bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–09–27
57 papers selected by
Christian Frezza, Universität zu Köln
  1. Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
  2. Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.
  3. FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
  4. Dietary α-ketoglutarate modulates lung adenocarcinoma growth and epigenetic remodeling in a sex-dependent fashion.
  5. Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.
  6. Surprising protein links dietary restriction to increased lifespan in flies.
  7. RamanOmics decodes the spatial vibrational-molecular architecture of senescence in aging and repair.
  8. How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
  9. Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.
  10. Accumulation of the immunosuppressive metabolite 1-methylnicotinamide in human basal cell carcinoma.
  11. Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.
  12. Circadian temperature compensation is intrinsically linked with metabolism and redox signaling.
  13. Itaconate metabolism in regulated cell death.
  14. CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer.
  15. Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism.
  16. Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
  17. Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.
  18. Mitotic assembly of respiratory supercomplexes ensures accurate cell division and fuels tumor growth.
  19. The ubiquitin system in normal and infected germinal center B cells.
  20. Targeting lipidated amino acid deficiency mitigates fibrosis via a PPARα/CCL2 axis in metabolic dysfunction-associated steatohepatitis models.
  21. ATAD3A structurally links mtDNA replication and mitochondrial fission.
  22. Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
  23. SIRT1 in Senescence: Mitochondria and Immune Crosstalk.
  24. Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
  25. An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.
  26. Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
  27. Rare science, real impact: shaping the future of research on rare metabolic diseases.
  28. Multi-modality profiling identifies Neisseria flavescens as a central geroprotective oral commensal in humans.
  29. Scientific culture in the age of AI.
  30. Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
  31. MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness.
  32. Dendritic cell PD-L2 restrains intratumoral CD8 + T cell immunity.
  33. Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
  34. Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch.
  35. Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
  36. Proteolytic remodeling by Yme1 enables mitochondrial-derived compartment formation.
  37. mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
  38. Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma.
  39. Molecular underpinnings of metastatic small renal masses.
  40. Tumor Heterogeneity and Metastatic Potential in Lung Cancer: How Early Can a Tumor Become Metastatic?
  41. Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
  42. Longitudinal digital phenotyping of activity rhythms and biological aging using commercial wearables.
  43. Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.
  44. Chemoproteomic profiling of itaconate-derived protein modifications.
  45. Spiny mouse fibroblasts exhibit a baseline preference for glycolysis and are resilient to oxidative stress across lifespan.
  46. King sulfur.
  47. Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.
  48. All the ways a cell can die - and why the variety matters.
  49. Initial perturbations triggered by p53 loss in stem cells.
  50. Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
  51. B cells enter the synaptic conversation.
  52. mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
  53. A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer.
  54. Senescent Cell Heterogeneity: Tissue-Dependent Signatures and Age Dynamics Revealed by Human scRNA-Seq Data.
  55. The predicted interactome of the human mitochondrial proteome.
  56. Tissue expansion mass spectrometry imaging (TEMI) for high-spatial-resolution multiomics molecular mapping.
  57. Unraveling the lexicon of complex mutational phenomena in human cancers.
  1. Nature. 2026 Sep 23.
    Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
    Koelina Ganguly, Keisuke Yamamoto, Jason Rodencal, Joel Encarnacion-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Ruohong Wang, Carolina Alcantara Hirsch, Anthony Sorrentino, Elshaddai Z White, Paul M Grandgenett, Michael A Hollingsworth, Miwako Kakiuchi, Richard Possemato, Dafna Bar-Sagi, Mitsuhiro Fujishiro, Alec C Kimmelman.
      The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3-5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron-tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5-CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K-AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5-CXCR2-PI3K-AKT-FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell-hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.
    DOI:  https://doi.org/10.1038/s41586-026-11051-z
  2. Science. 2026 Sep 24. 393(6818): eaec5473
    Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.
    Uladzimir Barayeu, Seiryo Ogata, Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Masanobu Morita, Tomoaki Ida, Mike Lange, Yuka Unno, Saber Boushehri, Paulius Greicius, Akira Nishimura, Lorenzo Catti, Yuexuan Pan, Tianli Zhang, Takayuki Shimizu, Ryo Ushioda, Takakazu Nakabayashi, Seji Asamitsu, Kazuki Fusegawa, Takashi Suzuki, Takanori Ishida, Naoko Tanda, Yasuo Watanabe, Yukihiro Tsuchiya, Ryo Yamaguchi, Shintaro Noguchi, Eikan Mishima, Fumiko Yano, Mieko Arisawa, Dennis J Stuehr, Ning Xia, Huige Li, Bernd Moosmann, Frauke Gräter, Camilo Aponte-Santamaría, James A Olzmann, Marcus Conrad, Albert van der Vliet, Tobias P Dick, Hozumi Motohashi, Michito Yoshizawa, Takaaki Akaike.
      Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo-octasulfur (S8). We found that S8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet-associated nitric oxide synthase as a source of S8 biosynthesis and found that S8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.
    DOI:  https://doi.org/10.1126/science.aec5473
  3. Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01107-1. [Epub ahead of print]45(10): 118029
    FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
    Manas Kohli, Aurélien Tripp, Anastasiia Shcherbakova, George Poulogiannis.
      Metabolic reprogramming is a hallmark of cancer, yet dynamic metabolic flux has been difficult to study systematically. Here, we present FluxAtlas, a pan-cancer atlas of metabolic flux generated from genome-scale metabolic modeling of over 10,000 tumors across 28 The Cancer Genome Atlas (TCGA) cancer types. By integrating enzyme constraints and nutrient diffusion limits, we reveal conserved and tissue-specific metabolic rewiring, including alterations in bile acid recycling, urea metabolism, and amino acid biosynthesis. We identify a bile acid-associated program that remodels glutathione homeostasis and drives gastrointestinal-specific lipid metabolism. Comparisons with matched normal models uncover tumor-selective metabolic dependencies, such as increased reliance of renal cancers on de novo purine synthesis. Under nutrient limitation, modeling predicts convergence on glutamine-dependent aspartate synthesis while preserving tissue-specific metabolic states. Machine learning models based on fluxomics predict patient survival and highlight biotin uptake as a prognostic biomarker. FluxAtlas defines the functional metabolic landscape of human cancer and is accessible at https://software.icr.ac.uk/app/flux-atlas.
    Keywords:  CP: cancer; CP: metabolism; FluxAtlas; cancer; genome-scale metabolic modeling; metabolic flux; metabolic reprogramming; prognostic biomarkers; therapeutic targets
    DOI:  https://doi.org/10.1016/j.celrep.2026.118029
  4. Cell Rep. 2026 Sep 23. pii: S2211-1247(26)01130-7. [Epub ahead of print]45(10): 118052
    Dietary α-ketoglutarate modulates lung adenocarcinoma growth and epigenetic remodeling in a sex-dependent fashion.
    Martín Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Abigail S Krall, Bin Liu, Heather R Christofk, Steven M Dubinett, Xue Li, Claudio Scafoglio.
      Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (αKG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we demonstrate that dietary calcium αKG (Ca-αKG) is associated with remodeling of LUAD in a sex-dependent manner. In female mice, Ca-αKG is associated with reduced tumor area, decreased repressive histone marks (H3K27me3 and H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, Ca-αKG is associated with increased tumor area and elevated H3K27me3. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support Ca-αKG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.
    Keywords:  CP: cancer; Tbx5; chemoprevention; dietary supplement; differentiation; epigenetics; histone methylation; lung cancer; metabolism; sexual dimorphism; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2026.118052
  5. Science. 2026 09 24. 393(6818): eadw8520
    Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.
    Swagata Goswami, Qiming Zhang, Abdullah Burak Yildiz, Upasana Das Adhikari, Akhouri Kishore Raghawan, Manon Bulliard, Sabhyata Sedhain, Odai Darawshi, Cigdem Elif Celik, Feyza Cansiz, Constantin P Krempe, Jonas Rösler, Gabriele Allies, Sven W Meckelmann, Chiashin Chi, Felix-Levin Hormann, Sven Heiles, Joseph Sedlak, Wesley Grace, George Eng, Ethan Reich, Chiara Alquati, Kevin J Williams, Benjamin J Read, Edrees H Rashan, Zhixin Li, Anup Jnawali, Jose A Ortiz, Chesta Jain, Charles A Whittaker, Osman H Yilmaz, Vikram Deshpande, Oliver J Schmitz, Albert Sickmann, Autumn G York, Douglas S Kwon, Ulf Neumann, Maria Fedorova, Matthew G Vander Heiden, Besim Ogretmen, Nilay S Sethi, Alpaslan Tasdogan, Ömer H Yilmaz.
      Mechanisms by which primary tumor cells acquire metastatic capability through metabolic and signaling adaptations are currently poorly understood. We demonstrate that tumor-intrinsic ceramide metabolism, amplified by dietary fat, initiates colorectal cancer metastasis. We observed that dietary fat exposure triggers a sustained increase in de novo ceramide biosynthesis, mediated by the dihydroceramide desaturase Degs1. Ceramide accumulation activates yes-associated protein (YAP) through protein phosphatase 2A (PP2A)-mediated dephosphorylation, promoting a durable shift toward a distinct YAP-driven regenerative (YAP-DR) program, marked by Basp1, that promotes metastasis. Selective elimination of Basp1high cancer cells prevented metastatic seeding. Degs1 loss reduced ceramide levels, YAP activity, YAP-DR signatures, and metastasis without affecting primary tumor growth, whereas blocking ceramide degradation enhanced YAP activity and metastasis. These findings identify ceramide-induced YAP signaling as a key mediator of metastatic initiation, operating independently of primary tumor expansion.
    DOI:  https://doi.org/10.1126/science.adw8520
  6. Nature. 2026 Sep 23.
    Surprising protein links dietary restriction to increased lifespan in flies.
    Linda Partridge.
      
    Keywords:  Ageing; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-02774-0
  7. Nat Aging. 2026 Sep 21.
    RamanOmics decodes the spatial vibrational-molecular architecture of senescence in aging and repair.
    Ke Zhang, Xingjian Chen, Francesco Monticolo, Salvatore Sorrentino, Haochun Huang, Claire Callahan, Yueqing Qiao, Judy Zhou, Sonia Brodowska, Styliani Sapantzi, Jianhuan Qi, Yinghan Wu, Thai Nam Son Dang, Yanwan Cao, Sumin Kang, Francesca Viggiani, Chia-Kang Ho, Yanxin Xu, Koseki J Kobayashi-Kirschvink, Thang Mung, Hemali Phatnani, Zhixun Dou, Jeon Woong Kang, Peter T C So, Jian Shu.
      Aging and tissue repair involve heterogeneous remodeling across transcriptional, biochemical and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how these states co-evolve. Here we present RamanOmics, a multimodal framework integrating label-free hyperspectral Raman imaging with single-nucleus RNA sequencing and spatial transcriptomics to link biochemical states with transcriptional programs at single-cell spatial resolution. Applied to young and old mouse lung and skin, RamanOmics reveals tissue-specific programs: lung senescent cells are enriched for extracellular matrix remodeling and transforming growth factor-β signaling, whereas skin senescence is dominated by epidermal differentiation genes (Krt10, Lor and Sbsn). Across tissues, we identified a conserved lipid-linked Raman signature (1,131-1,135 cm-1) marking p21+ senescent cells and developed a machine learning-derived, multimodal barcode enabling nondestructive senescence identification in situ. In a mouse wound-healing model, RamanOmics reveals reactivation of epidermal differentiation genes (Krt10, Lor and Sbsn) in senescent cells, alongside increased lipid-associated Raman signatures. Together, RamanOmics provides a tissue-agnostic framework for scalable, multimodal profiling of cellular states.
    DOI:  https://doi.org/10.1038/s43587-026-01219-7
  8. Commun Biol. 2026 Sep 24. pii: 1248. [Epub ahead of print]9(1):
    How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
    Pierre-Jean Desmaison, Giulia Bertolin.
      Mitochondria are traditionally viewed as a homogeneous network supporting cellular energy production. However, increasing evidence reveals substantial heterogeneity across biological scales, from intramitochondrial microdomains to specialised mitochondrial populations within cells and tissues. These subpopulations differ in morphology, metabolism, bioenergetics, and spatial organisation, reflecting adaptation to local functional demands. In this Review, we discuss the mechanisms underlying mitochondrial heterogeneity, the emerging concept of mitochondrial subclasses, their functional integration within cellular metabolism, and the challenge of distinguishing stable subclasses from transient states. We propose a shift from a network-based view toward a dynamic mitochondrial ecosystem with important implications for physiology and disease.
    DOI:  https://doi.org/10.1038/s42003-026-11029-7
  9. bioRxiv. 2026 Sep 14. pii: 2026.09.13.750663. [Epub ahead of print]
    Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.
    Ryan Elbashir, Keene L Abbott, Diya L Ramesh, Ahmed Ali, Anna Shevzov-Zebrun, Anna M Barbeau, Michelle Wu, Abigail P Ward, Yetiş Gültekin, Brian T Do, Sharanya Sivanand, Azucena Ramos, Tenzin Kunchok, Millenia Waite, Edrees H Rashan, Muhammad Bin Munim, Michael T Hemann, Matthew G Vander Heiden.
      Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions.
    DOI:  https://doi.org/10.64898/2026.09.13.750663
  10. J Invest Dermatol. 2026 Sep 22. pii: S0022-202X(26)03716-4. [Epub ahead of print]
    Accumulation of the immunosuppressive metabolite 1-methylnicotinamide in human basal cell carcinoma.
    Luisa Bopp, Robert Seitz, Manuel Huerta Arana, Sarah Helene Schmidt, Omid Omrani, Henning Klapproth, Maria Lopéz Martinez, Dimitrios Prymidis, Maksym Cherevatenko, Theodoros Georgomanolis, Philipp Koll, Daniela Neumayer, Esther von Stebut, Paola Zigrino, Steve Hoffmann, Jan-Wilm Lackmann, Christian Frezza, Ramon I Klein Geltink, Mario Fabri.
      
    Keywords:  1-methylnicotinamide; PD-1; T cells; basal-cell carcinoma; immunometabolism
    DOI:  https://doi.org/10.1016/j.jid.2026.09.845
  11. Nature. 2026 Sep 23.
    Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila.
    Jun Wang, Zixin Cai, Jiaojiao Gu, Shiqi Xiong, Jianhan Yi, Meng Yang, Kexin Chang, Xinrui Ning, Yilin Wen, Yan Yan, Jiongming Lu, Yirong Wang, Zongzhao Zhai.
      Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.
    DOI:  https://doi.org/10.1038/s41586-026-11029-x
  12. Nat Commun. 2026 Aug 26. pii: 10200. [Epub ahead of print]17(1):
    Circadian temperature compensation is intrinsically linked with metabolism and redox signaling.
    Yao Xu, Tetsuya Mori, Himanshu Mehra, Alessandro Ustione, Kenya Tanaka, Yuta Kitaguchi, Koichiro Uriu, Shuji Nakanishi, David W Piston, David Vinyard, Carl Hirschie Johnson.
      Circadian rhythms are a universal property of organisms, and a defining property of these oscillators is the ability to maintain a precise period at different temperatures. Indeed, the discovery in the 1950s of this property, known as "temperature compensation," was a watershed event in our understanding of biological timekeeping. Since that time, however, almost no general principles have emerged that uncover the mechanistic basis of how circadian timekeepers defy the "rules" of temperature dependence of biochemical reactions. A genetic investigation of circadian temperature compensation reveals that the sensing of metabolism and ensuing modulation of the core mechanism preserves a constant circadian period. Intracellular redox sensing of metabolic rate is intrinsic to this compensation, and this relationship is conserved in bacterial and mammalian cells. These insights explain previously inexplicable observations of the interaction between redox reactions and circadian timekeeping. These results introduce a previously unknown linkage between temperature compensation and metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-77031-z
  13. Mol Cell Biochem. 2026 Sep 21.
    Itaconate metabolism in regulated cell death.
    Daolin Tang, Rui Kang.
      Itaconate, a metabolite generated from the tricarboxylic acid cycle through aconitate decarboxylase 1 (ACOD1, also known as IRG1), has emerged as a key link between cellular metabolism, immunity, and regulated cell death. Although initially recognized for its anti-inflammatory properties, accumulating evidence indicates that the biological functions of itaconate extend far beyond immunomodulation to encompass multiple forms of regulated cell death. The ACOD1-itaconate axis regulates apoptosis, ferroptosis, pyroptosis, necroptosis, and other emerging cell-death programs through coordinated control of mitochondrial metabolism, redox homeostasis, inflammatory signaling, and covalent protein modification. These effects are context dependent and are further shaped by the distinct biological activities of endogenous itaconate, synthetic derivatives, and the recently recognized itaconate-independent functions of ACOD1. In this review, we summarize recent advances in immunometabolism and regulated cell death, discuss the mechanistic basis by which the ACOD1-itaconate axis governs cell fate, and highlight how intercellular metabolic communication and non-canonical ACOD1 signaling expand its biological functions. We also highlight unresolved questions regarding target selectivity, context-dependent signaling, and therapeutic translation. A deeper understanding of the ACOD1-itaconate network may provide new insights into therapeutic strategies targeting regulated cell death in inflammatory diseases, infection, and cancer.
    Keywords:  ACOD1; Immunometabolism; Itaconate; Protein itaconation; Regulated cell death
    DOI:  https://doi.org/10.1007/s11010-026-05743-3
  14. Cell. 2026 Sep 23. pii: S0092-8674(26)01018-4. [Epub ahead of print]
    CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer.
    Li Qiang, Megan T Hoffman, Jung-Ho Chun, Brendan Parent, Felix Hambitzer, Frank Peprah, Courtney T S Kureshi, Birkley S Lim, Eugena Chang, Michael J Walsh, Julissa G Tello, Tavus Atajanova, Hojeong Shin, Corey Perkins, Rakeeb Kureshi, Yaniris Molina-Aponte, James M Dougan, Chong Zuo, Lauren Brais, Thomas E Clancy, James M Cleary, Jason L Hornick, Brandon M Huffman, Joseph D Mancias, George Molina, Mark Fairweather, Jonathan A Nowak, Kimberly J Perez, Douglas A Rubinson, Sarah Slater, Ritchell van Dams, Jiping Wang, Brian M Wolpin, Kwok-Kin Wong, Harshabad Singh, Andrew J Aguirre, David Baker, Michael Dougan, Stephanie K Dougan.
      Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon γ (IFN-γ), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-γ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.
    Keywords:  CD4 T cells; IL-21; KRAS; MRTX1133; Th1 cells; cDC2; cytokines; daraxonrasib; designed proteins; immunotherapy; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cell.2026.08.045
  15. bioRxiv. 2026 Sep 17. pii: 2026.09.15.751849. [Epub ahead of print]
    Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism.
    Woo Sung Kim, Rebecca Danner, Juyeong Cho, Jonathan Williams, Luiz Lopez, Yutong Bao, Julia K Hansen, Elizabeth M Poad, Haania Khan, Daehan Kim, Brian W Parks, Jonathan G Van Vranken, David A Harris, Andrea Galmozzi, Mary Elizabeth Patti, Snehal N Chaudhari.
      Adipocyte signaling adaptively responds to macronutrients, but how essential micronutrients impact lipid homeostasis remains poorly understood. Here, we demonstrate that folate polyglutamylation, the sequential conjugation of glutamate residues to folate, serves as a dynamic biochemical process regulating metabolic signaling. Using our folate metabolomics platform, we show that polyglutamylated folic acid accumulates in healthy adipose tissue, but is depleted in obesity across mice and humans, independent of circulating folate levels. Genetic ablation of the polyglutamylation enzyme folylpolyglutamate synthase (Fpgs) in adipocytes suppresses lipid catabolism to induce cell-autonomous lipid accumulation, operating independently of canonical adipogenesis or downstream one-carbon flux. Target-engagement proteomics identifies monoglutamylated folic acid as a Map2k5-interacting molecule that inhibits Map2k5 activity, whereas Fpgs-mediated folic acid polyglutamylation acts as a chemical switch that disrupts this interaction to promote lipolysis. In vivo , whole-body inhibition of Map2k5 or adipose-targeted genetic depletion of Fpgs increases body fat mass in the absence of dietary obesogenic triggers. Furthermore, single-cell and single-nuclear transcriptomic analyses establish the Fpgs-Map2k5 pathway as a core transcriptional signature of mouse and human adipose tissues. These findings uncover a non-canonical signaling role for folate that regulates adipocyte lipid homeostasis.
    DOI:  https://doi.org/10.64898/2026.09.15.751849
  16. Science. 2026 Sep 24. 393(6818): eaeg4791
    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
    Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, Kristen C Vogt, Ana Marie Perea, Logan R Hillger, Stephen Ruiz, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Hannah C Styers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M Rudin, Paul B Romesser, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe.
      Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.
    DOI:  https://doi.org/10.1126/science.aeg4791
  17. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2612774123
    Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.
    Yuanqin Yang, Yunyi Wang, Amanda Wicki, Qianpeng Li, Chunrun Qu, Brian Debo, Berna Bou Tayeh, Tingyu Wen, Hui Huang, Amir Hosseini, Vinnycius Pereira Almeida, Carol S Leung, Georg A Holländer, Benoit Van den Eynde, Yang Shi.
      The developmental timing of T cell generation imprints durable functional programs, yet how this shapes antitumor immunity remains unclear. Here, we combine genetic fate mapping with functional assays to dissect how thymic age and peripheral residency regulate CD8+ T cell behavior within the same host. We find that, compared with adulthood-derived CD8+ T cells, the adolescent-derived counterparts consistently exhibit enhanced tumor infiltration, increased effector cytokine production, and superior proliferative fitness. Transcriptomic and phenotypic profiling identify a CXCR3+IL-18Rα+ subset preferentially enriched among adolescent-derived T cells that shares core virtual memory-like features and displays elevated cytotoxic potential. Mechanistically, thymic origin timing and time spent in the periphery independently regulate the abundance and activity of this subset, revealing a two-tier control comprising developmental bias and postthymic remodeling. Functionally, CXCR3+IL-18Rα+ CD8+ T cells mediate potent tumor killing and confer robust therapeutic benefit in adoptive transfer models. Together, these findings establish developmental imprinting as an important determinant of CD8+ T cell heterogeneity and identify CXCR3+IL-18Rα+ CD8+ T cells as key effectors for antitumor immunity.
    Keywords:  CD8+ T cells; antitumor immunity; developmental timing; fate mapping; thymus
    DOI:  https://doi.org/10.1073/pnas.2612774123
  18. EMBO Rep. 2026 Sep 23.
    Mitotic assembly of respiratory supercomplexes ensures accurate cell division and fuels tumor growth.
    Ting Wang, Aoxing Cheng, Lingyu Kong, Weiyi You, Jihua Liu, Xing Liu, Xuebiao Yao, Yi Yang, Yuzheng Zhao, Weiwei Yang, Kaiguang Zhang, Zhenye Yang, Jing Guo.
      As cells progress from interphase into mitosis, fluctuating metabolic demands coincide with mitochondrial fission. However, the mechanisms by which mitochondria coordinate morphological changes and metabolic adjustments during mitosis remain poorly understood. Using proteomic analysis of BN-PAGE fractions, we show that assembly of the mitochondrial respiratory supercomplexes, comprising electron transport chain complexes I, III, and IV, is markedly enhanced during mitosis in HeLa and MDA-MB-468 cancer cells. Mechanistically, the upregulation of specific CI subunits, including NDUFA3, drives the modular assembly of supercomplexes in mitosis. We further demonstrate that CDK1 promotes the translation of NDUFA3 to enable supercomplex formation. Disruption of this process impairs mitochondrial integrity, energy production, and redox homeostasis, leading to ROS accumulation that triggers mitotic cell death and chromosome segregation defects across multiple models. Importantly, inhibiting mitotic supercomplex assembly induces chromosome mis‑segregation and suppresses tumor growth in vivo. Our findings reveal supercomplex assembly as a key mechanism coordinating mitochondrial fission with metabolic adaptation to support cell division and tumor proliferation in these cancer cell contexts.
    DOI:  https://doi.org/10.1038/s44319-026-00937-8
  19. FEBS Lett. 2026 Sep 21.
    The ubiquitin system in normal and infected germinal center B cells.
    Destiny Davis, Lesly Mejia, Emily K Moser.
      The ubiquitin system is a highly regulated cellular mechanism that plays a central role in germinal center (GC) B cells, essential for protective humoral immunity and the site of gammaherpesvirus latency establishment. GC B cells undergo extraordinary levels of proliferation, DNA damage, and apoptosis prior to differentiating to long-lived memory or plasma cells, and ubiquitin pathways underpin these activities. Oncogenic gammaherpesviruses infect B cells and drive them through a GC activation program. Viral programs exploit ubiquitin biology to establish latency in GC B cells and persist for life in long-lived memory B cells, poised to drive lymphomagenesis over time. Here, we will first define how ubiquitin regulates normal GC B cells. Within this framework, we will describe how gammaherpesviruses interact with these mechanisms to establish latency, highlighting common and divergent mechanisms of GC control in infected and normal B cells. Further understanding ubiquitin mechanisms in GC B cells will aid the discovery of highly specific molecular circuits that regulate B-cell fate and function, with broad relevance to antiviral immunity and cancer biology.
    Keywords:  B cell; gammaherpesvirus; germinal center; ubiquitin
    DOI:  https://doi.org/10.1002/1873-3468.70470
  20. J Clin Invest. 2026 Sep 24. pii: e204511. [Epub ahead of print]
    Targeting lipidated amino acid deficiency mitigates fibrosis via a PPARα/CCL2 axis in metabolic dysfunction-associated steatohepatitis models.
    Sumit Kumar Anand, Sandeep Das, Fabio Arias, Koral Se Richard, Sumati Rohilla, Alia Ghrayeb, M Peyton McKinney, Lu Wang, Lin Tan, Jibin Ding, Dhananjay Kumar, Nilesh Pandey, Jennifer Lee, Ying Zhao, Suman Mohajan, Gurranna Male, Kelley Nunez, Alexandra C Finney, Brenna H Pearson-Gallion, Reethika Gade, Jemiah Maxie, Yu Liu, Harpreet Kaur, Rajan Pandit, Cyrine Ben Dhaou, Joseph Eniafe, Xiaolu Zhang, Zhipeng Liu, Andrew D Yurochko, Minerva T Garcia-Barrio, Babak Razani, Fei Chang, Francisco J Schopfer, Xin Huang, Bishuang Cai, Eyal Gottlieb, Bo Wen, Duxin Sun, Wanqing Liu, Paul T Thevenot, Ari J Cohen, Jifeng Zhang, Y Eugene Chen, A Wayne Orr, Nirav Dhanesha, Arif Yurdagul, Oren Rom.
      Metabolic dysfunction-associated steatohepatitis (MASH) is rising globally despite recent therapeutic advances, highlighting the need to identify new targetable pathways. While dysregulated lipid and amino acid metabolism are established features of MASH, the interplay between these two metabolic pathways remains unexplored. Here, metabolomics of livers from humans and mice with MASH uncovered depletion of lipidated amino acids, where these two distinctive pathways converge. Notably, hepatic levels of N-oleoyl-leucine (C18:1-Leu) were inversely correlated with the severity of MASH-fibrosis. The C18:1-Leu-regulating enzyme, peptidase M20 domain containing 1 (PM20D1), was suppressed in MASH due to attenuated de novo transcription, and stable-isotope tracing confirmed impaired hepatic biosynthesis of C18:1-Leu in MASH. Hepatocyte-specific PM20D1 ablation lowered hepatic C18:1-Leu and exacerbated MASH, whereas hepatocyte-specific PM20D1 overexpression restored C18:1-Leu and ameliorated both MASH progression and established disease. Exogenous administration of C18:1-Leu similarly ameliorated MASH-fibrosis. In silico modeling, transcriptomics, metabolic flux analyses and hepatocyte-specific in vivo manipulations revealed that C18:1-Leu binds and activates peroxisome proliferator-activated receptor alpha to suppress C-C motif chemokine ligand 2, concurrently enhancing fatty acid β-oxidation and attenuating monocyte recruitment to reduce MASH-fibrosis. These findings highlight C18:1-Leu deficiency as a driver and a therapeutic target in MASH-fibrosis, warranting further clinical evaluation.
    Keywords:  Amino acid metabolism; Fatty acid oxidation; Fibrosis; Hepatology; Metabolism
    DOI:  https://doi.org/10.1172/JCI204511
  21. bioRxiv. 2026 Jun 25. pii: 2026.06.23.733767. [Epub ahead of print]
    ATAD3A structurally links mtDNA replication and mitochondrial fission.
    Nitish Dua, Boyuan Ma, Samantha Oviedo, Hamidreza Rahmani, Tumara Boyd, Donghyun Park, R Luke Wiseman, Danielle A Grotjahn.
      Mitochondrial function depends on the maintenance of its genome, and disruptions in copy number and distribution are hallmarks of mitochondrial disorders. Mitochondrial DNA (mtDNA) replication is spatially and temporally linked to mitochondrial division (i.e., fission). However, the signal that coordinates these two events, which are physically separated by the barrier of two mitochondrial membranes, remains unknown. To gain insight into this coordination, we employed correlative cryo-electron tomography (cryo-ET) to analyze the microenvironment surrounding replicating nucleoids. Mitochondrial regions containing replicating mtDNA exhibit a unique membrane architecture defined by the presence of clustered, membrane-spanning tethers that traverse the inner membrane space. Using a combination of superresolution microscopy and genetically encoded cryo-ET tagging technology, we identify these tethers as the AAA+ ATPase ATAD3A. We further show that ATAD3A knockdown reduces recruitment of the mitochondrial fission machinery, whereas overexpression promotes its recruitment and subsequent fission. Our work suggests that ATAD3A forms nanoscale linkages that coordinate these two distinct processes, revealing a new structural paradigm for organellar communication across distinct membrane-defined environments.
    Highlights: Replicating mitochondrial DNA (mtDNA) nucleoids are surrounded by a distinct membrane microenvironment.ATAD3A forms membrane-spanning tethers enriched at replicating mtDNA sites.ATAD3A enrichment is necessary and sufficient to recruit mitochondrial fission machinery and induce fission at mtDNA replication sites.ATAD3A structurally couples mtDNA replication state to mitochondrial fission across distinct organellar subcompartments.
    DOI:  https://doi.org/10.64898/2026.06.23.733767
  22. Elife. 2026 Sep 24. pii: RP108681. [Epub ahead of print]14
    Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
    Farheen Akhtar, Dania M Malik, Arjun Sengupta, Paula Haynes, Andrew D Nguyen, C Jaco Klok, Amita Sehgal, Aalim Weljie.
      Sleep and circadian rhythms shape organismal energy patterns, but how this timing connects to oxygen use and carbon dioxide production remains incompletely understood. We combined high-resolution respirometry with liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster, resolving genotype-specific impacts of sleep disruption and circadian regulation. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. Short-sleep mutants (fmn, sss) exhibited elevated metabolic rates, with reactive shifts of fuel preferences toward lipid and amino acid catabolism, and altered mitochondrial respiration. The clock mutant (per01) and flies under constant darkness (WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems contribute to aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.
    Keywords:  D. melanogaster; biochemistry; chemical biology; circadian rhythms; metabolic flexibility; metabolism; metabolomics; respirometry; sleep
    DOI:  https://doi.org/10.7554/eLife.108681
  23. Biology (Basel). 2026 Sep 08. pii: 1573. [Epub ahead of print]15(18):
    SIRT1 in Senescence: Mitochondria and Immune Crosstalk.
    Jirapat Namkaew, Pornparn Kongpracha, Tanakamol Mahawan, Thiranut Jaroonwitchawan.
      Cellular senescence is one of the hallmarks of aging. These growth-arrested cells actively secrete inflammatory mediators that reshape the tissue microenvironment and fuel age-related pathology. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that regulates senescence largely through its control over mitochondrial integrity and inflammatory signaling. SIRT1 levels and activity fall with age, and this decline directly promotes senescence. SIRT1 maintains mitochondrial function through three interconnected pathways: PGC-1α-driven mitochondria biogenesis, FOXO-dependent antioxidant defense, and mitophagic clearance of damaged organelles. When SIRT1 activity is in an unsteady state, mitochondria become unhealthy. This leads to excessive ROS generation and the leakage of mitochondrial DNA (mtDNA) into the cytosol, which activates the innate immune pathway, consequently resulting in the production of inflammatory cytokines that further inhibit SIRT1. This self-amplifying loop drives cells to irreversible senescence. In this study, we integrate the current understanding of the SIRT1-mitochondria-immune axis within the framework of senescence by examining the biological roles of SIRT1 and the mechanisms that lead to its reduction with aging, while also exploring the interrelated mitochondrial pathways and inflammatory signaling. Furthermore, we assess possible therapeutic strategies targeting this axis and highlight essential questions that necessitate additional research.
    Keywords:  SASP; SIRT1; aging; cellular senescence; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/biology15181573
  24. Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):
    Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
    Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.
      Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77023-z
  25. Nat Cancer. 2026 Sep 22.
    An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.
    Jung Seung Nam, Sung Shin Ahn, Yeonoh Shin, Ariana Vargas-Castillo, Maya S Dixon, Pardis Ahmadi, Kathrin Schilling, Fereshteh Zandkarimi, Alex Chen, Nal Ae Yoon, Harrison Cullen, Yanping Sun, Thomas C Caffrey, Kelsey A Klute, Benjamin J Swanson, Jordan Lu, Samuel Pan, Yuxuan Chen, Shu Ichimiya, Geena Kim, Jeanine M Genkinger, Kazuki Sugahara, Michael D Kluger, Paul Grandgenett, Michael A Hollingsworth, Luke Berchowitz, Anthony W Ferrante, Lori M Zeltser, Sabrina Diano, Iok In Christine Chio.
      Adipose browning and atrophy are early events of cachexia, a lethal metabolic disorder affecting nearly half of the population with cancer. Here, using individual-derived specimens and mouse models, we identified an iron-dependent pathway that initiates adipose browning in both physiological and cachectic settings. Upon adrenergic stimulation of adipocytes, an influx of iron induces the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding EXXH motif of two MSRA polypeptides serves to dimerize, stabilize and elevate its reductase activity. Iron-bound MSRA dimers in turn promote adipose browning by maintaining the reduced state of select substrates, including the catalytic subunit of protein kinase A. Remarkably, in mouse models, MsrA deletion impairs adipose browning, mitigates cachexia and prolongs the survival of tumor-bearing animals. Thus, as a key nexus of cancer-associated cachexia, the β3 adrenergic receptor-iron-MSRA axis is a promising target for clinical intervention.
    DOI:  https://doi.org/10.1038/s43018-026-01234-y
  26. bioRxiv. 2026 Sep 15. pii: 2026.09.09.750228. [Epub ahead of print]
    Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories.
    Wenyu Tang, Haoyu Xu, Steven Beck, Marcus T Cicerone, Sung Min Han, Wei-Wen Chen.
      Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo .
    DOI:  https://doi.org/10.64898/2026.09.09.750228
  27. Nat Metab. 2026 Sep 23.
    Rare science, real impact: shaping the future of research on rare metabolic diseases.
    Anu Suomalainen, Ralph J DeBerardinis, Julien Baruteau, Hélène Puccio, Takanobu Otomo, Marni J Falk.
      
    DOI:  https://doi.org/10.1038/s42255-026-01631-8
  28. Nat Aging. 2026 Sep 24.
    Multi-modality profiling identifies Neisseria flavescens as a central geroprotective oral commensal in humans.
    Jiawei Chen, Ya Ren, Yong Zhou, Ziyang Wang, Jiyang Li, Xiaoxiao Guo, Hao Xu, Yiyang Wang, Huiru Tang, Jing-Dong J Han.
      Aging is accompanied by progressive physiological decline, yet the microbiome determinants that modulate aging remain unclear. Here, we identify Neisseria flavescens (Nf) as an oral commensal associated with decelerated aging in humans. Using AURORA, a generative multi-modality framework, we developed multi-modality aging clocks, performed in silico screening for age-gap-reducing interventions and predicted Nf as a top hit. In silico perturbations linked increased Nf abundance to favorable physiological signatures, beneficial gut taxa and biosynthesis of beneficial metabolites. We isolated two Nf strains and validated their production of beneficial metabolites. Functional assays demonstrated that live Nf extended lifespan and healthspan in Caenorhabditis elegans. In aged mice, heat-killed Nf supplementation restored the serum metabolome, liver transcriptome and gut microbiome toward younger states. By establishing an AI-driven intervention discovery engine and identifying Nf as a geroprotective microorganism, these findings highlight the oral microbiome as an underestimated axis of systemic aging and a candidate for geroprotective interventions.
    DOI:  https://doi.org/10.1038/s43587-026-01220-0
  29. Nat Cell Biol. 2026 Sep 24.
    Scientific culture in the age of AI.
    Ivan Dikic, Henning Walczak.
      
    DOI:  https://doi.org/10.1038/s41556-026-02070-z
  30. Cell Biochem Biophys. 2026 Sep 23.
    Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
    Asif Ahmad Bhat, Shivkanya Fuloria, Riya Thapa, Nina Varghese, Rohini Karunakaran, Sumita Bhatia, Kamal Narain, Anupam Biswas, Sangita Biswas, Neeraj Kumar Fuloria.
      Inflammatory activation rewires cellular metabolism and generates electrophilic metabolites that can modify reactive cysteine residues. This review focuses on two metabolite-derived cysteine modifications: itaconation, driven by aconitate decarboxylase 1 (ACOD1)-dependent itaconate production, and succination, driven by fumarate accumulation. Although both involve cysteine engagement, they differ in chemical stability, metabolite source, cellular distribution, glutathione competition, and functional outcome. Itaconation is linked to Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) signalling, glycolytic control, kinase regulation, innate immune sensing, interferon responses, and inflammatory cell death, whereas succination is most strongly associated with stable S-(2-succino)cysteine (2SC) formation, fumarate excess, mitochondrial dysfunction, redox stress, inflammasome regulation, and pyroptosis. A central theme of this review is that endogenous itaconate and fumarate must be distinguished from electrophilic derivatives such as 4-octyl itaconate, dimethyl itaconate, and dimethyl fumarate, because these compounds differ in uptake, reactivity, target engagement, and pharmacological interpretation. We distinguish direct adduct mass spectrometry from competitive cysteine profiling and metabolite-mapping approaches, which can quantify bulk adduct burden, relative cysteine engagement, metabolite distribution, or compartment-specific cysteine state, but do not necessarily establish endogenous site occupancy. Proteomic and chemoproteomic approaches can prioritise metabolite-responsive cysteines, but functional relevance requires site-level validation, residue perturbation, and biochemical rescue. By comparing itaconation and succination across chemistry, target selection, inflammatory signalling, and therapeutic translation, this review defines the evidence needed to identify metabolite-sensitive cysteines as genuine regulatory nodes rather than detectable covalent adducts.
    Keywords:  Chemoproteomics; Cysteine Modification; Immunometabolism; Inflammatory Signalling; Itaconation; Succination
    DOI:  https://doi.org/10.1007/s12013-026-02184-z
  31. Nature. 2026 Sep 23.
    MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness.
    David Billing, Monica Selvaraj, Megan E Kelley, Gabriel Matos-Rodrigues, Benton Bailey, Finnja Becker, Gang Zhen, Matthew A Myers, Alessandra Brambati, Oluchi Ezekwenna, Ashley Nichols, Yi-Zhen Jiang, Lucia Wang, Shih-Chun Wang, Marie-Claude Mathieu, Davide Pradella, Hugo Poirier, Elias Rodriguez-Fos, Stephen J Morris, Michal Zimmermann, Elsa Callen, Michael Zinda, Andrea Ventura, John Maciejowski, Andrew McPherson, Sohrab P Shah, Anton George Henssen, André Nussenzweig, Agnel Sfeir.
      Extrachromosomal DNA (ecDNA) comprises megabase-sized circular DNA elements that frequently carry oncogene amplifications, driving aggressive tumour phenotypes, therapeutic resistance and poor clinical outcomes across many cancers1-4. Although ecDNA is thought to arise from canonical double-strand break repair, the pathways that maintain it remain unclear. Here we show that inhibition of microhomology-mediated end joining, but not non-homologous end joining or homologous recombination, selectively depletes ecDNA, induces ecDNA-specific damage and promotes its sequestration into micronuclei, compromising the fitness of cancer cells that depend on ecDNA-driven oncogene amplification. Mechanistically, TA-rich loci on ecDNA are hotspots for DNA damage and breakage5,6. The DNA translocase FANCM suppresses break formation at these sites, while breaks that escape FANCM surveillance are cleaved by ERCC1-ERCC4 and channelled into microhomology-mediated end joining for repair. Single-cell whole-genome sequencing shows that disrupting FANCM or polymerase θ (Polθ) in COLO320DM cells causes structural instability characterized by deletions and small duplications, with breakpoints enriched at TA-rich regions. This fragility is recapitulated in human tumours, in which ecDNA rearrangements are enriched at TA repeats. Collectively, our findings reveal TA repeat fragility as an intrinsic vulnerability of circular DNA and identify Polθ inhibition as a promising strategy to potentially destabilize ecDNA and sensitize ecDNA-driven tumours to therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41586-026-11048-8
  32. bioRxiv. 2026 Sep 16. pii: 2026.09.10.750646. [Epub ahead of print]
    Dendritic cell PD-L2 restrains intratumoral CD8 + T cell immunity.
    Jinwoo Nah, Amanda Sun, Anushka Yadav, Adina Scheinfeld, Tamjeed Azad, Samuel Rose, Burkhard Becher, James W Smithy, Michael A Postow, Charlotte E Ariyan, Yuri Pritykin, Chrysothemis C Brown.
      Blockade of inhibitory PD-1 signaling on T cells is a cornerstone of cancer immunotherapy, with current strategies targeting PD-1 or its ligand PD-L1. However, PD-1 engages an alternative ligand, PD-L2, whose role in tumor immunity remains poorly defined. Here, we show that PD-L2 is upregulated on intratumoral CCR7⁺ conventional dendritic cells (cDCs) in both mouse and human melanoma. Using genetic mouse models enabling selective ablation of PD-L1 or PD-L2 in cDCs, we identify a division of labor between these ligands: PD-L1 controls the size of the progenitor CD8⁺ T cell pool in tumor-draining lymph nodes by modulating stem-like CD8⁺ T cells, whereas PD-L2 limits progenitor exhausted CD8 + T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8⁺ T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7⁺ cDC1s. Consistent with this, increased CCR7 + cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7⁺ cDC1s and Tpex within CCL19 hi niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7⁺ cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC- associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8⁺ T cell differentiation. Our results suggest that the abundance of CCR7⁺PD-L2⁺ cDC1s may guide the choice between anti-PD-1 and anti- PD-L1 therapies and support the development of PD-L2-directed blockade.
    DOI:  https://doi.org/10.64898/2026.09.10.750646
  33. bioRxiv. 2026 Sep 20. pii: 2026.09.17.752159. [Epub ahead of print]
    Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
    Madison T Jones, Natalie Noble, Robert B Darnell, Ezgi Hacisuleyman.
      Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.
    DOI:  https://doi.org/10.64898/2026.09.17.752159
  34. bioRxiv. 2026 Sep 18. pii: 2026.09.16.752001. [Epub ahead of print]
    Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch.
    Sharon Kaisari, Ethan Lane, Raymond Wang, Jeffrey Estrada, Marta Collu, Daniele Simoneschi, Yeon-Tae Jeong, Mengxi Liu, Qingyue Zhang, Yuki Kito, Ifat Abramovich, Jason Yin, Tori Rodrick, Gyles Ward, Tyler Cropley, Adriana Heguy, Sang Yong Kim, Ran Brosh, Herman Wolosker, Namrat D Udeshi, Steven A Carr, Cynthia A Loomis, Feng-Xia Liang, Beatrix Ueberheide, Drew Jones, Ning Zheng, Michele Pagano.
      Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.
    DOI:  https://doi.org/10.64898/2026.09.16.752001
  35. J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02464-6. [Epub ahead of print] 113592
    Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
    Michael D Guile, Kyle A Anderson, Akash Jain, Alexandre Toulmay, William A Prinz, Catherine F Clarke.
      Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.
    Keywords:  Saccharomyces cerevisiae; Vps1; autophagy; dynamin; lipid raft; lipid trafficking; mitochondria; ubiquinone; vacuole; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113592
  36. bioRxiv. 2026 Apr 05. pii: 2026.04.03.716366. [Epub ahead of print]
    Proteolytic remodeling by Yme1 enables mitochondrial-derived compartment formation.
    Sai Sangeetha Balasubramaniam, Amy E Curtis, Jonathan R Friedman, Adam L Hughes.
      Mitochondrial-derived compartments (MDCs) are remodeling domains that form from the outer mitochondrial membrane during metabolic and proteotoxic stress and selectively sequester hydrophobic membrane proteins. Although MDC formation depends on mitochondrial lipid composition and occurs at organelle contact sites, the molecular mechanisms that permit their biogenesis remain poorly defined. Here we identify the conserved inner mitochondrial membrane i-AAA protease Yme1 as a critical regulator of MDC formation. Loss of Yme1 blocks MDC biogenesis in response to multiple stressors, and this requirement depends on its proteolytic activity rather than secondary defects in mitochondrial morphology. Quantitative mitochondrial proteomics under MDC-inducing conditions revealed Yme1-dependent remodeling of lipid transfer proteins of the Ups family and components of the MICOS complex. Disruption of either pathway partially restores MDC formation in yme1Δ cells, while combined perturbation substantially bypasses the requirement for Yme1. Finally, Yme1 overexpression drives MDC formation in the absence of stress, although this activity remains constrained by metabolic conditions. Together, these findings support a model in which Yme1-dependent proteolysis relieves lipid- and MICOS-dependent constraints to permit MDC formation.
    DOI:  https://doi.org/10.64898/2026.04.03.716366
  37. Aging (Albany NY). 2026 Sep 19. 18(1): 1280-1315
    mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
    Natalia Bobok.
      The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses. This review presents a three-section framework in which mTOR functions as a dynamic signaling hub coordinating multiple biological processes underlying the aging process. Evidence from genetic, experimental, and translational studies supports a causal role for mTOR signaling in lifespan regulation in model organisms, whereas human data remain predominantly associative but biologically consistent. mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) regulate distinct yet complementary aspects of cellular metabolism, proteostasis, autophagy, stress adaptation, and tissue homeostasis. Major geroprotective interventions-including autophagy activation, dietary interventions, physical activity, and senotherapeutics-partly converge on mTOR signaling but also engage parallel pathways. This adaptive regulation restores anabolic-catabolic balance, enhances stress resilience, and improves metabolic flexibility. Collectively, the available evidence identifies mTOR as an important integrative node linking multiple hallmarks of aging and diverse geroprotective interventions. Rather than representing a single therapeutic target, mTOR should be viewed as a context-dependent signaling hub which precise, tissue-specific modulation may promote healthy aging and support future geroscience-based interventions.
    Keywords:  geroprotective interventions; hallmarks of aging; mTOR signaling; mTORC1; mTORC2
    DOI:  https://doi.org/10.18632/aging.206423
  38. Nat Commun. 2026 Aug 26. pii: 10191. [Epub ahead of print]17(1):
    Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma.
    Prathyusha Konda, Alexandra J Wakolbinger, Yantong Cui, Gabriel Roberti de Oliveira, Yasmin L Nabil, Cary N Weiss, Maxwell D Seager, Riva Deodhar, Jiao Li, Sayed Matar, Jinyu Wang, Jack Horst, Sabrina Y Camp, Aseman B Sheshdeh, Jonathan L Hecht, David J Einstein, Yashika Rustagi, Anwesha Nag, Aaron R Thorner, Cheng-Zhong Zhang, Eliezer M Van Allen, Sabina Signoretti, Toni K Choueiri, Srinivas R Viswanathan.
      Renal cell carcinomas (RCC) comprise multiple molecularly distinct cancers but most are treated empirically with therapies designed for clear cell RCC (ccRCC), the most common subtype, due to incomplete understanding of subtype-specific biology. We analyzed single-cell transcriptomes and chromatin accessibility profiles from translocation renal cell carcinoma (tRCC), an aggressive RCC defined by oncogenic TFE3 gene fusions. We show that, despite arising from a proximal tubule cell of origin similar to ccRCC, tRCCs display distinct oncogenic programs and an immunosuppressive tumor microenvironment (TME). tRCCs exhibit six conserved tumor meta-programs, including epithelial-mesenchymal transition (EMT) and proximal tubule identity programs whose balance is regulated by TFE3 fusion activity. The fusion-driven EMT program drives a suppressive TME marked by progenitor-exhausted CD8 + T cells, anti-inflammatory SPP1+ macrophages, and matrix-associated fibroblasts. Our findings highlight unique TFE3 fusion-driven biology in tRCC, explaining its reduced immunotherapy responsiveness relative to ccRCC, and suggesting strategies for targeting fusion-driven oncogenic programs and TME reprogramming.
    DOI:  https://doi.org/10.1038/s41467-026-76858-w
  39. JCI Insight. 2026 Sep 22. pii: e209036. [Epub ahead of print]11(18):
    Molecular underpinnings of metastatic small renal masses.
    Payal Kapur, Daria Beshnova, Hua Zhong, Ruby Sharma, Pooja Ghatalia, Angela Yoo, Daniel D Le, Ratna Mukhopadhyay, Alana Christie, Jeffrey Miyata, Shuanzeng Wei, Rana R McKay, Dinesh Rakheja, Satwik Rajaram, Robert G Uzzo, A Ari Hakimi, Zora Modrusan, James Brugarolas.
      Metastases in renal cell carcinoma (RCC) typically arise from large primary tumors. However, a subset of patients with small renal masses (SRMs; ≤4 cm) can develop metastatic disease. Identifying these tumors is clinically important, as many SRMs are managed with active surveillance, and their study may provide insight into the early acquisition of metastatic competence. It remains unclear whether these tumors acquire distinct metastatic programs or instead show premature activation of the same aggressive programs typically associated with larger tumors. Here, we performed integrated morphological and molecular profiling of a multiinstitutional cohort of metastatic SRMs, including whole-exome sequencing and RNA-Seq, using nonmetastatic primary tumors as controls. Among metastatic, non-clear cell SRMs, we identified NF2-altered tumors, ELOC-mutated RCC, and an mTOR-driven eosinophilic vacuolated tumor. Metastatic clear cell SRMs were enriched by multi-hit aggressive genotypes, including recurrent losses of chromosomes 8p, 9, and 14q, as well as co-occurring driver alterations (≥2 events), including BAP1 and mTOR pathway genes. Transcriptomic analyses revealed enrichment of the non-negative matrix factorization 3 (NMF3) subtype from the IMmotion151 trial-based taxonomy, along with metabolic rewiring and reduced cytotoxic immune effector function. Collectively, these findings identify molecular programs associated with metastatic competence in SRMs, highlight the importance of genomic studies of equivocal non-clear cell SRMs, and provide a biological framework for risk stratification in patients often considered for active surveillance.
    Keywords:  Clinical Research; Genetics; Molecular pathology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.209036
  40. Arch Bronconeumol. 2026 Sep 24. pii: S0300-2896(26)00330-3. [Epub ahead of print]
    Tumor Heterogeneity and Metastatic Potential in Lung Cancer: How Early Can a Tumor Become Metastatic?
    Ariana Huebner.
      
    DOI:  https://doi.org/10.1016/j.arbres.2026.08.019
  41. bioRxiv. 2026 Sep 14. pii: 2026.09.07.749965. [Epub ahead of print]
    Mitochondrial perturbation adapts the proteome from early to advanced immune responses.
    Jessica Alvarez, Sofia Rivera, Sarahbeth Roberts, Natalia Herrera, Tyron Chang, Krishna Kanth Chitta, Jeon Lee, Andrew Lemoff, Dustin C Hancks.
      Dysregulated immunity, a hallmark of many human diseases, co-occurs with mitochondrial dysfunction and is commonly associated with misprimed primary immune signaling. While transcriptionally well-characterized, the impact of mitochondria on the host response at the protein level is less clear. Using in vitro and in vivo approaches including proteotranscriptomics, our data suggest that OXPHOS promotes expression of early, cell autonomous immune proteins whereas mitochondrial perturbation favors mediators of cell extrinsic responses like inflammation. This response is independent of immune cues, time-dependent, conserved, and occurs across tissues in mouse models of mitochondrial dysfunction. These data illustrate unappreciated roles for mitochondrial state in adapting host responses at the protein level, which have implications for complex disease etiology and the ancestral origins for eukaryotic immune sensing.
    DOI:  https://doi.org/10.64898/2026.09.07.749965
  42. Nat Commun. 2026 Aug 22. pii: 10155. [Epub ahead of print]17(1):
    Longitudinal digital phenotyping of activity rhythms and biological aging using commercial wearables.
    Jinjoo Shim, Jukka-Pekka Onnela.
      Disrupted rest-activity rhythms have been associated with aging and chronic disease, yet longitudinal evidence from free-living populations has been lacking. Here we integrate multi-year Fitbit activity data from the All of Us Research Program with clinical biomarker-derived PhenoAge from 2,222 participants (8,447 person-years). Through high-dimensional digital phenotyping, we show that circadian rest-activity rhythm intensity, timing, and stability are associated with biological aging trajectories. Higher rhythm intensity was associated with 26-46% lower odds of accelerated aging. Associations of timing and regularity were stronger in females. In males, accelerated aging followed a biphasic instability pattern with early-morning surges and late-evening rebounds. These findings provide large-scale longitudinal evidence that consumer wearable-derived rest-activity rhythms may serve as digital biomarkers of aging trajectories. By linking population-scale digital phenotyping to biological aging, this work highlights the potential of scalable digital measures for aging-related risk assessment and future healthy-aging research.
    DOI:  https://doi.org/10.1038/s41467-026-76147-6
  43. Eur J Cell Biol. 2026 Sep 21. pii: S0171-9335(26)00046-4. [Epub ahead of print]105(4): 151575
    Mitochondria-associated programmed cell death in colorectal cancer: molecular mechanisms, metabolic plasticity, and therapeutic opportunities.
    Shaojie Liu, Jiaqi Zhang, Zihan Zhang, Shilong Yan, Wenyu Di, Jie Yang, Wei Su, Na Song, Haijun Wang.
      Mitochondria integrate bioenergetics, redox homeostasis, calcium signaling, metabolite synthesis, organelle quality control, innate immune sensing, and regulated cell death. In colorectal cancer (CRC), mitochondrial function is not simply suppressed by aerobic glycolysis; rather, tumor cells dynamically redistribute flux between glycolysis, oxidative phosphorylation, glutaminolysis, fatty-acid metabolism, and the mevalonate pathway to meet stage- and treatment-specific demands. This metabolic plasticity determines whether mitochondrial stress is buffered or converted into a lethal signal. Here, we critically synthesize recent evidence linking mitochondrial bioenergetics, reactive oxygen species (ROS), mitophagy, fusion-fission dynamics, mitochondrial DNA (mtDNA) damage and release, mitochondrial biogenesis, and oncogenic signaling to apoptosis and non-apoptotic forms of programmed cell death, including ferroptosis, pyroptosis, necroptosis, PANoptosis, and cuproptosis. We further discuss mtDNA sensors-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Toll-like receptor 9 (TLR9), NOD-like receptor family pyrin domain-containing 3 (NLRP3), and Z-DNA-binding protein 1 (ZBP1)-as links between mitochondrial injury, tumor-cell death, and antitumor immunity. Particular attention is given to B-cell lymphoma 2 (BCL-2) homology 3 (BH3) mimetics, metabolic inhibitors, patient-derived organoids (PDO), patient-derived organoid xenografts (PDOX), and immunocompetent models. Current evidence supports mitochondria as a therapeutically actionable network, but also reveals major context dependencies related to tumor genotype, cell state, treatment schedule, immune competence, and normal-tissue mitochondrial requirements. Biomarker-guided combinations and model systems that preserve patient heterogeneity will therefore be essential for clinical translation.
    Keywords:  Apoptosis; Colorectal cancer; Ferroptosis; Metabolic plasticity; Mitochondria; PANoptosis
    DOI:  https://doi.org/10.1016/j.ejcb.2026.151575
  44. Cell Chem Biol. 2026 Sep 23. pii: S2451-9456(26)00326-0. [Epub ahead of print]
    Chemoproteomic profiling of itaconate-derived protein modifications.
    Youjia Wang, Chu Wang.
      Itaconate is an emerging immunomodulatory metabolite produced in macrophages upon inflammatory activation and exhibits both immunoregulatory and bacterial-regulatory properties. Structurally, itaconate is a reactive α,β-unsaturated carboxylic acid that undergoes Michael addition with nucleophilic cysteine residues in proteins, generating a unique type of covalent post-translational modification termed itaconation. Here, we review recent progress in the systematic identification of itaconation by chemoproteomic methods. These studies have identified an expanding repertoire of itaconation targets in both host cells and pathogens, providing mechanistic insight into how itaconate regulates immune responses and modulates pathogen tolerance. We further highlight the recent discovery of lysine itaconylation, a novel acylation mediated by itaconate, and briefly review chemoproteomic studies that have globally profiled the non-covalent targets of this immunoregulatory metabolite. Collectively, these chemoproteomic efforts provide rich resources to guide future functional studies and deepen our understanding of the multifaceted roles of itaconate in host-pathogen interactions.
    Keywords:  chemoproteomics; host-pathogen interface; immunomodulatory metabolite; itaconate; post-translational modifications
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.016
  45. J Biol Chem. 2026 Sep 24. pii: S0021-9258(26)02477-4. [Epub ahead of print] 113605
    Spiny mouse fibroblasts exhibit a baseline preference for glycolysis and are resilient to oxidative stress across lifespan.
    Ebenezer Aryee, Ajoy Aloysius, Sandeep Saxena, Renee Donahue, Brennan Riddell, Hemendra Vekaria, Patrick G Sullivan, Huazhen Liu, Pradeep Kachroo, Ashley W Seifert.
      Although metabolism was originally studied across an array of mammals, contemporary metabolic studies moved towards human and mouse cells. A newfound interest in how metabolism regulates cell state during homeostasis, tissue repair and disease has uncovered key roles for energy flux inside and outside of mitochondria. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit enhanced resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from spiny mice, rabbits, laboratory mice and rats, we show that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting lower ROS-production. Mitochondria from spiny mouse fibroblasts were generally low respiring and depolarized while exhibiting a large, spherical morphology. We observed this large, spherical phenotype consistently across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice and cells from all ages were highly resistant to oxidative stress. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype that increases cellular resilience.
    Keywords:  aging; electron transport system; mitochondria; mitochondrial metabolism; reactive oxygen species; regeneration
    DOI:  https://doi.org/10.1016/j.jbc.2026.113605
  46. Science. 2026 Sep 24. 393(6818): 1300-1301
    King sulfur.
    Richard Possemato.
      Mammalian cells produce and store a sulfur compound for antioxidant protection.
    DOI:  https://doi.org/10.1126/science.ael0139
  47. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00034-1. [Epub ahead of print]406 1-42
    Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.
    Satoshi Minami, Maho Hamasaki.
      Lysosomes were once considered terminal degradative organelles responsible for disposing of cellular waste. However, recent studies have revealed that lysosomes serve as dynamic signalling and metabolic hubs at the center of diverse biological processes, including nutrient sensing, metabolic regulation, membrane trafficking, autophagy, inflammation, and cell death. To support this broad functional repertoire, lysosomes must possess robust mechanisms to maintain their integrity in the face of damage or stress. In response to lysosomal membrane damage, cells engage multilayered adaptive mechanisms that act in coordination-membrane repair (Repair), selective removal of damaged organelles (Removal), and de novo biogenesis of lysosomes (Regeneration). These processes are mediated by a range of molecular pathways, including the ESCRT complex, the PITT pathway, lysophagy, and TFEB-dependent lysosomal regeneration. Notably, recent findings highlight the noncanonical autophagy-like pathway known as ATG8ylation (conjugation of ATG8s on single membranes), which is activated via the STING-V-ATPase-ATG16L1 axis and functions as a critical hub connecting multiple arms of the lysosomal damage response. In this review, we systematically outline the molecular basis of lysosomal damage responses, including ATG8ylation, and explore how these networks are implicated in a broad spectrum of pathological conditions such as aging, neurodegeneration, cancer, obesity-related disorders, and immune dysfunction. Understanding these lysosomal quality control mechanisms not only sheds light on the fundamental principles of organelle homeostasis but also opens new avenues for therapeutic innovation.
    Keywords:  Lysophagy; Lysosome; Organelle damage; Selective autophagy
    DOI:  https://doi.org/10.1016/bs.ircmb.2026.04.002
  48. Nature. 2026 Sep;657(8133): 870-872
    All the ways a cell can die - and why the variety matters.
    Amber Dance.
      
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-02929-z
  49. Genes Dev. 2026 Sep 22.
    Initial perturbations triggered by p53 loss in stem cells.
    Yang Fan, Amanda E Jones, Yulei Wei, Yi Ding, Chendong Yang, Ralph J DeBerardinis, Jun Wu, John M Abrams.
      p53 is frequently mutated in human cancers, but how it normally acts to prevent transformation is not fully understood. The initial events triggered by p53 loss are commonly extrapolated from cell lines, patient tumors, or mouse models in which p53 has been absent for long durations (e.g., months, years). In these contexts, collateral changes, competitive selection, and secondary adaptations may obscure the immediate impact of p53 elimination. Therefore, to inspect the direct consequences triggered by p53 loss in real time, we developed a platform that enables conditional removal of p53 in unstressed mouse embryonic stem cells. Within 48 h, activated germline programs were accompanied by altered chromatin profiles and downregulated canonical p53 targets. At the single-cell level, extensive heterogeneity was observed in the form of erupting retroelements, increased SINE accessibility, features of Warburg metabolism, and functional germ cell effectors (e.g., Dmrt1 and PGC7/Dppa3). Together, these findings expose ground state functions for p53 and establish that germline transitions, activated mobile elements, and metabolic reprogramming define acute perturbations caused by p53 loss.
    Keywords:  ESCs; Warburg metabolism; depletion; germline; p53; perturbations; retroelements
    DOI:  https://doi.org/10.1101/gad.353794.126
  50. Cell Metab. 2026 09 01. pii: S1550-4131(26)00289-5. [Epub ahead of print]38(9): 1916
    Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
    Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.016
  51. Trends Pharmacol Sci. 2026 Sep 23. pii: S0165-6147(26)00233-6. [Epub ahead of print]
    B cells enter the synaptic conversation.
    Terry R Suk, David Gate.
      Synapse loss is a defining feature of neurodegenerative disease, yet the signals that orchestrate synaptic elimination remain incompletely understood. Crowley and colleagues uncover an unexpected link between neuronal hyperactivity and adaptive immunity, showing that antibody-secreting B cells and immunoglobulins can drive complement-dependent synapse loss.
    DOI:  https://doi.org/10.1016/j.tips.2026.09.004
  52. Sci Adv. 2026 Sep 25. 12(39): eaee1905
    mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
    Alex Zaufel, Wenfei Sun, Nunzia Pastore, Ulrike Taschler, Carina Wagner, Hubert Hackl, Judith Sommer, Dagmar Silbert-Wagner, Jan G Hengstler, Brigitte Begher-Tibbe, Rudolf Stauber, Dagmar Kolb, Martin Troetzmueller, Benjamin Gottschalk, Chelsea Thorsheim, Eva-Lena Stange, Mathias W Hornef, Olga Pivovarova-Ramich, Andreas F H Pfeiffer, Kylie P Matchett, Anne Loft, Stephan Herzig, Neil C Henderson, Andrea Ballabio, Zoltan Arany, Christian Wolfrum, Peter Fickert, Tarek Moustafa.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non-12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.
    DOI:  https://doi.org/10.1126/sciadv.aee1905
  53. bioRxiv. 2026 Sep 14. pii: 2026.09.07.749862. [Epub ahead of print]
    A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer.
    Kayla Carter, Olajumoke Ogunlusi, Mrinmoy Sarkar, Stephen Akanbi, Christian Nguyen, Manasa Nekkanti, Akash Agarwal, Danielle Fails, Gayan I Nawaratna, Cory Klemashevich, James Cai, Devon J Boland, Tapasree Roy Sarkar.
      Cancer-associated fibroblasts (CAFs) are major regulators of the tumor microenvironment, yet how distinct CAF states suppress innate immunity in HER2-low breast cancer remains poorly understood. Here, we identify an S100A4-enriched CAF population that expands during HER2-low breast tumor progression and establishes a metabolically immunosuppressive niche. Spatial transcriptomics and multiplex imaging of human HER2-low tumors reveal progressive CAF accumulation and an inverse spatial association between S100A4-enriched CAFs and immune infiltration, including natural killer (NK) cells. Using an immunocompetent HER2-low mammary tumor model, we show that S100A4-enriched CAFs promote tumor initiation and progression while suppressing NK-cell cytotoxicity, IFN-γ production, perforin, and granzyme B. Fractionation of CAF-conditioned media and metabolic profiling identify a low-molecular-weight immunosuppressive program characterized by enhanced branched-chain amino acid catabolism and accumulation of branched-chain α-keto acids (BCKAs). Mechanistically, BCKAs directly suppress NK-cell IFN-γ production, whereas inhibition of the branched-chain aminotransferase BCAT1 reduces CAF-mediated NK-cell suppression and restores antitumor cytotoxicity. BCAT1 inhibition also suppresses HER2-low tumor growth in vivo , an effect attenuated by NK-cell depletion, establishing NK-cell restoration as a functional component of its antitumor activity. Together, these findings uncover a CAF-driven metabolic immune checkpoint in which S100A4-enriched CAFs exploit BCAT1-dependent BCKA production to suppress NK-cell surveillance and promote HER2-low breast tumor progression. Targeting stromal BCAT1 therefore represents a potential strategy to dismantle CAF-mediated immune suppression and restore innate antitumor immunity.
    DOI:  https://doi.org/10.64898/2026.09.07.749862
  54. Int J Mol Sci. 2026 Sep 21. pii: 8416. [Epub ahead of print]27(18):
    Senescent Cell Heterogeneity: Tissue-Dependent Signatures and Age Dynamics Revealed by Human scRNA-Seq Data.
    Kseniia Matveeva, Daniil Shevyrev.
      It is well established that aging is accompanied by the accumulation of senescent cells across tissues. The triggers inducing cellular senescence are diverse and vary across cell types and organs, underpinning the high diversity of senescence phenotypes within individual cell types as well as at the tissue and organismal levels. Identifying common transcriptional patterns and senescence triggers while accounting for the remarkable diversity of aged and dysfunctional cells is fundamental to developing strategies aimed at reducing senescent cell burden. The aim of this study was to investigate the heterogeneity of human senescent cells across tissues at single-cell transcriptome resolution. We selected publicly available scRNA-seq data from healthy donors for the skin, lungs, small and large intestine, kidneys, and heart. The final dataset comprised 1.5 million cells from six tissues, encompassing 64 annotated cell types across 177 donors aged 15 to 88 years. To identify cell type-specific senescence signatures, we reproduced and adapted the signature identification algorithm underlying the SenePy library. This enabled us to identify de novo genes associated with aging and senescent status within a given dataset. Next, for senescent cells of each cell type, we obtained differentially expressed gene sets and performed gene set enrichment analysis (GSEA) using a broad collection of terms reflecting functional status, metabolic activity, and adaptive responses to various forms of cellular stress. As a result, we identified organ-specific aging features in senescent cells of different cell types. We also assessed the enrichment of antigen presentation pathways and the production of senescence-associated pro-inflammatory factors (SASP) in senescent cells across tissues. Furthermore, our analysis revealed novel tissue-specific patterns of ligand-receptor interactions between senescent cells and their microenvironment.
    Keywords:  DEG; GSEA; SenMayo; SenePy; human senescent cell mapping; senescence; senescence signature; senescent cell age dynamic; senescent cell heterogeneity; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/ijms27188416
  55. Nat Commun. 2026 Aug 25. pii: 10162. [Epub ahead of print]17(1):
    The predicted interactome of the human mitochondrial proteome.
    Abhinav B Swaminathan, Mohammad Zulkifli, Rachel M Guerra, Sofia M Calabrese, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Despite the fundamental importance of mitochondria in cellular metabolism, the molecular function(s) of many mitochondrial proteins remain unknown. Since protein function can be inferred from their interacting partners, we repurpose the protein structure prediction algorithm AlphaFold Multimer (AFM) as a classification model to predict protein-protein interactions of the entire human mitochondrial proteome. By screening 630,003 protein pairs, we create a compendium of 2,895 previously known and newly observed interactions, which include the interacting partner(s) of 85 uncharacterized mitochondrial proteins, thereby linking them to a known biochemical pathway. Extending the AFM-based analysis to 11 diverse eukaryotes identifies evolutionarily conserved interactions among human hits, including regulators of core bioenergetic pathways. Our experiments, guided by these predictions, nominate protein interactions that form the coenzyme Q metabolon and define the mitochondrial copper delivery pathway to cytochrome c oxidase. Our compendium represents a powerful resource for the systematic, structure-based functionalization of the human mitochondrial proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77112-z
  56. Nat Protoc. 2026 Sep 21.
    Tissue expansion mass spectrometry imaging (TEMI) for high-spatial-resolution multiomics molecular mapping.
    Hua Zhang, Lang Ding, Thao Duong, Kendra G Selby, Wan-Jo Lee, Amy Hu, Haiyan Lu, Paul W Tillberg, Meng Wang, Lingjun Li.
      High-spatial-resolution in situ mapping of biomolecules within tissue reveals critical insights into the complex molecular landscape and spatial organization of biological systems. Mass spectrometry imaging (MSI) is a powerful tool for spatially resolved molecular analysis of biological samples, with ongoing demand for improved spatial resolution. Tissue expansion combined with MSI (TEMI) is a recently developed approach that enables multiomics molecular mapping across various biological tissues with significantly improved spatial resolution. Unlike conventional methods that depend on instrument-based enhancements in spatial resolution, TEMI physically enlarges tissue samples via harsh-condition-free hydrogel expansion, achieving more than 3.5-fold increase in effective imaging resolution using standard MSI instrumentation. TEMI delivers single-cell spatial resolution in tissue samples and enables detection of biomolecular heterogeneity that remains uncharacterizable in unexpanded tissue using conventional MSI. Notably, TEMI supports high-spatial-resolution mapping of multiple biomolecular classes-including lipids, metabolites, N-glycans, peptides and proteins-within a single tissue sample. Here, we provide a detailed, step-by-step guide for TEMI, including hydrogel-based tissue expansion under mild conditions, cryosectioning of the expanded tissue-hydrogel sample, a comprehensive experimental workflow for multiomics TEMI on a single tissue section, data acquisition and visualization pipelines, as well as troubleshooting tips. Overall, we demonstrate that TEMI overcomes the long-standing spatial limitations of MSI without requiring hardware modifications, ensuring compatibility with existing MSI instruments and promoting broad accessibility and adoption within the research community.
    DOI:  https://doi.org/10.1038/s41596-026-01427-w
  57. Nat Cancer. 2026 Sep 25.
    Unraveling the lexicon of complex mutational phenomena in human cancers.
    Ting Yang, Erik N Bergstrom, Stanley Clarke, Marcin Imieliński, Ludmil B Alexandrov.
      Although most mutations found in cancer genomes are randomly distributed, some form complex genomic patterns. Over the past 15 years, genomics studies have systematically uncovered multiple mutational phenomena, assigning several of them evocative Greek terms including kataegis, omikli, kyklonas, chromothripsis, chromoplexy, pyrgo, rigma and tyfonas. These phenomena are associated with distinct, often incompletely understood, molecular mechanisms and have important implications for tumor evolution and clinical outcomes. This Perspective provides a comprehensive lexicon of these mutational phenomena, addressing ambiguities in their definitions and mechanisms while highlighting their diversity, proposed origins and known associations with mutational processes, drug resistance and clinical outcomes.
    DOI:  https://doi.org/10.1038/s43018-026-01242-y
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