bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–07–20
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
  2. Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
  3. Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
  4. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
  5. mtKO: A dedicated guide RNA library for mitochondria research.
  6. Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.
  7. Phosphoenolpyruvate carboxykinase 1-mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression.
  8. Cancer mortality and senescence: Is redox therapy an option?
  9. Mitochondrial DNA: how does it leave mitochondria?
  10. Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
  11. Ensemble quantitation of absolute metabolite concentrations in T cells reveals conserved features of immunometabolism.
  12. MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
  13. Direct genetic transformation bypasses tumor-associated DNA methylation alterations.
  14. Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis.
  15. Mitochondria dysfunction: cause or consequence of physiologic aging?
  16. Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
  17. Collagen hydroxylation couples NAD+/NADH dynamics to tumor dormancy and reactivation.
  18. MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
  19. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
  20. Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
  21. What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.
  22. Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
  23. Cancer progression through the lens of age-induced metabolic reprogramming.
  24. Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
  25. The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.
  26. SLC7A11 protects amoeboid-disseminating cancer cells from oxidative stress.
  27. Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis.
  28. Bidirectional Mendelian Randomization Indicates Causal Relationships Between Circulating Branched-Chain Amino Acids and Metabolic Health.
  29. The Aging Microenvironment as a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
  30. Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
  31. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
  32. Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.
  33. Tumour tissue: heterogeneous, but not disordered.
  34. The interplay between senescence, inflammation, and the immune system.
  35. Accumulation of SA-βGal-High Cells in Human Naïve T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State.
  36. CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
  37. Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
  38. Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.
  39. Why and how paternal mitochondrial DNA gets cut out of the inheritance.
  40. cGAS: Bridging Immunity and Metabolic Regulation.
  41. Specialized high-capacity mitochondria fuel cell invasion.
  42. Recent evolution of the developing human intestine affects metabolic and barrier functions.
  43. Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors.
  44. The proteostatic landscape of healthy human oocytes.
  45. Killing wisely: precision senolytics in the age of frailty.
  46. Inhibition of formate production blocks CD8 + T-cell responses and delays disease onset in a mouse model of type 1 diabetes.
  47. Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
  48. Exploring the oncogenic impact of heteroplasmic de novo MT-ND5 truncating mutations.
  49. A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic Control.
  50. Mitochondrial origins of the pressure to sleep.
  51. JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux.
  1. Nat Chem Biol. 2025 Jul 15.
    Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.
    Guinevere L Grice, Eleanor Minogue, Hudson W Coates, Mekdes Debela, Richard J Stopforth, Niek Wit, Zongyu Li, Joseph P Crowley, Arthur Kaser, Nicole Kaneider-Kaser, P Robin Antrobus, Marcia C Haigis, Randall S Johnson, James A Nathan.
      Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity. Glutarate exerts its effects either by directly inhibiting metabolite-dependent enzymes or through conjugation to substrates. Intriguingly, glutarylation can occur on protein and nonprotein substrates, but our understanding of these distinct glutaryl modifications is in its infancy. Here we uncover ABHD11 as a noncanonical deglutarylating enzyme critical for maintaining the tricarboxylic acid (TCA) cycle. Mechanistically, we find ABHD11 removes glutaryl adducts from lipoate-an essential fatty acid modification required for the TCA cycle. Loss of ABHD11 results in the accumulation of glutaryl-lipoyl adducts that drive an adaptive program, involving 2-oxoglutarate accumulation, that rewires mitochondrial metabolism. Functionally, this role of ABHD11 influences the metabolic programming of human CD8+ T cells. Therefore, our findings reveal lipoyl glutarylation as a reversible modification that regulates the TCA cycle.
    DOI:  https://doi.org/10.1038/s41589-025-01965-6
  2. Nat Metab. 2025 Jul 14.
    Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
      
    DOI:  https://doi.org/10.1038/s42255-025-01326-6
  3. bioRxiv. 2025 May 10. pii: 2025.05.09.653205. [Epub ahead of print]
    Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
    Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Anna Shevzov-Zebrun, Keene L Abbott, Matthew G Vander Heiden.
      The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can also increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affects cancer cell proliferation.
    DOI:  https://doi.org/10.1101/2025.05.09.653205
  4. Nat Metab. 2025 Jul 14.
    Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
    Simon Andersson, Hien Bui, Arto Viitanen, Daniel Borshagovski, Ella Salminen, Sami Kilpinen, Angelika Gebhart, Emilia Kuuluvainen, Swetha Gopalakrishnan, Nina Peltokangas, Martyn James, Kaia Achim, Eija Jokitalo, Petri Auvinen, Ville Hietakangas, Pekka Katajisto.
      Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01325-7
  5. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2502285122
    mtKO: A dedicated guide RNA library for mitochondria research.
    Karambir Kaur, Javeria Zaheer, Fengchao Lang, Diego Luis Ribeiro, Meili Zhang, Hua Song, Wei Zhang, Raj Chari, Hussam Alkaissi, Chunzhang Yang.
      Mitochondria are multifunctional organelles central to both physiological and pathological processes. In malignant cancer cells, mitochondrial reprogramming establishes the metabolic foundation to meet cellular demands, which is particularly important in tumor cells with existing metabolic perturbations. To identify key mitochondrial pathways supporting cancer development, we developed mitochondria Knockout (mtKO), a robust and unbiased CRISPR screening platform to pinpoint critical mitochondria-associated pathways. The mtKO screen revealed that the mitochondrial antioxidant enzyme SOD2 is essential for cells harboring IDH1 mutations. Mechanistically, SOD2 activity determines the disease manifestation of IDH1-mutated cancers, through maintaining redox homeostasis and mitochondrial fitness. This study introduces a powerful functional genomic tool to identify mitochondrial-centered pathways and reveals the selective mitochondrial vulnerability in Krebs cycle-deficient cancers for future therapeutic intervention.
    Keywords:  CRISPR screen; IDH1; SOD2; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2502285122
  6. FASEB J. 2025 Jul 31. 39(14): e70825
    Deletion of Skeletal Muscle Mitochondrial Glutamic-Oxaloacetic Transaminase (GOT2) Enhances Oxaloacetate Inhibition of Succinate Dehydrogenase and Alters Substrate Selectivity.
    Brian D Fink, Ritu Som, Liping Yu, William I Sivitz.
      Oxaloacetate (OAA) is converted to aspartate by mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) along with the conversion of glutamate to alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. In past work, we found that in skeletal muscle mitochondria energized by succinate alone, oxaloacetate accumulates and inhibits succinate dehydrogenase (complex II) in a manner dependent on inner membrane potential (ΔΨ). Here, we tested the hypothesis that deleting GOT2 would increase OAA concentrations, decrease complex II-energized respiration, and alter the selectivity of succinate versus glutamate for energy. Incubating wild-type mitochondria with succinate and glutamate revealed that increments in ADP increased OAA and caused a preferential use of glutamate for energy. Deletion of GOT2 compared to wild-type decreased complex II energized respiration, increased OAA, and decreased consumption of glutamate relative to succinate. OAA accumulation was also associated with decreased conversion of succinate to fumarate and malate. These findings are consistent with GOT2 control of metabolite flow through succinate dehydrogenase via regulation of OAA and consequent inhibition of succinate dehydrogenase. In contrast to respiration energized at complex II, when mitochondria were energized at complex I by pyruvate + malate, respiration did not differ between GOT2KO and WT mitochondria, and oxaloacetate was not detectable. In summary, GOT2 and OAA mediate complex II respiration and mitochondrial energy substrate selectivity.
    Keywords:  glutamic‐oxaloacetic transaminase‐2; mitochondria; mitochondrial complex II; mitochondrial inner membrane potential; oxaloacetate; respiration; skeletal muscle; succinate dehydrogenase
    DOI:  https://doi.org/10.1096/fj.202501071R
  7. Kidney Int. 2025 Jul 09. pii: S0085-2538(25)00513-7. [Epub ahead of print]
    Phosphoenolpyruvate carboxykinase 1-mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression.
    Delal Dalga, Anna Rinaldi, Xiaorong Fu, Lucie Chanvillard, Aurelie Huber, Anna Faivre, David Jaques, Lena Berchtold, Julien Boccard, Gregoire Arnoux, Arnaud Lyon, Joseph M Rutkowski, Quentin Gex, Deborah Paolucci, Mario Kreuzfeld, Thomas Cagarelli, Lea Lutz, Alban Longchamp, Solange Moll, Nicolas Hulo, Belen Ponte, Shawn C Burgess, Pietro E Cippà, Thomas Verissimo, Sophie de Seigneux.
       INTRODUCTION: Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains debatable. Here, we investigate the role of phosphoenolpyruvate carboxykinase 1 (PCK1), an enzyme involved in gluconeogenesis and cataplerosis (removal of tricarboxylic acid (TCA) cycle intermediates from the mitochondrial matrix) in kidney disease progression.
    METHODS: We used mice with kidney tubular cell-specific deletion or overexpression of the PCK1 enzyme, and different models of kidney injury such as ischemia-reperfusion injury or cis-platin-induced nephropathy. Furthermore, we measured metabolites in kidney biopsy tissue from patients with stage 3b/4 chronic kidney disease (CKD).
    RESULTS: Using flux analysis, we confirm that cataplerosis and the TCA cycle are blocked by PCK1 deficiency. This results in injured mitochondria leading to inflammation, tubular injury and impaired tubular cell repair. Inversely, maintaining PCK1 function in different models of kidney injury preserves kidney structure, improves TCA cycle metabolite clearance and increase ATP production. In kidney biopsies from different patient cohorts, we confirm the correlation between PCK1 loss, mitochondrial injury and a failed tubular cell repair phenotype. Furthermore, in CKD, accumulation of TCA cycle metabolites is consistent with disrupted cataplerosis.
    CONCLUSIONS: Overall, we demonstrate that PCK1 loss in kidney tubular cells leads to decreased respiration and the accumulation of TCA cycle metabolites. Maintenance of cataplerosis is an important factor of tubular physiology and repair, with PCK1 serving as a causal and potential therapeutic target in this process. PCK1 restoration enhances mitochondrial health, limiting progression to inflammation and fibrosis.
    Keywords:  Cataplerosis; Kidney disease; Mitochondria; PCK1
    DOI:  https://doi.org/10.1016/j.kint.2025.06.018
  8. Genes Dev. 2025 Jul 14.
    Cancer mortality and senescence: Is redox therapy an option?
    Shan Kuang, Manojit M Swamynathan, Lloyd C Trotman.
      Patient genomics and mouse functional genetics have revealed that senescence is a barrier to metastatic progression of prostate cancer. Many efforts focus on eliminating senescent cells, whereas others aim to elucidate distinct characteristics that set them apart from normal and aging cells. Here, we discuss how exploration of the redox state of senescent cells could help define new markers and pro-oxidant vulnerabilities, drawing analogy to what is known about the redox sensitivity of proliferating cancer cells.
    Keywords:  aging; cancer; senescence
    DOI:  https://doi.org/10.1101/gad.353129.125
  9. Trends Cell Biol. 2025 Jul 10. pii: S0962-8924(25)00146-1. [Epub ahead of print]
    Mitochondrial DNA: how does it leave mitochondria?
    Vladimir Gogvadze, Boris Zhivotovsky.
      In recent years, studies have reported the presence of mitochondrial DNA (mtDNA) in the cytosol. However, a certain number of publications on the mechanisms of mtDNA release contain uncertainties. mtDNA is located in the mitochondrial matrix and cannot be released through the same pathways as intermembrane space proteins. This forum article aims to examine the assumptions and elucidate the processes underlying this phenomenon.
    Keywords:  Bcl-2 family proteins; inner mitochondrial membrane; mitochondria; mtDNA; outer mitochondrial membrane
    DOI:  https://doi.org/10.1016/j.tcb.2025.06.005
  10. bioRxiv. 2025 Jun 20. pii: 2025.06.16.659985. [Epub ahead of print]
    Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
    Joy Omini, Inga Krassovskaya, Taiwo Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.
      The tricarboxylic acid (TCA) cycle enzymes, malate dehydrogenase (MDH1) and citrate synthase (CIT1), form a multienzyme complex called 'metabolon' that channels intermediate, oxaloacetate, between the reaction centers of the enzymes. Since the MDH1-CIT1 metabolon enhances the pathway reactions in vitro, it is postulated to regulate the TCA cycle flux through dynamic assembly in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the pathway flux was enhanced by acetate. Pharmacological TCA cycle inhibitions dissociated the complex, while electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially the buffer pH significantly changed the MDH1-CIT1 affinity within the pH range between 6.0 and 7.0, which is observed in the mitochondrial matrix under physiological conditions. These results show a dynamic association and dissociation of a metabolon in the mitochondria and its relationship with pathway flux, supporting the metabolon's role in metabolic regulation. Multiple factors, including pH and metabolite availabilities, possibly regulate MDH1-CIT1 interaction.
    DOI:  https://doi.org/10.1101/2025.06.16.659985
  11. bioRxiv. 2025 Jun 12. pii: 2025.06.09.658709. [Epub ahead of print]
    Ensemble quantitation of absolute metabolite concentrations in T cells reveals conserved features of immunometabolism.
    Samantha O'Keeffe, Harin Sim, Elle McCue, Junyoung O Park.
      Cells regulate metabolite levels to efficiently utilize metabolic networks and avoid toxic buildup. In turn, metabolites dictate metabolic activity by acting as substrates, products, and effectors. Despite their foundational role in cell physiology, kinetics, and thermodynamics, absolute metabolite concentrations are seldom known. Here we develop an ensemble method for absolute metabolite quantitation and quantify 84 metabolites in T cells. Liquid chromatography-mass spectrometry of metabolites co-extracted from T cells and 13 C-labeled reference cells reveals absolute concentrations en masse . Across subtypes and individuals, T cell metabolomes resemble one another. T cells possess high adenylate energy charge and favorable redox ratios for energy and biomass production without compromising the forward driving force in glycolysis. Across metabolism, metabolite concentrations exceed their associated Michaelis constants and inhibitor constants two thirds and half of the time, respectively. The conserved features of T cell metabolomes underlie a design principle: metabolite levels prime cells for adaptive immune response.
    DOI:  https://doi.org/10.1101/2025.06.09.658709
  12. Res Sq. 2025 Jun 26. pii: rs.3.rs-6346822. [Epub ahead of print]
    MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
    John Elrod, Henry Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Joanne Garbincius, Adyson Johnson, Tyler Stevens, Jordan Howe, Emily Megill, Jennyfer Ngo, Dhanendra Tomar, Nathaniel Snyder, Wolfgang Graier.
      Mitochondrial matrix Ca2+ concentration ([matrixCa2+]) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. This begs the question, what are the primary molecular mechanisms regulating calcium-dependent changes in metabolism? The primary function of MICU proteins (MICU1, MICU2, and MICU3) is reported to be gatekeeping of the mtCU and regulating mitochondrial Ca2+ uptake. Here, we demonstrate that MICU proteins function in coordination to impart Ca2+-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independent of the mtCU and [matrixCa2+]. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Utilizing an equimolar expression platform coupled with unbiased proteomics we reveal unique interactomes for MICU1/2 versus MICU1/3 heterodimers and demonstrate that MICU proteins control coupling of Mitochondrial Glycerol-3-Phosphate Dehydrogenase with Succinate Dehydrogenase/Complex II and impart Ca2+-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological Ca2+ signaling mechanism regulating homeostatic energetics - not mtCU-dependent changes in [matrixCa2+].
    DOI:  https://doi.org/10.21203/rs.3.rs-6346822/v1
  13. Genome Biol. 2025 Jul 17. 26(1): 212
    Direct genetic transformation bypasses tumor-associated DNA methylation alterations.
    Sara Hetzel, Eran Hodis, Elena Torlai Triglia, Alexander Kovacsovics, Kathleen Steinmann, Andreas Gnirke, Meiying Cui, Daniel McQuaid, Raha Weigert, Georg Pohl, Mandar D Muzumdar, Serge Leyvraz, Ulrich Keilholz, Marie-Laure Yaspo, Aviv Regev, Helene Kretzmer, Zachary D Smith, Alexander Meissner.
       BACKGROUND: Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, there are key unresolved questions about the conditions that support a cell's initial transformation, which cannot be easily captured in patient populations and are instead modeled using transgenic cellular or animal systems.
    RESULTS: Here, we use extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and apply this benchmark to evaluate 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation rarely recapitulates the widespread de novo methylation of Polycomb regulated promoter sequences as found in clinical samples, but can trigger global changes in DNA methylation levels that are consistent with extensive proliferation in vitro.
    CONCLUSIONS: Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis as well as provide an important molecular reference for evaluating existing and emerging tumor models.
    Keywords:  Cancer; DNA methylation; Disease models; Epigenetics; Genetically engineered mouse models
    DOI:  https://doi.org/10.1186/s13059-025-03650-2
  14. bioRxiv. 2025 Jun 15. pii: 2025.06.10.658925. [Epub ahead of print]
    Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis.
    Michael C Noji, Christina Demetriadou, Madelyn Landis, Jennifer Pennise, Laura V Pinheiro, Alison Jaccard, Adam Chatoff, Jack Drummond, Kevin Guo, Romie Azor, Maggie R Robertson, Ryo Kawakami, Mariola M Marcinkiewicz, John W Tobias, Nathaniel W Snyder, David Feldser, Zoltan Arany, Kathryn E Wellen.
      Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis is unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC ( p48-Cre ; Kras LSL-G12D/+ ) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation.
    DOI:  https://doi.org/10.1101/2025.06.10.658925
  15. Genes Dev. 2025 Jul 11.
    Mitochondria dysfunction: cause or consequence of physiologic aging?
    G R Scott Budinger, Navdeep S Chandel.
      Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.
    Keywords:  aging; mitochondria; senescence
    DOI:  https://doi.org/10.1101/gad.353106.125
  16. J Exp Med. 2025 Sep 01. pii: e20241426. [Epub ahead of print]222(9):
    Tumor-instructed glutamine synthesis in cancer-associated fibroblasts promotes pro-tumor macrophages.
    Xiaoyun Li, Sofie Hedlund Møller, Jaeoh Park, Yu-Ming Chuang, Pei-Chun Hsueh, Tzu-Hsuan Chang, Kung-Chi Kao, Hector Gallart-Ayala, Yi-Hao Wang, Jhan-Jie Peng, Alessio Bevilacqua, Yi-Ru Yu, Zhiyu Li, Yann Kieffer, Domitille Peigney, Hugo Croizer, Yingxi Xu, Alfred Zippelius, Isabel C Lopez-Mejia, Lluis Fajas, Fatima Mechta-Grigoriou, Julijana Ivanisevic, Zhengtao Xiao, Ming-Chih Ho, Ying-Chun Shen, Ping-Chih Ho.
      In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor progression by creating an immunosuppressive environment through cytokine secretion and antigen presentation. While previous studies have demonstrated that CAFs exhibit distinct metabolic profiles compared with normal fibroblasts, it remains unclear how these metabolic programs influence the immune landscape within tumors and which factors drive metabolic reprogramming in CAFs. Here, we found that glutamine synthesis by CAFs promotes the polarization of pro-tumorigenic tumor-associated macrophages (TAMs) and supports tumor growth by altering TAM composition, highlighting the pivotal role of CAFs in shaping the immunosuppressive TME. Mechanistically, we found that tumor-derived palmitic acid activates a signaling cascade involving TLR4, Syk, and NF-κB in fibroblasts, leading to inflammatory CAF polarization and IL-6-induced glutamine synthesis. These findings uncover a novel metabolic symbiosis whereby tumor cells manipulate TAM polarization through CAF-mediated glutamine metabolism, presenting potential therapeutic targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20241426
  17. Res Sq. 2025 Jul 10. pii: rs.3.rs-6986228. [Epub ahead of print]
    Collagen hydroxylation couples NAD+/NADH dynamics to tumor dormancy and reactivation.
    Jose Javier Bravo-Cordero, Daniela De Martino, Begoña Zapateria, Jaclyn Jaclyn Dunne, Stanislav Drapela, Kailie Matteson, Duncan Oruko, Taylor Humphrey, Tyler Jonhston, Betsy Varghese, Alessandra Riggio, Kanishka Tiwary, Erin Bresnahan, Jonathan Barra, Allison Sowa, William Janssen, Simone Sidoli, Alana L Welm, Margarida Barroso, Wayne Stallaert, Ana Gomes, Peggi M Angel, Esperanza Arias.
      Metastasis remains the leading cause of cancer-related mortality. Disseminated tumor cells (DTCs) colonize distant organs where they enter a prolonged state of quiescence, named cellular dormancy, within collagen-rich extracellular matrix (ECM) niches. How dormant cells regulate the formation of collagen-rich niches and the mechanisms maintaining collagen proteostasis during dormancy and reactivation are not understood. Here, we identify prolyl hydroxylase P4HA2 as a key regulator of tumor dormancy through its dual role in collagen proline hydroxylation and mitochondrial function. We demonstrate that P4HA2-mediated proline hydroxylation of collagens balances the NAD+/NADH ratio, sustaining dormancy by limiting mitochondrial activity. Loss of P4HA2 disrupts collagen proteostasis, induces autophagy, and activates the proline catabolism enzyme ALDH4A1, lowering the NAD+/NADH ratio, which fuels mitochondrial energetics and triggers DTC awakening. Notably, ALDH4A1 is essential for the survival of these reactivated dormant cells, and its depletion induces apoptosis upon awakening, revealing a metabolic vulnerability in reactivated dormant cells. Our findings establish a previously unrecognized link between collagen homeostasis, NADH metabolism and tumor cell dormancy, unveiling a mechanistic framework for identifying actionable targets to eliminate DTCs and prevent metastatic relapse.
    DOI:  https://doi.org/10.21203/rs.3.rs-6986228/v1
  18. bioRxiv. 2025 May 05. pii: 2025.04.30.651453. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function contributes to CD8 + T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo . MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.
    DOI:  https://doi.org/10.1101/2025.04.30.651453
  19. Nat Immunol. 2025 Jul 16.
    Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
    Elizabeth M Steinert, Beatriz Furtado Bruza, Veronika D Danchine, Rogan A Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E Weinberg, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites1. Mitochondrial electron transport is required for T cell proliferation2-4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8+ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8+ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8+ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8+ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.
    DOI:  https://doi.org/10.1038/s41590-025-02202-x
  20. bioRxiv. 2025 Jun 18. pii: 2025.06.17.660237. [Epub ahead of print]
    Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
    Maria G Ayala-Hernandez, Anetzy Bermudez Torales, Hannah Camille Tan, Claire B Montgomery, Abhilash Padavannil, Gino Cortopassi, James A Letts.
      Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III 2 , proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.
    DOI:  https://doi.org/10.1101/2025.06.17.660237
  21. J Clin Invest. 2025 Jul 15. pii: e191940. [Epub ahead of print]135(14):
    What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.
    Colin Sheehan, Alexander Muir.
      The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.
    DOI:  https://doi.org/10.1172/JCI191940
  22. PLoS Biol. 2025 Jul 14. 23(7): e3003284
    Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
    Yajing Qiu, Yihan Xu, Xinyuan Ding, Congcong Zhao, Hongcheng Cheng, Guideng Li.
      Cancer cells and T cells engage in dynamic crosstalk within the tumor microenvironment (TME), shaping tumor progression and anti-tumor immunity. While cancer cells reprogram metabolism to support growth and immune evasion, T cells must adapt their metabolic states to maintain effector functions. Tumor-driven metabolic perturbations, such as nutrient depletion and accumulation of immunosuppressive metabolites, profoundly impair T cell function and fate. Conversely, metabolically reprogrammed T cells can modulate the TME and influence tumor growth. This reciprocal metabolic crosstalk represents both metabolic competition and intercellular communication, offering promising therapeutic targets.
    DOI:  https://doi.org/10.1371/journal.pbio.3003284
  23. Nat Rev Cancer. 2025 Jul 11.
    Cancer progression through the lens of age-induced metabolic reprogramming.
    Felicia Lazure, Ana P Gomes.
      Ageing is an important risk factor for cancer incidence and augments cancer progression. A shared hallmark of ageing and cancer is metabolic reprogramming, which has been suggested to be not only a cause but also a consequence of ageing. Strikingly, many age-regulated pathways are known to also drive tumour progression, suggesting that metabolic reprogramming connects ageing and tumorigenic processes and shapes whether malignant phenotypes manifest, thrive and evolve. With the rising average age of the world population, understanding how age-related changes in the body influence cancer progression is of paramount importance. In this Perspective, we discuss the metabolic changes that occur with ageing and their potential links with tumour initiation and progression and the development of metastatic disease. Finally, we discuss age-induced metabolic divergences that cause racial disparities and their consequences for the tumorigenic process.
    DOI:  https://doi.org/10.1038/s41568-025-00845-4
  24. bioRxiv. 2025 Jul 11. pii: 2025.07.10.663832. [Epub ahead of print]
    Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
    Hoda Ahmed, Mack B Reynolds, Gary Kasof, Gerald S Shadel, Reuben Shaw.
      Mitophagy is a selective autophagic process that eliminates damaged mitochondria via lysosomal degradation, playing a crucial role in maintaining cellular metabolic balance. Mitophagy can occur through two pathways: ubiquitin-dependent and ubiquitin-independent. Recently, we and others have shown that, upon mitochondrial stress, AMP-activated protein kinase (AMPK) contributes to Parkin-mediated, ubiquitin-dependent mitophagy. The ubiquitin-independent pathway involves multiple outer mitochondrial membrane (OMM) "mitophagy receptors" that contain LC3-interacting region (LIR) motifs, including BNIP3, NIX/ BNIP3L, FUNDC1, and BCL2L13. LIR motifs bind Atg8/LC3 family proteins, facilitating the recruitment of the autophagosome membrane to target damaged mitochondria for degradation. The kinase Unc-51 Like autophagy activating kinase 1 (ULK1) phosphorylates the serine preceding the LIR motif in BNIP3, NIX, and FUNDC1, enhancing their binding to LC3 and promoting mitophagy. However, while BCL2L13 has been identified as a ULK1 binding partner, its regulation by phosphorylation remains unclear. We utilized mass spectrometry (MS) to map phosphorylation sites in BCL2L13 following mitochondrial stress and developed phospho-specific antibodies against two sites, Ser261 and Ser275, which were induced after exposure to the mitochondrial uncoupler, CCCP. Endogenous BCL2L13 Ser261 and Ser275 were both phosphorylated in an AMPK-dependent manner in cells and tissues. As neither site matches the established AMPK substrate consensus motif, we sought to identify which kinases directly mediate their phosphorylation downstream of AMPK. Surprisingly, genetic studies revealed that ULK1 is not regulating either site, but instead, TBK1 is controlling Ser275. This work reveals that BCL2L13 is unique amongst mitophagy receptors in being activated by mitochondrial stress and innate immune stimuli in an AMPK- and TBK1-dependent manner.
    DOI:  https://doi.org/10.1101/2025.07.10.663832
  25. Mol Metab. 2025 Jul 15. pii: S2212-8778(25)00115-2. [Epub ahead of print] 102208
    The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.
    Joanna Krawczyk, William O'Connor, Pedro Vendramini, Mareike Schell, Kiran J Biddinger, Matt Kanke, George Pengo, Ivana Semova, Tiffany Fougeray, Marcia Haigis, Krishna G Aragam, Wouter H Lamers, Linus T Tsai, Praveen Sethupathy, Sudha B Biddinger.
      TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find that liver-specific deletion Tcf7l2 has little effect on plasma glucose, but disrupts hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2, these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in the plasma of individuals harboring the rs7903146 variant in TCF7L2. Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.
    Keywords:  Zonation; diabetes; metabolism; transcription
    DOI:  https://doi.org/10.1016/j.molmet.2025.102208
  26. Cell Rep. 2025 Jul 04. pii: S2211-1247(25)00710-7. [Epub ahead of print] 115939
    SLC7A11 protects amoeboid-disseminating cancer cells from oxidative stress.
    Vittoria Graziani, Jaume Barcelo, Aurelien Tripp, Dipanwita Das, Oscar Maiques, Joshua Alexander James Martin, Joanne Sewell, Andrea Vinaga, Manon Liautard, Rosa M Marti, Xavier Matias-Guiu, George Poulogiannis, Eva Crosas-Molist, Victoria Sanz-Moreno.
      Oxidative stress limits metastasis, and amoeboid cancer cells have been identified in a variety of cancers as a subset of metastatic cancer cells characterized by high Rho-ROCK-driven Myosin II activity. They display fast individual migration and have increased survival abilities during metastasis. Amoeboid migrating cells require lower mitochondrial metabolism, but how they maintain low oxidative stress remains unclear. Using a combination of cancer cell lines in complex matrices, mouse xenografts, patient databases, and tissue microarrays, we show that SLC7A11 is highly expressed in amoeboid cancer cells, at the invasive front of primary tumors, and in metastatic lesions. We find that high SLC7A11 expression supports cancer cell survival and 3D invasion by promoting Myosin II activity while protecting cancer cells against oxidative stress. Targeting SLC7A11 effectively impairs amoeboid behavior, highlighting its potential as a therapeutic vulnerability in metastatic melanomas.
    Keywords:  CP: Cancer; CP: Metabolism; ROCK-myosin II; SLC7A11; ameboid cancer cells; cytoskeleton; glutathione; invasion and metastasis; oxidative stress
    DOI:  https://doi.org/10.1016/j.celrep.2025.115939
  27. bioRxiv. 2025 Jun 12. pii: 2025.06.10.656791. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masillioni, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The transition from benign to malignant growth is a pivotal yet poorly understood step in cancer progression that marks the shift from a pathologically inert condition to a clinically lethal disease. Here, we integrate lineage tracing, single-cell and spatial transcriptomics to visualize the molecular, cellular and tissue-level events that promote or restrain malignancy during the tumor initiation in mouse models of pancreatic ductal adenocarcinoma (PDAC). We identify a discrete progenitor-like population of KRAS -mutant cells that co-activates oncogenic and tumor-suppressive programs-including p53, CDKN2A, and SMAD4-engaging senescence-like responses and remodeling their microenvironment, ultimately assembling a niche that mirrors invasive PDAC. KRAS inhibition depletes progenitor-like cells and dismantles their niche. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state as the convergence point of cancer-driving mutations, plasticity, and tissue remodeling-revealing a critical window for intercepting malignancy at its origin.
    DOI:  https://doi.org/10.1101/2025.06.10.656791
  28. Diabetes. 2025 Jul 18. pii: db241162. [Epub ahead of print]
    Bidirectional Mendelian Randomization Indicates Causal Relationships Between Circulating Branched-Chain Amino Acids and Metabolic Health.
    Raina Y Jia, Jian-Hua Chen, Sam Lockhart, Brian Y H Lam, Katherine A Kentistou, Yajie Zhao, Eugene J Gardner, John R B Perry, Stephen O'Rahilly, Felix R Day, Ken K Ong.
       ARTICLE HIGHLIGHTS: We undertook this study to estimate the causal role of circulating branched-chain amino acids (BCAAs) in metabolic health using genetics. Are circulating BCAAs a cause or consequence of metabolic health? We found that a higher circulating level of BCAAs likely reflects poorer metabolic health. There is a potential bidirectional causal link between BCAAs and dyslipidemia that warrants further tissue-specific functional studies. Our findings suggest that BCAAs may causally affect lipid metabolism, with adipocytes as a key site. Understanding tissue-specific pathways of BCAA-induced lipid dysregulation could guide BCAAs' potential as a clinical intervention target.
    DOI:  https://doi.org/10.2337/db24-1162
  29. bioRxiv. 2025 May 10. pii: 2025.05.08.652966. [Epub ahead of print]
    The Aging Microenvironment as a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
    Priyanka Gupta, Rabi Murad, Lily Ling, Yijuan Zhang, Karen Duong-Polk, Swetha Maganti, Cheska Galapate, Cosimo Commisso.
      Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrate that organismal aging accelerates PDAC progression and metastasis. Through transcriptomic profiling, we identify a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. To directly test the functional impact of stromal aging, we employed heterochronic co-implantation models, revealing that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, fail to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, our work establishes a new conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, this work raises compelling questions about the underlying molecular mechanisms-questions now accessible through our models-and lays the foundation for future efforts to therapeutically target stromal aging in PDAC.
    Statement of Significance: Our study links aging, stromal remodeling, and PDAC aggressiveness, highlighting how age-dependent stromal changes drive progression and suggesting that rejuvenating the aged microenvironment may improve outcomes in older patients.
    DOI:  https://doi.org/10.1101/2025.05.08.652966
  30. bioRxiv. 2025 Jun 26. pii: 2025.06.24.661357. [Epub ahead of print]
    Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans.
    Miriam Valera-Alberni, Anne Lanjuin, Silvia Romero-Sanz, Kristopher Burkewitz, Adam L Hughes, William B Mair.
      Mitochondrial morphology is dynamically regulated through remodeling processes essential for maintaining mitochondrial function and ensuring cellular and metabolic homeostasis. While classical models of mitochondrial dynamics center on cycles of fragmentation and elongation, emerging evidence highlights additional membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and mitochondrial-derived compartments (MDCs). These mitochondrial-derived structures, however, have been predominantly characterized in cultured cells and unicellular organisms, leaving their relevance in multicellular systems largely unexplored. Here, we identify a previously uncharacterized class of mitochondrial-derived structures in Caenorhabditis elegans muscle cells that are induced in response to intermittent fasting. We show that these structures appear specifically during the refeeding phase- coinciding with mitochondrial elongation -and are absent during fasting. Consistent with MDCs, the structures, approximately 1 µm in size, are enriched in outer mitochondrial membrane markers such as TOMM-20 aa1-49 and TOMM-70, but notably lack components of the inner mitochondrial membrane. Their formation requires the microtubule-associated MIRO-1/2 proteins, and their size is modulated by the mitochondrial dynamics machinery. Together, our findings reveal a nutritionally regulated mitochondrial remodeling event in C. elegans muscle that may play a role in mitochondrial quality control and adaptation to metabolic cues.
    DOI:  https://doi.org/10.1101/2025.06.24.661357
  31. Nature. 2025 Jul 16.
    Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
    Andrew McPherson, Ignacio Vázquez-García, Matthew A Myers, Duaa H Al-Rawi, Matthew Zatzman, Adam C Weiner, Samuel Freeman, Neeman Mohibullah, Gryte Satas, Marc J Williams, Nicholas Ceglia, Danguolė Norkūnaitė, Allen W Zhang, Jun Li, Jamie L P Lim, Michelle Wu, Seongmin Choi, Eliyahu Havasov, Diljot Grewal, Hongyu Shi, Minsoo Kim, Roland F Schwarz, Tom Kaufmann, Khanh Ngoc Dinh, Florian Uhlitz, Julie Tran, Yushi Wu, Ruchi Patel, Satish Ramakrishnan, DooA Kim, Justin Clarke, Hunter Green, Emily Ali, Melody DiBona, Nancy Varice, Ritika Kundra, Vance Broach, Ginger J Gardner, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Sarah H Kim, Rachel N Grisham, Ying L Liu, Agnes Viale, Nicole Rusk, Yulia Lakhman, Lora H Ellenson, Simon Tavaré, Samuel Aparicio, Dennis S Chi, Carol Aghajanian, Nadeem R Abu-Rustum, Claire F Friedman, Dmitriy Zamarin, Britta Weigelt, Samuel F Bakhoum, Sohrab P Shah.
      Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1-6. Here we examine the impact of WGD on somatic evolution and immune evasion at single-cell resolution in patient tumours. Using single-cell whole-genome sequencing, we analysed 70 high-grade serous ovarian cancer samples from 41 patients (30,260 tumour genomes) and observed near-ubiquitous evidence that WGD is an ongoing mutational process. WGD was associated with increased cell-cell diversity and higher rates of chromosomal missegregation and consequent micronucleation. We developed a mutation-based WGD timing method called doubleTime to delineate specific modes by which WGD can drive tumour evolution, including early fixation followed by considerable diversification, multiple parallel WGD events on a pre-existing background of copy-number diversity, and evolutionarily late WGD in small clones and individual cells. Furthermore, using matched single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signalling and cGAS-STING pathway activation result from ongoing chromosomal instability, but this is restricted to predominantly diploid tumours (WGD-low). By contrast, predominantly WGD tumours (WGD-high), despite increased missegregation, exhibited cell-cycle dysregulation, STING1 repression, and immunosuppressive phenotypic states. Together, these findings establish WGD as an ongoing mutational process that promotes evolvability and dysregulated immunity in high-grade serous ovarian cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09240-3
  32. bioRxiv. 2025 Jun 29. pii: 2025.06.26.661633. [Epub ahead of print]
    Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.
    Stefan Bjelosevic, Rahel Fauth, Brian T Do, Gabriela Alexe, Lucy A Merickel, Thomas D Jackson, Allen T Basanthakumar, Audrey Taillon, Silvi Salhotra, Birgitta Ryback, Constanze Schneider, Giulia DiGiovanni, Ryan Elbashir, Nils Burger, Muhammad Bin Munim, Shan Lin, Pere Puigserver, David E Root, Matthew G Vander Heiden, Kimberly Stegmaier.
      Riboflavin is a diet-derived vitamin in higher organisms that serves as a precursor for flavin mononucleotide and flavin adenine dinucleotide, key cofactors that participate in oxidoreductase reactions. Here, using proteomic, metabolomic and functional genomics approaches, we describe a specific riboflavin dependency in acute myeloid leukemia and demonstrate that, in addition to energy production via oxidative phosphorylation, a key biological role of riboflavin is to enable nucleotide biosynthesis and iron-sulfur cluster metabolism. Genetic perturbation of riboflavin metabolism pathways or exogenous depletion in physiological culture medium induce nucleotide imbalance and DNA damage responses, as well as impair the stability and activity of proteins which utilize [4Fe-4S] iron-sulfur clusters as cofactors. We identify a window of therapeutic opportunity upon riboflavin starvation or chemical riboflavin metabolism perturbation and demonstrate that this strongly synergizes with BCL-2 inhibition. Our work identifies riboflavin as a critical metabolic dependency in leukemia, with functions beyond energy production.
    DOI:  https://doi.org/10.1101/2025.06.26.661633
  33. Nat Rev Cancer. 2025 Jul 14.
    Tumour tissue: heterogeneous, but not disordered.
    Barbara T Grünwald, Rama Khokha.
      
    DOI:  https://doi.org/10.1038/s41568-025-00852-5
  34. Genes Dev. 2025 Jul 11.
    The interplay between senescence, inflammation, and the immune system.
    Jesús Gil.
      The past 40 years have witnessed significant progress in aging research. Although aging was once considered a stochastic process, it is now understood to be regulated by pathways and processes that can be dissected with modern cellular and molecular biology approaches. The aberrant accumulation of cells undergoing cellular senescence and an increase in chronic, sterile inflammation are two of those aging hallmarks. Here we discuss how these processes are connected and how the relationship between senescent cells and the immune system dictates the extent of inflammatory processes contributing to age-related dysfunction and disease.
    Keywords:  aging; inflammation; senescence
    DOI:  https://doi.org/10.1101/gad.353125.125
  35. bioRxiv. 2025 Jun 14. pii: 2025.06.10.658841. [Epub ahead of print]
    Accumulation of SA-βGal-High Cells in Human Naïve T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State.
    Andreea Cristina Alexandru, Genesis Vega Hormazabal, Hiroyuki Matsui, Herbert Kasler, Sierra Lore, Carlos Galicia Aguirre, Andrea Roberts, Indra John Heckenbach, Ritesh Tiwari, Ryan Kwok, Sydney Becker, Eric Verdin.
      Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated β-galactosidase (SA-βGal) activity is a well-established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naïve CD4⁺ and CD8⁺ T cells displaying high SA-βGal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-βGal-high naïve T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naïve CD4⁺ SA-βGal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naïve T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.
    DOI:  https://doi.org/10.1101/2025.06.10.658841
  36. Cell Rep. 2025 Jul 11. pii: S2211-1247(25)00744-2. [Epub ahead of print]44(7): 115973
    CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
    Molly S Cook, Ellen King, Katie R Flaherty, Khadiza Siddika, Sophie Papa, Reuben Benjamin, Anna Schurich.
      Chimeric antigen receptor (CAR)-T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signaling pathways. Previous work has highlighted the importance of T cell metabolism in fueling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signaling endows T cells with preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite the differences in metabolic programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator. In contrast, in non-responders, CD28- and 4-1BB-co-stimulated CAR-T cells were metabolically distinct from each other.
    Keywords:  4-1BB; CAR-T cells; CD28; CP: Cancer; CP: Metabolism; DLBCL; co-stimulation; glycolysis; lymphoma; metabolism; mitochondria; translational
    DOI:  https://doi.org/10.1016/j.celrep.2025.115973
  37. bioRxiv. 2025 May 07. pii: 2025.05.07.652626. [Epub ahead of print]
    Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
    Jong Shin, Yann Cormerais, Khaled Tighanimine, Pratima Niroula, Madi Y Cisse, Samuel C Lapp, Krystle C Kalafut, Sandra Schrötter, Brendan D Manning.
      The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), as a sensor of growth signals that subsequently controls cell growth, has been predominantly studied in actively proliferating cells. Primary cilia are sensory organelles present on most quiescent cells, where they play essential roles in receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences the growth of primary cilia. Here, we show that mTORC1 promotes primary cilia elongation, without effects on ciliogenesis or cell growth, by suppressing autophagy. Inhibition of mTORC1 signaling through pharmacological, nutritional, or genetic interventions gave rise to shortened primary cilia, while activation of the pathway resulted in elongation. Furthermore, pharmacological or genetic inhibition of autophagy, a key downstream process blocked by mTORC1, also elongated primary cilia and rendered them resistant to mTORC1 inhibition. Notably, these mTORC1-mediated effects on primary cilia extend to mouse neurons ex vivo and in vivo. These findings highlight a previously unrecognized role for mTORC1 signaling in the control of primary cilia length that may contribute to diseases where ciliary function is altered, referred to as ciliopathies.
    DOI:  https://doi.org/10.1101/2025.05.07.652626
  38. Curr Opin Cell Biol. 2025 Jul 14. pii: S0955-0674(25)00105-X. [Epub ahead of print]96 102567
    Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer.
    Fernanda G Kugeratski, Emily J Kay, Sara Zanivan.
      Cancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest in the field of anticancer therapy: immunotherapy, metabolism, and extracellular vesicles. We also highlight the substantial role of CAFs in modulating the immune microenvironment and the recent advances in targeting CAFs for cancer treatment.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102567
  39. Curr Opin Genet Dev. 2025 Jul 16. pii: S0959-437X(25)00073-5. [Epub ahead of print]94 102381
    Why and how paternal mitochondrial DNA gets cut out of the inheritance.
    Mayu Shimomura, Thomas R Hurd.
      Mitochondrial DNA (mtDNA) is inherited maternally across animals, yet the evolutionary rationale behind this unusual mode of inheritance remains a longstanding mystery. Understanding the processes that prevent the transmission of paternal mtDNA and thus ensure maternal-only inheritance is crucial to uncovering the evolutionary significance of this widespread phenomenon. Historically, research has focused on mechanisms that act within eggs to destroy sperm mitochondria via autophagy and the ubiquitin-proteasome degradation system. However, recent discoveries across multiple animal species, including humans, reveal a surprising twist: paternal mtDNA is actively degraded within mitochondria independently of and prior to the complete breakdown of the organelle itself, often even prior to fertilization. Only a few studies have begun to illuminate the molecular machinery responsible for this early mtDNA elimination. In this review, we explore the emerging landscape of paternal mtDNA elimination mechanisms across species, highlighting newly discovered pathways, evolutionary implications, and open questions that are furthering our understanding of mitochondrial inheritance.
    DOI:  https://doi.org/10.1016/j.gde.2025.102381
  40. J Mol Cell Biol. 2025 Jul 17. pii: mjaf018. [Epub ahead of print]
    cGAS: Bridging Immunity and Metabolic Regulation.
    Jing Wang, Wen Meng.
      Recent advances have revealed that cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS), classically recognized as a cytosolic DNA sensor, plays crucial roles beyond innate immunity. Particularly in the adipose tissue, cGAS functions as a metabolic sentinel, responding to mitochondrial stress and contributing to inflammation, insulin resistance, and energy imbalance. These effects occur through both stimulator of interferon genes (STING)-dependent and STING-independent pathways, involving autophagy, chromatin remodeling, and transcriptional reprogramming. Here, we propose a paradigm shift positioning cGAS at the intersection of immunity and metabolism. We explore its multifaceted roles in adipocytes and other metabolic tissues, highlighting emerging therapeutic opportunities and future research directions.
    DOI:  https://doi.org/10.1093/jmcb/mjaf018
  41. bioRxiv. 2025 May 03. pii: 2025.05.02.651978. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Caitlin Su, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive, and how an invading cell produces high ATP levels to power invasion is understudied. By generating 20 endogenously tagged mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP to fuel invasion. These ETC-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through a Src kinase directs microtubule polarization, which facilitates metaxin adaptor complex dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP by generating and localizing high-capacity mitochondria. This might be common strategy used by other cells to meet energy demanding processes.
    DOI:  https://doi.org/10.1101/2025.05.02.651978
  42. Science. 2025 Jul 17. eadr8628
    Recent evolution of the developing human intestine affects metabolic and barrier functions.
    Qianhui Yu, Umut Kilik, Stefano Secchia, Lukas Adam, Yu-Hwai Tsai, Christiana Fauci, Jasper Janssens, Charlie J Childs, Katherine D Walton, Rubén López-Sandoval, Angeline Wu, Marina Almató Bellavista, Sha Huang, Calen A Steiner, Yannick Throm, Michael James Boyle, Zhisong He, Joep Beumer, Barbara Treutlein, Craig B Lowe, Jason R Spence, J Gray Camp.
      Diet, microbiota, and other exposures place the intestinal epithelium as a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a uniquely human environment. Here, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid/xenobiotic metabolism, and that human-specific genetic features impact these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily significant enhancers of Lactase (LCT) and Insulin-like Growth Factor Binding Protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system, and show that great ape organoids provide insight into human biology.
    DOI:  https://doi.org/10.1126/science.adr8628
  43. Sci Adv. 2025 Jul 18. 11(29): eadw5228
    Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors.
    William Yang, Qianyu Guo, Songhua Quan, Zachary R Chalmers, J Brandon Parker, Mihai Truica, Mary F Dufficy, Megan M Kerber, Karthik Vasan, Dikshat G Gupta, Adam W T Steffeck, Hao Pan, Mohammed Siddiqui, H Tran Pham, Gary E Schiltz, Debabrata Chakravarti, Navdeep S Chandel, Sarki A Abdulkadir.
      MYC is a key driver in many aggressive and therapy-resistant cancers. We have developed and characterized a small-molecule MYC inhibitor named MYCi975. To uncover combination strategies for MYC inhibitors, we conducted a genome-wide CRISPR screen using MYCi975. This screen revealed a notable synthetic lethality when MYC inhibition was paired with disruption of mitochondrial complex I components, but not other complexes. Mechanistically, MYC inhibition reduced oxidative phosphorylation and glycolysis, triggering a compensatory up-regulation of complex I genes. Consequently, genetic or pharmacological targeting of complex I sensitized tumors to MYCi975 treatment, leading to increased purine catabolism and infiltration of CD8+ T cells and macrophages into tumors. Additionally, a wide range of tumor cells with lower complex I expression showed increased MYC dependency. These results indicate that metabolic adaptation to MYC inhibition exposes a targetable weakness at complex I and provide a rational strategy for combination therapy with emerging MYC inhibitors.
    DOI:  https://doi.org/10.1126/sciadv.adw5228
  44. EMBO J. 2025 Jul 16.
    The proteostatic landscape of healthy human oocytes.
    Gabriele Zaffagnini, Miquel Solé, Juan Manuel Duran, Nikolaos P Polyzos, Elvan Böke.
      Oocytes, female germ cells that develop into eggs, are among the longest-lived cells in the animal body. Recent studies on mouse oocytes highlight unique adaptations in protein homeostasis (proteostasis) within these cells. However, the mechanisms of proteostasis in human oocytes remain virtually unstudied. We present the first large-scale study of proteostatic activity in human oocytes using over 100 freshly donated oocytes from 21 healthy women aged 19-34 years. We analysed the activity and distribution of lysosomes, proteasomes, and mitochondria in both immature and mature oocytes. Notably, human oocytes exhibit nearly twofold lower proteolytic activity than surrounding somatic cells, with further decreases as oocytes mature. Oocyte maturation is also coupled with lysosomal exocytosis and a decrease in mitochondrial membrane potential. We propose that reduced organelle activity preserves key cellular components critical for early embryonic development during the prolonged maturation of human oocytes. Our findings highlight the distinctive biology of human oocytes and the need to investigate human-specific reproductive biology to address challenges in female fertility.
    Keywords:  Female Fertility; Human Oocytes; Lysosomes; Mitochondria; Proteostasis
    DOI:  https://doi.org/10.1038/s44318-025-00493-2
  45. Genes Dev. 2025 Jul 15.
    Killing wisely: precision senolytics in the age of frailty.
    Valentin J A Barthet, Scott W Lowe.
      Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.
    Keywords:  aging; senescence; senolytics
    DOI:  https://doi.org/10.1101/gad.353134.125
  46. bioRxiv. 2025 Jul 08. pii: 2025.07.04.663229. [Epub ahead of print]
    Inhibition of formate production blocks CD8 + T-cell responses and delays disease onset in a mouse model of type 1 diabetes.
    Gabriela Ramirez-Hernandez, Micah Bell, Byungsoo Kong, Samuel Block, Matthew G Vander Heiden, Nora Kory.
      The one-carbon metabolic pathway is essential for proliferating cells and has recently been identified as an immunomodulatory target in CD4⁺ T cells. However, its role in other immune cell types has not been fully established. We investigated the function of the one-carbon pathway in CD8⁺ T cells, which are the primary effectors responsible for the destruction of pancreatic beta cells that causes type 1 diabetes. Enzymes involved in the one-carbon pathway, as well as levels of formate-a critical intermediate-were upregulated during CD8⁺ T-cell activation. Pharmacological inhibition of MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, suppressed CD8⁺ T-cell activation, proliferation, and effector function. Mechanistically, this effect was mediated by reduced signaling through KRAS and the mTORC1 downstream targets HIF1α, S6, and STAT3. As previously shown in CD4⁺ T cells, formate supplementation reversed the effects of MTHFD2 inhibition on activation, proliferation, and function of CD8 + T cells, and prevented the reduction of the TCF1 high CD8⁺ progenitor cell population, which has been shown to drive anti-beta cell autoimmunity. Formate levels were elevated in the immune cells isolated from pancreatic lymph nodes during the insulitis stage in non-obese diabetic mice. Treatment of euglycemic non-obese diabetic mice with an MTHFD2 inhibitor during the insulitis stage delayed CD8⁺ T-cell infiltration into pancreatic islets and postponed the onset of type 1 diabetes. These findings reveal a new paradigm for preventing and delaying the onset of type 1 diabetes.
    DOI:  https://doi.org/10.1101/2025.07.04.663229
  47. bioRxiv. 2025 May 01. pii: 2025.04.28.651077. [Epub ahead of print]
    Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
    Yan-Ting Chen, Ya-Hui Lin, Jahan Rahman, Justin Cross, Natalya N Pavlova, Santosha A Vardhana.
      Loss of effector function is a hallmark of tumor-infiltrating CD8 + T-cells that have lost therapeutic efficacy. This impaired capacity occurs despite expression of transcripts encoding cytotoxic proteins, raising the possibility that post-transcriptional suppression of cytotoxic protein synthesis limits anti-tumor immunity. Whether altered protein synthesis contributes to CD8 + T-cell dysfunction has not been explored. Here we show that intratumoral amino acid availability restricts the cytotoxic capacity of CD8 + TILs by perturbing their ability to sustain protein synthesis. mRNA translation rates in antigen-specific CD8 + T-cells were rapidly and specifically suppressed within tumors but not tumor-draining lymph nodes, due to a combination of increased amino acid demand and reduced amino acid availability. Mechanistically, amino acid-dependent uncharging of tRNA Gln in T-cells persistently exposed to antigen was sufficient to suppress protein synthesis in a manner that is independent of either activation of the integrated stress response or suppression of mTORC1 activation. Finally, suppressing intracellular glutaminase activity or ectopically overexpressing the amino acid transporter SLC6A15 was sufficient to restore CD8 + T-cell effector function. These results establish a novel mechanism by which nutrient availability in the tumor microenvironment limits T-cell function and demonstrate how enhancing T cell-specific amino acid availability can sustain T-cell effector function and potentiate anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2025.04.28.651077
  48. Mitochondrial Commun. 2025 ;3 26-43
    Exploring the oncogenic impact of heteroplasmic de novo MT-ND5 truncating mutations.
    Yuanyuan Wu, Jiangbin Ye, Zhenglong Gu.
      Numerous mitochondrial DNA (mtDNA) variants are associated with cancers, yet the causal link remains inconclusive. Using DddA-derived cytosine base editors, we induced de novo truncating mutations in MT-ND5 in HEK293 cells, establishing heteroplasmy, the coexistence of mutant and wild-type mtDNA. This study aimed to investigate the full molecular etiology following these deleterious mtDNA mutations, particularly in oncogenesis. We found that low to moderate heteroplasmic levels of the mutants were sufficient to impair mitochondrial functions and alter cellular redox status. Cellular adaptation to elevated ROS (Reactive Oxygen Species), energy crisis, and altered redox status was observed across varying heteroplasmy levels. Increased oncogenic potential was confirmed through in vitro oncogenesis and in vivo xenograft assays. Transcriptomic analysis revealed upregulated migration, invasion, and genome instability pathways, and downregulated ROS scavenging pathways. Our results demonstrate that MT-ND5 mutations drive cancer progression by increasing cellular ROS and genome instability, and by altering the redox balance and epigenetic landscapes.
    Keywords:  MT-ND5 variants; Mitochondrial dysfunction; Oncogenesis; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1016/j.mitoco.2025.03.001
  49. bioRxiv. 2025 May 09. pii: 2025.05.05.652276. [Epub ahead of print]
    A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic Control.
    Stephen T Decker, Precious C Opurum, Ran Hee Choi, Venisia L Paula, Anu S Kurian, Deborah Stuart, Linda S Nikolova, Alejandro Sanchez, Laith Al-Rabadi, Nirupama Ramkumar, Kelsey H Fisher-Wellman, Katsuhiko Funai.
      Mitochondrial function varies widely across kidney nephron segments, yet conventional approaches lack the resolution and control needed to assess cell-type-specific bioenergetics in situ. We present a methodological platform that enables segment-resolved profiling of mitochondrial respiration, conductance, and membrane potential in freshly isolated mouse nephron segments. Combining mechanical sieving and adhesion-based enrichment with permeabilized high-resolution respirometry, we adapted the creatine kinase clamp to quantify oxygen flux and mitochondrial membrane potential across defined free energies. Using this approach, we found that proximal tubules exhibit high respiratory conductance and dynamic mitochondrial polarization, while distal tubules and glomeruli maintain static membrane potential and low conductance. In a model of adenine-induced nephropathy, only proximal tubule mitochondria showed marked reductions in respiration and ATP production. This segment-specific dysfunction was not detectable in bulk mitochondrial isolates. Our approach provides thermodynamically anchored, segment-resolved insight into mitochondrial adaptation under physiological and pathological conditions. It is broadly applicable to other tissues with metabolic heterogeneity and compatible with disease models, genetic tools, and pharmacological interventions. This platform bridges a critical gap between conventional respirometry and functional mitochondrial phenotyping in native tissue structures.
    DOI:  https://doi.org/10.1101/2025.05.05.652276
  50. Nature. 2025 Jul 16.
    Mitochondrial origins of the pressure to sleep.
    Raffaele Sarnataro, Cecilia D Velasco, Nicholas Monaco, Anissa Kempf, Gero Miesenböck.
      To gain a comprehensive, unbiased perspective on molecular changes in the brain that may underlie the need for sleep, we have characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies. Here we report that transcripts upregulated after sleep deprivation, in sleep-control neurons projecting to the dorsal fan-shaped body1,2 (dFBNs) but not ubiquitously in the brain, encode almost exclusively proteins with roles in mitochondrial respiration and ATP synthesis. These gene expression changes are accompanied by mitochondrial fragmentation, enhanced mitophagy and an increase in the number of contacts between mitochondria and the endoplasmic reticulum, creating conduits3,4 for the replenishment of peroxidized lipids5. The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow6,7 in the respiratory chain. Inducing or preventing mitochondrial fission or fusion8-13 in dFBNs alters sleep and the electrical properties of sleep-control cells in opposite directions: hyperfused mitochondria increase, whereas fragmented mitochondria decrease, neuronal excitability and sleep. ATP concentrations in dFBNs rise after enforced waking because of diminished ATP consumption during the arousal-mediated inhibition of these neurons14, which augments their mitochondrial electron leak7. Consistent with this view, uncoupling electron flux from ATP synthesis15 relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump16) precipitates sleep. Sleep, like ageing17,18, may be an inescapable consequence of aerobic metabolism.
    DOI:  https://doi.org/10.1038/s41586-025-09261-y
  51. bioRxiv. 2025 Jun 08. pii: 2025.06.06.657909. [Epub ahead of print]
    JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux.
    Layla M Nassar, Xiaojian Shi, Agnes Roczniak-Ferguson, Hongying Shen, Shawn M Ferguson.
      Lysosomes break down macromolecules, clear cellular waste and recycle nutrients such as cystine. We describe a novel mechanism whereby JIP4 regulates lysosomal cystine storage by controlling the abundance of cystinosin (CTNS), the transporter responsible for lysosomal cystine efflux. To this end, JIP4, previously characterized as a motor adaptor and kinase signaling scaffold, suppresses TMEM55B-dependent ubiquitylation of CTNS. Loss of JIP4 reduces CTNS protein levels, leading to lysosomal cystine accumulation and lysosomal storage defects that phenocopy loss of CTNS in both human cells and the renal proximal tubules of JIP4 knockout mice. These phenotypes mirror cystinosis, the lysosomal storage disease caused by CTNS loss-of-function. Our findings thus reveal a fundamental process that controls the efflux of lysosomal cystine and has relevance to understanding human disease arising from JIP4 mutations.
    DOI:  https://doi.org/10.1101/2025.06.06.657909
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