; debris; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2026.08.002
  20. Trends Microbiol. 2026 Aug 26. pii: S0966-842X(26)00211-8. [Epub ahead of print]
    Shiny metal catalysts at the origin of metabolism.
    William F Martin, Nadja K Hoffmann, Manon L Schlikker.
      Metabolism is the reaction network that converts inanimate matter into living cells. There is no life without it. The network of approximately 400 enzymatic reactions that synthesize amino acids, nucleosides, and cofactors from compounds in the environment is conserved across life. Before enzymes, how did metabolism arise? The subsurface chemical environment of Earth's crust reveals clues. Serpentinizing (H2 producing) hydrothermal vents contain naturally deposited, shiny metals in their reduced (native) state and phosphite, a reduced form of phosphate. In the laboratory, native metal catalysts fix CO2, replacing hydrogenases, the acetyl-CoA pathway to pyruvate, the Krebs cycle, amino acid syntheses, NADH, and ferredoxin. Native metals also phosphorylate organic compounds in water using phosphite, uncovering a new source of energy at the origin of metabolism.
    Keywords:  acetyl–CoA pathway; autotrophic origins; hydrothermal vents; origin of life; prebiotic phosphorylation; serpentinization
    DOI:  https://doi.org/10.1016/j.tim.2026.07.012
  21. Nat Commun. 2026 07 28. pii: 9130. [Epub ahead of print]17(1):
    The OmniAge compendium of aging omic biomarkers links mitotic clocks to clonal hematopoiesis and causality.
    Zhaozhen Du, Yunchao Ling, Huige Tong, Xiaolong Guo, Andrew E Teschendorff.
      Interest in aging 'omic' biomarkers has grown due to their ability to quantify biological age. Most of these biomarkers have been derived in blood and fall into many diverse categories, yet relatively little is known about their correlative patterns, especially between biomarkers from different categories. Here we present the OmniAge R and Python package, a collection of 413 aging omic biomarkers representing 12 different categories, including traditional epigenetic clocks, epigenetic mitotic clocks, DNA methylation-based proxies for clonal hematopoiesis and inflammaging, causal clocks, cell-type specific epigenetic clocks and single-cell transcriptomic clocks. By studying their inter-class correlations across large blood datasets, we reveal associations of mitotic age with clonal hematopoiesis subtypes and causal clocks, which are predictive of cancer risk. Using proxies of serum protein levels, we further dissect associations with mitotic clocks, clonal hematopoiesis and causal clocks into distinct biological processes mapping to key aging pathways. Applying OmniAge to multi-modal data of sorted immune cell-types reveals that age-acceleration derived from transcriptomic and epigenetic clocks correlate, but that this is driven by underlying cell-type heterogeneity. In summary, the OmniAge package is an exploratory tool for evaluating large numbers of aging omic biomarkers, and to aid discovery and generate new hypotheses.
    DOI:  https://doi.org/10.1038/s41467-026-76038-w
  22. Int J Mol Sci. 2026 Aug 17. pii: 7334. [Epub ahead of print]27(16):
    Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine.
    Victoriano Pérez-Vázquez, Juan Manuel Guzmán-Flores, Katya Vargas-Ortiz, Carmen Palacios-Reyes, Joel Ramírez-Emiliano.
      Obesity and type 2 diabetes (T2D) are multifactorial metabolic disorders characterized by progressive dysfunction of multiple organs and biological systems. Although mitochondrial dysfunction is a hallmark of disease progression, the mechanisms linking metabolic stress to coordinated tissue dysfunction remain incompletely understood. Comparative proteomic studies have consistently identified coordinated remodeling of oxidative phosphorylation, fatty acid oxidation, tricarboxylic acid cycle activity, redox regulation, mitochondrial proteostasis, and adaptive signaling across metabolically affected organs, revealing conserved organizational principles underlying mitochondrial adaptation. However, these findings have largely been interpreted within reductionist, pathway-centered frameworks. Here, we integrate evidence from comparative proteomics, mitochondrial biology, bioenergetics, redox biology, signaling, and systems biology to propose the concept of mitochondrial-centered biological networks (MCBNs), in which mitochondria function as dynamic regulatory hubs coordinating interconnected processes that collectively determine metabolic adaptation and tissue resilience. Building on this framework, we introduce the Mitochondrial Homeostasis Hypothesis, which proposes that preservation or restoration of mitochondrial homeostasis depends on coordinated regulation of MCBNs and constitutes a fundamental systems-level mechanism underlying resistance to obesity, T2D, and hypercaloric diet-induced metabolic dysfunction. Curcumin represents a well-studied network-modulating intervention that coordinately influences mitochondrial bioenergetics, metabolic flexibility, redox homeostasis, proteostasis, inflammatory signaling, and adaptive stress responses, supporting the concept that mitochondrial homeostasis is preserved through coordinated network regulation rather than isolated modulation of individual molecular pathways. Finally, we discuss how emerging technologies, including functional proteomics, redox proteomics, spatial and single-cell proteomics, acetylomics, integrated multi-omics, and artificial intelligence-assisted network analysis, provide unprecedented opportunities to quantitatively characterize MCBNs, validate the proposed hypothesis, identify network-based biomarkers, and accelerate the development of network-guided precision mitochondrial medicine.
    Keywords:  comparative proteomics; curcumin; mitochondrial homeostasis; mitochondrial-centered biological networks; network medicine; obesity; precision mitochondrial medicine; systems biology; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms27167334
  23. Development. 2026 Aug 15. pii: dev205785. [Epub ahead of print]153(16):
    A developmental biologist's guide to mechanics.
    Jialing Cao, Alessandro Chiappori, Sylvain Landiech, Raphaël Clément, Pierre-François Lenne.
      Developmental biology seeks to explain how living systems self-organize into functional, robust forms. While molecular and genetic approaches have revealed how biological information is encoded and processed, they often do not explain how this information is translated into physical shape. Here, we introduce the mechanical principles underlying tissue morphogenesis, aimed at developmental biologists with little background in physics. This Primer is structured around three core pillars. First, force generation describes how active and passive processes within cells and tissues drive deformation and motion. Second, constitutive behavior defines how living matter responds to these forces, spanning elastic, viscous and plastic regimes. Third, geometry and boundary constraints set the spatial constraints that shape mechanical interactions at the tissue and organismal levels. Together, these elements provide a framework for understanding how form emerges from the interplay between forces, material properties and geometry. We illustrate key examples across developmental processes and highlight recent advances and future challenges, integrating mechanical and molecular perspectives to guide the study of morphogenesis.
    Keywords:  Boundary constraints; Constitutive behavior; Force generation; Physics of morphogenesis; Shapes
    DOI:  https://doi.org/10.1242/dev.205785
  24. Curr Opin Struct Biol. 2026 Aug 27. pii: S0959-440X(26)00155-7. [Epub ahead of print]101 103373
    Integrating in situ single-particle cryo-electron microscopy with cryo-electron tomography for high-resolution structural biology in native cellular contexts.
    Jian Yue, Wangbiao Guo, Jun Liu.
      Single-particle cryo-electron microscopy (cryo-EM) has transformed structural biology by enabling atomic-resolution structure determination of purified macromolecular assemblies. Recent advances in in situ single-particle cryo-EM have extended this capability to near-atomic structural analysis directly within native cellular environments. However, major challenges remain because many cellular targets are low in abundance, structurally heterogeneous, and difficult to detect. In parallel, cryo-electron tomography (cryo-ET) combined with subtomogram averaging enables in situ visualization of macromolecular assemblies while preserving their three-dimensional cellular context, but limited throughput and resolution have constrained high-resolution analysis of rare or heterogeneous complexes. In this review, we discuss recent advances in sample preparation, data acquisition, image processing, and high-resolution refinement that improve the throughput, sensitivity, and resolution of in situ structural biology. We further highlight how integrating in situ single-particle cryo-EM with cryo-ET bridges cellular visualization and near-atomic structure determination, providing a scalable framework for investigating dynamic macromolecular assemblies directly in their native cellular context.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103373
  25. Cell. 2026 Aug 26. pii: S0092-8674(26)00931-1. [Epub ahead of print]
    Virtual Cell Challenge 2026: Benchmarking zero-shot generalization across cellular contexts.
    Arc Virtual Cell Initiative Team
      The Virtual Cell Challenge returns in 2026 with a more demanding test of biological generalization: zero-shot prediction across multiple independent cellular contexts. Participants will build models to predict gene knockdown responses in a new Arc-generated dataset comprising unseen cell lines. The goal is to determine whether the best models can meaningfully close the gap between preclinical experimental predictions and human biology.
    DOI:  https://doi.org/10.1016/j.cell.2026.08.004
  26. Nat Aging. 2026 Aug 25.
    cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
    John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova.
      Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.
    DOI:  https://doi.org/10.1038/s43587-026-01206-y
  27. Science. 2026 Aug 27. 393(6814): eaeh7112
    A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
    Jiyi Pang, Aysha H Al-Ani, Komal M Patel, Yunzhuo Zhou, Samuel N Young, Jinjin Chen, Isabella Kong, Marilou Barrios, James A Rickard, Siqi Chen, Xiuquan Ma, Farzaneh Shojaee, Seong-Beom Kim, Siavash Foroughi, Wayne Cawthorne, Annette V Jacobsen, Asha Jois, Ashley L Weir, Lachlan W Whitehead, Pradeep Rajasekhar, Christopher R Horne, Ruqian Lyu, Lucy J Mather, Raymond K H Yip, Ellen Tsui, Imadh Azeez, Tao Tan, Weiwei Liang, Suresh Sivanesan, Andrew Metz, Ash Patwardhan, Natalie Shea, Guru Iyngkaran, Daniel Schneider, Alexander T Elford, William Beattie, Finlay Macrae, Gianmaria Liccardi, Henning Walczak, Yuxia Zhang, Oliver M Sieber, Tim Spelman, Lisa Giulino-Roth, Michael Christie, Yunshun Chen, Kelly L Rogers, Rory Bowden, Sandra E Nicholson, Kate E Lawlor, Edwin D Hawkins, Britt Christensen, Andre L Samson, James E Vince, James M Murphy.
      Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identified aberrant epithelial cell death signaling as an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation skewed epithelial cells into an M1-macrophage-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. Thus, aberrant epithelial cell death signaling represents a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.
    DOI:  https://doi.org/10.1126/science.aeh7112
  28. Nat Rev Cancer. 2026 Aug 28.
    The long return on discovery science in cancer therapeutics.
    Cian Murphy, Samuel Hume, Charles Swanton.
      
    DOI:  https://doi.org/10.1038/s41568-026-00978-0
  29. Cell Chem Biol. 2026 Aug 27. pii: S2451-9456(26)00291-6. [Epub ahead of print]
    A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
    Songlin Yin, Yan Li, Ting Mei, Jiayao Li, Xueting Wang, Xiaoxiao Li, Liguo Yang, Junhong Lin, Weijie Ye, Fujia Lu, Weimin Wang.
      Renal ischemia-reperfusion injury (IRI), a leading cause of acute kidney injury, is driven by coordinated inflammatory signaling and ferroptotic cell death, yet effective therapies remain limited. Here, we show that H-151, a covalent stimulator of interferon genes (STING) inhibitor, also suppresses ferroptosis through a STING-independent mechanism. H-151 functions as a broad-spectrum radical-trapping antioxidant that directly scavenges radicals generated during the Fenton reaction, thereby blocking lipid peroxidation. In a murine renal IRI model, H-151 attenuated tissue damage and restored renal function through concurrent inhibition of STING signaling and ferroptosis. These findings establish radical-trapping antioxidant activity as an additional mechanism of H-151 and identify dual inhibition of inflammatory signaling and ferroptosis as a promising therapeutic strategy for IRI and related disorders.
    Keywords:  H-151; STING; ferroptosis; ischemia reperfusion injury
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.004
  30. Curr Issues Mol Biol. 2026 Aug 04. pii: 792. [Epub ahead of print]48(8):
    Mitochondrial Cristae as Separate Compartments: Linking Organization and Function.
    Alexander V Panov, Semen V Nesterov, Lev S Yaguzhinsky.
      Traditional bioenergetic paradigms historically relied on classical equilibrium thermodynamics to calculate mitochondrial kinetics, often overlooking the non-equilibrium processes dictated by complex structural architecture. Recent discoveries fundamentally challenge these outdated views by demonstrating that the inner mitochondrial membrane is strictly segregated into distinct functional domains, where individual cristae operate as autonomous, ultra-confined nanocompartments, where the transport of metabolites and protons is tightly controlled by ultrastructure-assisted electric and entropic effects. Compartmentalization prevents proton dissipation, allows for the rapid generation of a localized proton motive force optimized for efficient ATP synthesis and provides robust functional redundancy against localized membrane damage. Furthermore, recognizing cristae as isolated microspaces resolves the long-standing paradox of mitochondrial nicotinamide adenine dinucleotide transhydrogenase (TH). We describe a multi-stage transport pipeline-the TH-isocitrate dehydrogenase axis-wherein matrix-generated reducing equivalents are exported into the cytoplasm via an irreversible isocitrate/α-ketoglutarate loop. This universal pipeline continuously supplies uncommitted NADPH for biosynthesis, systemic antioxidant defense and detoxification. We also highlight the role of compartmentalization in ATP transport and utilization processes. Consequently, disruptions to cristae compartmentalization emerge as primary pathogenic drivers in ischemic, neurodegenerative, and cardiovascular diseases.
    Keywords:  NADPH transport; NADPH-isocitrate dehydrogenases; cellular bioenergetics; microcompartmentalization; mitochondrial cristae; nonequilibrium thermodynamics; proton motive force; transhydrogenase
    DOI:  https://doi.org/10.3390/cimb48080792
  31. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2532225123
    SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation.
    Kaeden K Hill, Ashley P Barry, Nicolas M Reinoso-Vizcaino, Lauren E Haynes, Emmanuela N Bonglack, Davis F Ferreira, Sara E Miller, Matthew D Hirschey, Lillian W Chiang, Stacy Remiszewski, Micah A Luftig.
      Sirtuin-2 (SIRT2) is a cellular deacylase, regulating cell cycle progression and metabolic homeostasis. Recently, SIRT2 has emerged as a target with both anticancer and antiviral potential. However, the role and targetability of SIRT2 in viral-driven cancers remains unexplored. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with oncogenic potential that establishes latency in B lymphocytes and is typically controlled by a robust T cell immune response. In settings that compromise this response, such as immune suppression following transplant, EBV can cause B cell lymphomas. With broad immunosuppression and varying response rates limiting the effectiveness of existing lymphoma therapeutics, new strategies are necessary. Here, we report that SIRT2-selective compounds block EBV-mediated B cell transformation and EBV or mitogen-driven B cell division in vitro. SIRT2 modulation significantly alters gene expression and metabolism of EBV-infected B cells, reducing mitochondrial respiration, driving mitochondrial swelling, and inducing nutrient stress and autophagy. Treatment with SIRT2 modulators drives hyperacetylation of targets involved in lipid metabolism, central carbon metabolism, and oxidative phosphorylation. EBV-positive and EBV-negative B cell lymphomas rely on glycolysis to avoid cell death after SIRT2 modulation, revealing a metabolic vulnerability that can be harnessed to kill lymphoma cells. Overall, we have identified how SIRT2 could be implicated as a target of therapeutic potential for B cell lymphomas, while also defining fundamental roles for extranuclear lysine acetylation in regulating B cell proliferation and metabolism.
    Keywords:  B cell; Epstein–Barr virus; lymphoma; mitochondria; sirtuin
    DOI:  https://doi.org/10.1073/pnas.2532225123
  32. Cell. 2026 Aug 28. pii: S0092-8674(26)00929-3. [Epub ahead of print]
    Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
    Ronghui Zhu, Emma Dann, Jun Yan, Justine Reyes Retana, Ryunosuke Goto, Reese C Guitche, Lillian Brixi, Mineto Ota, Austin Hartman, Theodore L Roth, Ansuman T Satpathy, Jonathan K Pritchard, Alexander Marson.
      Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.
    Keywords:  CD4(+) T cell polarization; CD4(+) T cells; CRISPR; CRISPR interference; CRISPRi; T cell aging; cell fate decision; functional genomics; gene regulatory networks; human T cells; human genetics; perturb-seq; perturbation signatures; primary human cells; probe-based perturb-seq
    DOI:  https://doi.org/10.1016/j.cell.2026.08.002
  33. Sci Adv. 2026 Aug 28. 12(35): eadw3811
    SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.
    Francesco Padovani, Ivana Čavka, Ana Rita Rodrigues Neves, Cristina Piñeiro López, Nada Al-Refaie, Leonardo Bolcato, Dimitra Chatzitheodoridou, Yagya Chadha, Pablo Lagos, Timon Stegmaier, Xiaofeng A Su, Jette Lengefeld, Daphne S Cabianca, Simone Köhler, Kurt M Schmoller.
      The analysis of spot-like structures is a widespread task in microscopy image analysis. Existing solutions are typically specific to single applications and do not use multidimensional information, often leaving manual annotation as the only option. Here, we present SpotMAX, a generalist AI-assisted framework for automated spot detection and quantification. SpotMAX detects spots in three-dimensional (3D) data and leverages the full scope of multidimensional datasets with an easy-to-use graphical user interface and a framework for cell segmentation and tracking. Tested on a large 3D dataset, SpotMAX outperforms or is on par with state-of-the-art tools and expert human annotators. We applied SpotMAX across diverse experimental questions, ranging from meiotic crossover events in Caenorhabditis elegans to mitochondrial DNA dynamics in Saccharomyces cerevisiae and telomere length in mouse stem cells, leading to new biological insights. With its flexibility in integrating other AI models into a holistic analysis workflow, we anticipate that SpotMAX will become the standard for spot analysis in microscopy data.
    DOI:  https://doi.org/10.1126/sciadv.adw3811
  34. Nucleus. 2026 Dec;17(1): 2709894
    Nuclear mechanobiology: a brief history and five unresolved questions.
    Jan Lammerding, Jorine Eeftens, Gregg G Gundersen, Megan C King, Tanmay P Lele, Song Li, Gant Luxton G W, Ohad Medalia, Matthieu Piel, Pere Roca-Cusachs, Jörg Renkawitz, Kyle Roux, Daniel A Starr, Amy R Strom, Hawa Racine Thiam, Sara A Wickström, Howard J Worman.
      
    DOI:  https://doi.org/10.1080/19491034.2026.2709894
  35. Cell. 2026 Aug 25. pii: S0092-8674(26)00871-8. [Epub ahead of print]
    Integrative spatial profiling of 3D genome organization and gene expression in tissue.
    Pengfei Guo, Yan Cui, Jincan He, Abraham J Waldman, Jiaxin Zhu, Yufan Chen, Zhi Huang, Jingtian Zhou, Jennifer E Phillips-Cremins, Yanxiang Deng.
      Three-dimensional genome organization shapes transcriptional regulation, yet measuring its spatial coordination in situ within intact tissues remains challenging. We present Spatial Hi-C-RNA, a multimodal platform that simultaneously maps genome-wide chromatin contacts and transcriptomes from the same tissue section at near-single-cell resolution. Across the mouse brain, developing embryos, and human melanoma, Spatial Hi-C-RNA generated multimodal maps that aligned with tissue anatomy while revealing complementary chromatin- and RNA-defined spatial patterns. Multiscale features, including A/B compartments, topologically associating domains, and chromatin loops, were associated with region- and cell-type-specific transcriptional programs. In mouse embryos, Spatial Hi-C-RNA resolved coordinated chromatin and transcriptional remodeling during neuronal maturation across developmental stages. In human melanoma, chromatin architecture delineated intratumoral subregions not detected by RNA alone and linked tumor-state transitions to changes in compartments, domain boundaries, and regulatory programs. Spatial Hi-C-RNA thus provides a broadly applicable framework for investigating genome structure-function relationships in development and disease within native tissue environments.
    Keywords:  3D genome; A/B compartments; Spatial Hi-C; chromatin remodeling; chromosome conformation capture; gene regulation; neuroepigenetics; neurogenesis; spatial multi-omics; spatial transcriptomics; tumor-state transitions
    DOI:  https://doi.org/10.1016/j.cell.2026.07.039
  36. Cell Rep Med. 2026 Aug 28. pii: S2666-3791(26)00430-1. [Epub ahead of print] 103013
    Pan-tumor spatial transcriptomics reveals conserved properties of tumor organization.
    Vivek Behera, Alexander Guzzetta, Hannah Giba, Ue-Yu Pen, Anna Di Lello, Bipul Pandey, Benjamin A Doran, Alessandra Esposito, Apameh Pezeshk, Aliya Husain, Christine M Bestvina, Justin Kline, Marina C Garassino, Arjun S Raman.
      Tumor microenvironments (TMEs) are compositionally and functionally heterogeneous, making it challenging to discover organizing structural principles. Through a study of 262 solid tumors profiled by spatial transcriptomics, we identify a conserved architecture where TMEs are partitioned into discrete, hierarchically organized multicellular sub-regions, which we term "spatial groups" (SGs). As indicated by orthogonal spatial measurements and expert pathologist review, SGs associate with recognizable biological domains spanning global tissue context to local cellular neighborhoods. Comparing tumors through SGs reveals a pan-tumor classification where the dominant axis of variation is spatial heterogeneity of immune biology. In an independent, retrospective cohort of non-small cell lung cancer patients treated with immune checkpoint blockade (ICB; n = 16), pan-tumor spatial biology classification distinguishes clinical response and captures structural and biological hallmarks associated with ICB sensitivity. Together, these findings suggest that SGs may be important organizing domains of the TME that relate spatial structure, biological function, and response to therapy.
    Keywords:  computational biology; immunotherapy; machine learning; spatial transcriptomics; systems biology; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103013
  37. Cell Signal. 2026 Aug 22. pii: S0898-6568(26)00491-2. [Epub ahead of print]148 112833
    Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells.
    Praveen Kumar Guttula, Ganesan Muthusamy, Chin-Chi Liu, Priscilla Devora, Emi Sasaki, Tyler Butsch, Hasand Gandhi, James Moran, Manas Ranjan Gartia, Andrea N Johnston.
      The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the transition from hepatic steatosis to hepatocellular carcinoma. Increased expression of PGAM5 in hepatocellular carcinoma correlates with reduced patient survival. Herein we demonstrate that loss of PGAM5 promotes mitochondrial oxidant injury and suppresses the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion reduces diacylglycerol concentrations by attenuating long-chain fatty acid uptake and suppressing its synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 in hepatocellular carcinoma.
    Keywords:  Diacylglycerol; Lysophosphatidylcholine; Mitochondrial metabolism; Sphingolipid
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112833
  38. Aging (Albany NY). 2026 Aug 26. 18(1): 1066-1076
    Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging.
    Lucrezia A Trastus, Fabrizio d'Adda di Fagagna.
      Understanding the primary molecular and cellular drivers of aging and how they trigger systemic functional decline remains a fundamental challenge. This review focuses on two proposed drivers of aging, cellular senescence and somatic DNA mutations, critically discusses the evidence for their association with organismal aging, and appraises their causal contribution to it. Several studies support the notion that cellular senescence can cause aging, acting through cell-intrinsic and, likely more significantly, cell-extrinsic mechanisms such as the senescence-associated secretory phenotype. Differently, the mutational burden is strongly correlated with aging, but we argue that the causal contribution of altered DNA sequences to age-related functional decline remains difficult to untangle from its originating genotoxic events.
    Keywords:  DNA damage; SASP; aging; cellular senescence; somatic mutations
    DOI:  https://doi.org/10.18632/aging.206414
  39. Genes Dev. 2026 Aug 26.
    Architectural logic of the 3D genome: mechanisms of dysregulation and emerging cancer therapeutics.
    Rebecca G Smith, Hannah M Wilson, Kathleen L Schiela, Yu Liu.
      The three-dimensional (3D) genome provides an essential layer of organization that shapes genome function in space and time. Chromatin compartments and topologically associating domains (TADs) arise from the interplay between intrinsic properties of chromatin and architectural factors, including cohesin and CTCF. Despite substantial progress in defining these structural features, whether 3D genome architecture plays a causal role in regulating processes such as transcription, DNA replication, and DNA repair, or instead reflects underlying regulatory activity, remains unresolved. Here, we use the distinction between chromatin-intrinsic features and architectural factors as a framework to evaluate evidence for causality in genome structure-function relationships. We extend this framework to cancer, where both intrinsic alterations (including noncoding mutations, structural variants, and changes in chromatin state) and architectural factor perturbations (such as mutations in architectural proteins and dysregulation of transcriptional machinery) disrupt genome organization and contribute to disease progression. These findings suggest that alterations in genome structure can, in some contexts, actively reshape oncogenic programs. A major limitation in applying 3D genome insights to cancer biology is the cost and complexity of omics assays. Recent advances in artificial intelligence (AI) and machine learning (ML) enable inference and prediction of 3D genome organization from sequence and epigenomic features, providing insight into the extent to which genome folding is encoded intrinsically versus dynamically regulated in architectural factors. This perspective provides a unified view of how genome structure is established, how it relates to function, and how its disruption contributes to tumorigenesis.
    Keywords:  3D genome; AI; cancer; function; mechanism
    DOI:  https://doi.org/10.1101/gad.353831.126
  40. Biochem Soc Trans. 2026 Sep 23. 54(9): 1145-1153
    Propionic acidemia as a framework for understanding the impact of disturbed propionyl-CoA on histone modifications.
    Pawel Swietach, Eleanor K Gill, Lorenz M W Holzner.
      Histone propionylation-the transfer of a three-carbon propionyl group from propionyl-CoA to lysine residues-is an emerging post-translational modification (PTM) with potential effects on gene expression. Interest in this PTM has grown because propionyl-CoA is at the interface between valine, isoleucine, methionine, and threonine catabolism, odd-chain fatty acid oxidation, gut-derived propionate assimilation, and anaplerotic entry into the tricarboxylic acid cycle. An informative context for studying the influence of disturbed propionyl-CoA metabolism on chromatin state and phenotype is propionic acidemia (PA), where loss-of-function mutations in genes coding propionyl-CoA carboxylase (PCC) lead to the accumulation of propiogenic substrates and propionyl-CoA. At least some of the clinical manifestations of PA (cardiomyopathy, arrhythmia, and neurological injury) may relate to altered histone propionylation, and a challenge is to distinguish these responses from metabolic toxicity. To that end, mouse models of PA are promising tools for connecting molecular-level histone changes to systems-level phenotypes. In this review, we describe recent advances in propionyl-CoA biology in the context of histone modifications and gene regulation. We present milestone studies that identified histone PTMs and described their association with phenotype. We also highlight emerging questions related to propionyl-CoA handling, its compartmentalization, and tissue specificity of actions, and discuss the relative contribution of histone propionylation versus other forms of acylation and broader metabolic stress. On balance, the literature supports a model in which propionyl-CoA exerts regulatory actions on chromatin state, but how this might be targeted therapeutically in PA and the implications for other metabolic disturbances remain important areas for further investigation.
    Keywords:  Heart; Liver; Propionate; Propionic acidemia
    DOI:  https://doi.org/10.1042/BST20260178
  41. J Clin Invest. 2026 Sep 01. pii: e204023. [Epub ahead of print]
    Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
    David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara R Price, Sandra Hj Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.
      Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
    Keywords:  Calcium signaling; Cell biology; Cellular immune response; Hepatology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI204023
  42. Mitochondrion. 2026 Aug 22. pii: S1567-7249(26)00095-4. [Epub ahead of print]91 102205
    Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
    Yang Yang, Nirajan Neupane, Jouni Kvist, Jonna Saarimäki-Vire, Matthias Schewe, Kalle Luopajärvi, Pooja Manjunath, Svetlana Konovalova, Rubén Torregrosa-Muñumer, Veijo Kinnunen, Pekka Katajisto, Timo Otonkoski, Eija Pirinen, Jayasimman Rajendran, Henna Tyynismaa.
      Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.
    Keywords:  Adipose tissue; Body weight homeostasis; Grpel2; Mitochondrial protein import; Nucleotide exchange factor; mtHSP70
    DOI:  https://doi.org/10.1016/j.mito.2026.102205
  43. J Inherit Metab Dis. 2026 Sep;49(5): e70236
    From Single Cells to Diagnosis: Proteomics Technologies in the Multi-Omics Landscape of Rare and Mitochondrial Diseases.
    Simon Wetzel, Sebastian Porsdam Mann, Florian A Rosenberger.
      Proteomics by mass spectrometry has rapidly matured from a niche method into a standard tool. The recent 10-year trajectory of single-cell proteomics has opened a new biological dimension for studying disease. Mitochondrial diseases, with their pronounced cell-to-cell heterogeneity, are particularly, well-suited to these methods. Here, we discuss how this approach can serve as an orthogonal functional layer for rare disease diagnostics. We trace the evolution of rare disease diagnostics from biochemical enzyme assays through genomics, transcriptomics, proteomics and metabolomics, highlighting incremental gains in diagnostic yield from individual omics layers and their integration. We discuss the limitations of bulk approaches in capturing the functional consequences of genetic perturbations, the new opportunities opened up by single-cell measurements and how spatial single-cell proteomics can further enrich the biological signal of affected cells in diagnostic tissues. We observe that the persisting diagnostic gap reflects not only technological limitations but, increasingly, challenges in data sharing and infrastructure as well as interpretive frameworks for functional molecular evidence. In this context, we consider opportunities for artificial intelligence and the ethical dimensions of single-cell proteomics in rare disease diagnostics. Finally, we propose a single-cell deep visual proteomics (scDVP) framework for clinical diagnostics of rare diseases with cell-to-cell variability, arguing that mitochondrial diseases are an ideal proof-of-concept.
    Keywords:  diagnostics; mitochondria; omics ethics; rare diseases; single‐cell proteomics; spatial proteomics
    DOI:  https://doi.org/10.1002/jimd.70236
  44. J Biomed Sci. 2026 Aug 27. pii: 86. [Epub ahead of print]33(1):
    Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
    Jing-Yiing Wu, Tzu-Ching Chang, Mei-Jen Chen, Shih-Han Cho, Jun-Yang Liou, Cheng-Chin Kuo, Kenneth K Wu.
       BACKGROUND: Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.
    METHODS: We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.
    RESULTS: The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH/succinate.
    CONCLUSIONS: These findings indicate that the mitochondrial fragmentation-SDH-succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.
    Keywords:  Cancer metabolism; Dynamin-related protein 1; Hepatocellular carcinoma; Mitochondrial dynamics; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1186/s12929-026-01289-0
  45. Sci Adv. 2026 Aug 28. 12(35): eaec0481
    Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling.
    Miranda L Lopez, Taekyung Kang, Ana M Espeleta, Varvara I Rubtsova, Jongwon Baek, Jakob Songcuan, Elena M Moyer, Joohwan Kim, Won-Suk Song, Sunhee Jung, Rochelle W Lai, Aiyana Binuya, Christopher H Lee, Amy R Lantz, Nicholas D'Sa, Alexis Anica, Elise Tran, Yujin Chun, Wonsuk Choi, Ki-Hong Jang, Sungji Cho, Miranda E Kelly, Ian J Tamburini, Yasmine H Alam, Johnny Le, Cuauhtemoc B Ramirez, Raghu P Kataru, Seon Pyo Hong, Thomas Q de Aguiar Vallim, Dequina A Nicholas, Katherine S Xue, Gina Lee, Hosung Bae, Cholsoon Jang.
      High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and diabetes, yet the underlying mechanisms, especially at the specific organ level, are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we report that inhibition of fructose catabolism specifically in the murine small intestine unexpectedly mitigates fructose-induced obesity and insulin resistance. Such phenotypes are attributed to decreased dietary fat absorption by the shortening of ileal lacteals. Fecal transplantation experiments revealed that the microbiome altered by blunted host intestinal fructose catabolism decreases ileal macrophages essential for lacteal growth. Thus, altered intestinal lacteal architecture likely contributes to the synergistic effects of high fat and sugar on metabolic disorders. It may also be relevant to the clinical evidence that pharmacologic suppression of fructose catabolism mitigates diet-induced obesity.
    DOI:  https://doi.org/10.1126/sciadv.aec0481
  46. Nat Commun. 2026 Jul 22. pii: 8948. [Epub ahead of print]17(1):
    Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
    Asmita Singh, Dylan J Johnson, Jeffrey Kuhn, Katina L Johnson, Jason G Williams, Ricardo Vancini, Deloris Sutton, Kedar Sharma, Jadranka Loncarek, Mario J Borgnia, Carlos M Guardia.
      Autophagy intersects with endocytic trafficking to regulate extracellular vesicle (EV) biogenesis, but how upstream lipid-handling autophagy proteins influence this crosstalk is unclear. Here we show that the autophagy lipid-supply proteins ATG9A and ATG2A/B restrain small EV (sEV) secretion by promoting amphisome formation and controlling cellular lipid composition. Deletion of ATG9A or ATG2A/B in cells, which abolishes autophagosome biogenesis, causes a RAB27A-dependent increase in secretion of CD63-enriched, smaller sEVs, and accumulation of intraluminal vesicles within multivesicular endosomes. Under lysosomal inhibition, wild-type cells release LC3- and autophagy cargo receptor-positive sEVs, whereas ATG9A- and ATG2A/B-deficient cells, despite hypersecretion of sEVs, fail to load LC3 or canonical cargo receptors, indicating a block in amphisome-mediated export. Proteomics reveals selective depletion of autophagy receptors and ferritinophagy factors and enrichment of RNA-binding proteins and endosomal trafficking regulators in sEVs from ATG9A- and ATG2A/B-deficient cells. Whole-cell lipidomics uncovers extensive rewiring of the lipidome, with accumulation of ceramides and neutral lipids, altered phospholipid balance, and transcriptional remodeling of lipid metabolic enzymes, while neutral sphingomyelinase inhibition normalizes sEV output. These findings identify ATG9A and ATG2A/B as lipid-dependent gatekeepers that couple autophagosome and amphisome formation, regulating membrane partition between degradative autophagy and exosome-mediated secretion.
    DOI:  https://doi.org/10.1038/s41467-026-75742-x
  47. J Cardiovasc Aging. 2026 ;pii: 12. [Epub ahead of print]6(2):
    Understanding cardiovascular aging as a disorder of mitochondrial network.
    Taslima Akter Shila, Dhrubo Ahmad, Jianli Zhao, Huilan Tan, Bo Wang, John Zhang, Yajing Wang.
      Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of "mitochondrial age", a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.
    Keywords:  Cardiovascular aging; endothelial dysfunction; epidemiology; heart failure with preserved ejection fraction; hypertension; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.20517/jca.2026.07
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