bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–05–10
fifty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
  2. Succinate calls a time-out on pyrimidine biosynthesis.
  3. Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
  4. Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
  5. Emerging roles and regulatory mechanisms involved in glutamine metabolism.
  6. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
  7. Fasting opens a metabolic window that favors anti-tumor immunity.
  8. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  9. pH-mediated activation of the lysosomal arginine sensor SLC38A9.
  10. Whole-genome doubling drives immune evasion by silencing antigen presentation.
  11. Bioengineered systems to exploit tumor microenvironment metabolism.
  12. Lysosomes contribute to the synthesis of tricarboxylic acid-related metabolites in the hippocampus.
  13. Lactylation landscape of mitochondrial proteins in myocardial infarction.
  14. Paired CRISPR screens identify mitochondrial metabolism and UBE2H as aneuploid-specific dependencies in human cancer cell lines.
  15. Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
  16. Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
  17. Peroxisome-derived ether lipids regulate lysosomal exocytosis.
  18. Tumors hijack immune-privileging regulons via distinct cell types to confer T cell desertion and immunotherapy resistance across various cancers.
  19. Age distinguishes selection from causation in cancer genomes.
  20. Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
  21. Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
  22. Mitochondrial mechanics nucleates axonal jamming and swelling.
  23. Expanding the human proteome with microproteins and peptideins.
  24. Cigarette smoke induces FASN-dependent fatty acid metabolic rewiring to drive bladder cancer progression.
  25. Selective Editing and Functionalization of the Mammalian Lipidome.
  26. PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer.
  27. FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
  28. How membranes shape up for lipid transfer.
  29. Global mitochondrial connectivity map reveals the landscape of yeast functional assemblies and conserved protein communities.
  30. Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction.
  31. Loss of Proximal Tubule Lactate Dehydrogenase A (LDHA) Exacerbates Nephrotoxic Acute Kidney Injury Through Metabolic Dysregulation.
  32. MOSAIC: a longitudinal phenotypic clock to dissect organismal aging trajectories in C. elegans.
  33. Membrane insertion of mitochondrial-encoded proteins regulates ribosome decoding speed.
  34. TFAM organizes DNA into compact higher order structures.
  35. Circadian biology and exercise: the time to move.
  36. MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.
  37. A redox-sensitive phosphatase regulates glycolysis as a metabolic switch in the bacterial inner membrane.
  38. The evolution of polyclonal competition in aging hematopoiesis.
  39. Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.
  40. SLX4IP limits replication stress globally and at ALT telomeres.
  41. Cytosolic DNA inhibits rDNA transcription by retaining the RNA polymerase I transcription machinery.
  42. Paternal folate deficiency reveals meiosis as a metabolic sensing window in the male germline.
  43. Disrupted molecular glue complex drives RAS inhibitor resistance.
  44. TranscriptFormer: A generative cell atlas across 1.5 billion years of evolution.
  45. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  46. Non-invasive profiling of the tumour microenvironment with spatial ecotypes.
  47. The role of glycolysis in inflammation.
  48. Tissue-specific tolerance mechanisms and lymph node co-drainage shape T cell immunity in the upper digestive system and pancreatic cancer progression.
  49. Non-enzymatic coupling of protometabolic reactions with a prebiotic redox cofactor.
  50. A screening pipeline to characterize stress-induced enzymes uncovers a cellular function for the poorly characterized alcohol dehydrogenase Bdh2.
  51. Calibrating T cell responsiveness through interactions with self.
  52. Ketone ester supplementation in aged mice reduces activation of B cell subsets.
  53. Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.
  54. Vascular Aging.
  55. Spatial metabolomics: design, pitfalls and data interpretation.
  56. Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
  1. Nat Metab. 2026 May 04.
    Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
    Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.
      Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    DOI:  https://doi.org/10.1038/s42255-026-01524-w
  2. Nat Metab. 2026 May 04.
    Succinate calls a time-out on pyrimidine biosynthesis.
    Désirée Schatton, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s42255-026-01523-x
  3. Elife. 2026 May 05. pii: RP106587. [Epub ahead of print]14
    Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
    David Papadopoli, Ranveer Palia, Predrag Jovanovic, Sébastien Tabariès, Emma Ciccolini, Valerie Sabourin, Sebastian Igelmann, Shannon McLaughlan, Lesley Zhan, HaEun Kim, Nabila Chekkal, Krzysztof J Szkop, Thierry Bertomeu, Jibin Zeng, Julia Vassalakis, Farzaneh Afzali, Slim Mzoughi, Ernesto Guccione, Mike Tyers, Daina Avizonis, Ola Larsson, Lynne-Marie Postovit, Sergej Djuranovic, Josie Ursini-Siegel, Peter M Siegel, Michael Pollak, Ivan Topisirovic.
      Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.
    Keywords:  cancer biology; cell biology; human; mRNA translation; metabolism; mouse; signal transduction
    DOI:  https://doi.org/10.7554/eLife.106587
  4. Redox Biol. 2026 Apr 30. pii: S2213-2317(26)00193-X. [Epub ahead of print]94 104195
    Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
    Lianne Jhc Jacobs, Sebastian Doll, Dietrich Trümbach, Matteo Veronese, Giada Di Pietro, Fatma Isil Yapici, Lidwina Hasberg, Pascal Gentzsch, Sarah Gerlich, Jens Hansen, Silvia von Karstedt, Elena I Rugarli, Marcus Conrad, Armindo Salvador, Jan Riemer.
      Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.
    DOI:  https://doi.org/10.1016/j.redox.2026.104195
  5. Trends Biochem Sci. 2026 May 07. pii: S0968-0004(26)00108-8. [Epub ahead of print]
    Emerging roles and regulatory mechanisms involved in glutamine metabolism.
    Keun Woo Ryu, Tak Shun Fung, Craig B Thompson.
      Glutamine is the most abundant circulating amino acid and a central nutrient supporting carbon and nitrogen metabolism. It donates nitrogen for nucleotide and amino acid biosynthesis, protein glycosylation, and provides carbon for the tricarboxylic acid cycle anaplerosis. Glutamine catabolism maintains redox homeostasis via glutathione production, as well as the synthesis of polyamines, urea cycle precursors, and neurotransmitters. Glutamine residues in proteins serve as sites for post-translational modification, while de novo glutamine synthesis is essential for ammonia detoxification. Although glutamine metabolism is regulated by mass action and product inhibition, emerging evidence reveals additional post-translational mechanisms, including regulation through higher-order structural assemblies of enzymes. In this review, we highlight the multifaceted roles of glutamine and emphasize emerging regulatory mechanisms that govern glutamine metabolism.
    Keywords:  carbon metabolism; enzyme filaments; glutamine; nitrogen metabolism; post-translational regulation
    DOI:  https://doi.org/10.1016/j.tibs.2026.04.008
  6. Nat Metab. 2026 May 08.
    Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
    Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.
      Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
    DOI:  https://doi.org/10.1038/s42255-026-01530-y
  7. Cell Metab. 2026 May 05. pii: S1550-4131(26)00109-9. [Epub ahead of print]38(5): 833-834
    Fasting opens a metabolic window that favors anti-tumor immunity.
    Ling Cai, Tao Dai.
      Short-term fasting reshapes the metabolic landscape of the tumor microenvironment, creating a transient window of altered nutrient availability that cytotoxic CD8⁺ T cells can exploit. Chen and colleagues report that intratumoral isoleucine accumulation during fasting supports T cell effector programs, enhancing responses to immune checkpoint blockade in mice and humans.
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.015
  8. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  9. FEBS Lett. 2026 May 03.
    pH-mediated activation of the lysosomal arginine sensor SLC38A9.
    Xuelang Mu, Ampon Sae Her, Tamir Gonen.
      Cells rely on metabolic control; the mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, particularly amino acids. Lysosomes maintain amino acid homeostasis through recycling. SLC38A9, a lysosomal amino acid transporter, functions as a critical sensor in the mTORC1 pathway. Here, we investigate how pH regulates SLC38A9 activity. We show that arginine uptake is pH-dependent, with His544 residue serving as the pH sensor. Mutating His544 abolishes pH dependence without impairing overall transport, indicating His544 influences transport through protonation/deprotonation, instead of involving in the substrate binding. We propose a working model for pH-induced activation, through comparing two determined SLC38A9 structures at different pH. These findings reveal how local ionic shifts regulate lysosomal transporters and fine-tune SLC38A9 function to control mTORC1 signaling.
    Keywords:  SLC family; amino acid transport; mTOR complex; pH‐regulation; transceptor
    DOI:  https://doi.org/10.1002/1873-3468.70352
  10. Cancer Cell. 2026 May 07. pii: S1535-6108(26)00218-7. [Epub ahead of print]
    Whole-genome doubling drives immune evasion by silencing antigen presentation.
    Pierre Foidart, Zheqi Li, Xinran Cai, Marco Seehawer, Daniel D Brown, Amatullah Tawawalla, Pilar Baldominos, Salma Parvin, Jun Nishida, Ernesto Rojas-Jimenez, Triet M Bui, Benedetto Diciaccio, Rahul Kumar, Brent T Schlegel, Marie-Anne Goyette, TashJae Scales, Pengze Yan, Xintao Qiu, Rong Li, Yijia Jiang, Yingtian Xie, Mahmoud Aarabi, Xiao-Yun Huang, Laura E Stevens, Paloma Cejas, Lise Mangiante, Cristina Irene Sotomayor Vivas, Kathleen E Houlahan, Christina Curtis, Steffi Oesterreich, Isaac S Harris, Anthony G Letai, Adrian V Lee, Henry W Long, Judith Agudo, Kornelia Polyak.
      Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.
    Keywords:  antigen presentation; breast cancer; epigenetic silencing; immune escape; whole genome doubling
    DOI:  https://doi.org/10.1016/j.ccell.2026.04.007
  11. Trends Cancer. 2026 May 07. pii: S2405-8033(26)00078-6. [Epub ahead of print]
    Bioengineered systems to exploit tumor microenvironment metabolism.
    Christine Sanganoo, Ilaria Caturegli, Zachary Mattes, Jordan Ryan, Wilson W Wong, Mark W Grinstaff.
      Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.
    Keywords:  antimetabolite delivery; biomaterials; cancer metabolism; immunosuppressive metabolite modulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.04.003
  12. Life Metab. 2026 Jun;5(3): loag005
    Lysosomes contribute to the synthesis of tricarboxylic acid-related metabolites in the hippocampus.
    Liangliang Kong, Hongying Tan, Xiaoting Zhu, Yiqing Wen, Yang Li.
      The central nervous system is highly sensitive to energy supply, and the hippocampus operates under sustained metabolic load due to continuous synaptic activity and information processing. Lysosomes couple nutrient status to cellular energetics through the mechanistic target of rapamycin complex 1 (mTORC1) and the autophagy-lysosome pathway, yet their -subcellular contribution to neuronal metabolic profiles remains unclear. To address this, we established an in vivo AAV-LysoTag/Lyso-IP workflow combined with metabolomics to quantify metabolites within mouse hippocampal lysosomes. An in vitro Lyso-IP platform and immunofluorescence provided cell-based validation. Under every-other-day fasting, hippocampal lysosomes exhibited reprogramming: small-molecule substrates derived from amino acids and fatty acids accumulated; bis(monoacylglycero)phosphate was upregulated, indicating enhanced intraluminal vesicle formation and lipid degradation/sorting; -sphingolipids and cardiolipin increased, consistent with selective mitophagy. Notably, high basal lysosomal levels of malic acid and α-ketoglutarate (α-KG) suggested additional sources beyond the mitochondria. Immunofluorescence further showed lysosomal localization of isocitrate dehydrogenase and fumarate hydratase, suggesting partial residency of these enzymes. The oxoglutarate carrier (SLC25A11) signals were observed in LAMP1+ compartments, suggesting potential transmembrane exchange of α-KG and malic acid. Together, our data indicate that lysosomal tricarboxylic acid -related metabolites are maintained by three parallel routes: mitochondrial delivery to lysosomes, local production by resident enzymes, and transporter-mediated exchange. These metabolites supplement and reshape neuronal carbon flux and metabolic resilience at the subcellular level. Our findings elevate lysosomes from degradative endpoints to mobilizable metabolic hubs in the brain and provide both methodological and conceptual frameworks for neurometabolic adaptation under energy scarcity.
    Keywords:  Lyso-IP; TCA cycle; lysosome; metabolomics; mouse hippocampus
    DOI:  https://doi.org/10.1093/lifemeta/loag005
  13. bioRxiv. 2026 Apr 28. pii: 2026.04.27.718938. [Epub ahead of print]
    Lactylation landscape of mitochondrial proteins in myocardial infarction.
    Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.
      Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
    Highlights: Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired.
    DOI:  https://doi.org/10.64898/2026.04.27.718938
  14. bioRxiv. 2026 Apr 28. pii: 2026.04.26.720636. [Epub ahead of print]
    Paired CRISPR screens identify mitochondrial metabolism and UBE2H as aneuploid-specific dependencies in human cancer cell lines.
    Klaske M Schukken, Saron M Akalu, Charles Zou, Pranav K Kandikuppa, Ryan A Hagenson, Jessica L Keane, Mason P Lynch, Toyoki Yoshimoto, Olaf Klingbeil, Erin L Sausville, Sanat Mishra, Christopher R Vakoc, Zuzana Storchova, Sarah J Aitken, Jason M Sheltzer.
      Aneuploidy is a hallmark of cancer and imposes widespread cellular stress, including proteotoxicity, transcriptional dysregulation, and increased metabolic demand. Although these stresses are predicted to create therapeutic vulnerabilities, the genetic dependencies of aneuploid cells remain incompletely characterized. Here, we performed paired CRISPR loss-of-function screens in isogenic aneuploid and near-euploid cancer cell line models to systematically identify aneuploidy-specific dependencies. Seven genome-wide paired screens identified ribosomes, rRNA processing, spliceosome-mediated RNA processing, proteasome subunits, and mitochondrial metabolism as top aneuploid-specific dependency gene groups. To identify therapeutically targetable aneuploid dependencies, we performed 18 additional paired CRISPR screens using a focused druggable genome library. This analysis identified the ubiquitin-conjugating enzyme UBE2H as a top aneuploid-selective dependency. Functional validation confirmed aneuploid cell dependency on UBE2H, and mechanistic analyses linked UBE2H to mitochondrial protein abundance, suggesting a role in maintaining mitochondrial proteostasis under aneuploid stress. Together, these findings define core cellular systems that support the viability of aneuploid cells and identify UBE2H as a potential therapeutic vulnerability connecting ubiquitin signaling to mitochondrial homeostasis.
    DOI:  https://doi.org/10.64898/2026.04.26.720636
  15. Mol Cell. 2026 May 07. pii: S1097-2765(26)00244-3. [Epub ahead of print]86(9): 1595-1597
    Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
    Edrees H Rashan, Sophie D'Halleweyn, Matthew G Vander Heiden.
      In a recent issue of Cell, Xie et al.1 report that an important function of mitochondrial aconitase is to limit toxic citrate accumulation, suggesting a role for the canonical TCA cycle in physiology beyond ATP production and precursor biosynthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.010
  16. Sci Transl Med. 2026 May 06. 18(848): eads2673
    Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
    David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Ce Gao, Sean A Prell, Niv Vigder, Sergio Poli, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Kevin S Wei, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.
      Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. Although glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how monocarboxylate transporters (MCTs) 1 and 4, key pulmonary lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings revealed that inhibiting MCT1 or MCT4 using RNA interference or small molecules reduced transforming growth factor-β1 (TGFβ)-stimulated myofibroblast differentiation in lung fibroblasts from healthy donors and patients with idiopathic pulmonary fibrosis. Small-molecule MCT inhibitors also decreased bleomycin-induced pulmonary fibrosis in C57Bl6/N mice aged 10 to 12 weeks. Through bioenergetic analyses, stable isotope tracing, metabolomics, and imaging mass spectrometry in both human cells and mice, we demonstrate that inhibiting lactate transport enhanced oxidative phosphorylation, reduced reactive oxygen species production, and diminished glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, an MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors as a therapy for patients with limited treatment options.
    DOI:  https://doi.org/10.1126/scitranslmed.ads2673
  17. EMBO J. 2026 May 02.
    Peroxisome-derived ether lipids regulate lysosomal exocytosis.
    Liang Chen, Danielle Henn, Zhongzheng Dong, Jiaxuan Liang, Aleksander Wielenga, Goncalo Vale, Bala Burugula, Junyi Zou, Yamuna Krishnan, Jeffrey G McDonald, Jacob Kitzman, Ming Li.
      Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
    DOI:  https://doi.org/10.1038/s44318-026-00791-3
  18. Nat Commun. 2026 May 08.
    Tumors hijack immune-privileging regulons via distinct cell types to confer T cell desertion and immunotherapy resistance across various cancers.
    Bashir Lawal, Akshat Gupta, Renu Sharma, Huayan Ren, Rohit Bhargava, Yue Wang, Xiao-Song Wang.
      Immune checkpoint blockade (ICB) has transformed oncology, yet most patients fail to respond, suffer from hyper-progressive disease, or face severe immune-related toxicities, underscoring the urgent need for biomarkers that identify non-responders. Here we show that tumors co-opt an immune-privileging regulon signature (IMPREG) mirroring transcriptional programs of immune-privileged organs - to enforce T-cell desertion and ICB resistance across solid tumor types. Single-cell and spatial transcriptomic analyses reveal that tumors activate IMPREG through three distinct cellular routes: malignant cells adopting immature neuronal states, cancer-associated fibroblasts assuming myofibroblast identities, or endothelial cells - each creating localized niches of immune suppression and antigen-presentation collapse. Across 4 discovery and 36 validation clinical datasets, IMPREG consistently predicts immunotherapy resistance in 14 distinct cancer types, functioning as an orthogonal marker independent of established biomarkers. Crucially, IMPREG-expressing tumors show enhanced sensitivity to EGFR inhibitors or anti-angiogenic therapies in specific tumor entities. These findings suggest IMPREG as a dual-utility predictive biomarker for personalized treatment stratification.
    DOI:  https://doi.org/10.1038/s41467-026-72538-x
  19. Nat Genet. 2026 May 05.
    Age distinguishes selection from causation in cancer genomes.
    David Cheek, Martin Blohmer, Martin A Nowak, Tibor Antal, Kamila Naxerova.
      Cancer-causing mutations have been identified primarily from positive selection signals in cancer genomes. However, positive selection is also a ubiquitous feature of normal tissue aging. Here we develop a statistical framework to disentangle selection in normal tissue and causation of carcinogenesis. By comparing cancer and normal tissue genomes, we estimate the effects of mutations on cancer risk in the blood, esophagus and colon. We determine that stronger cancer-causing mutations are enriched at younger patient ages. This enables cancer-causing mutations to be identified from patient age distributions, even without normal tissue data. Moreover, we show for acute myeloid leukemia that the age-dependence of purported causal mutations can be explained largely by normal blood evolution, challenging the long-standing notion that childhood cancers require distinct mutations. Broadly, our framework delineates carcinogenesis from normal tissue aging, improving the assessment of cancer risk conferred by mutations.
    DOI:  https://doi.org/10.1038/s41588-026-02593-z
  20. Nat Commun. 2026 May 09.
    Complex I protein NDUFB9 is a metabolic vulnerability in triple negative breast cancer brain metastases.
    Mingxi Lin, Zhexu Wen, Cheng Zeng, Yizi Jin, Teng Zhou, Yuxin Yan, Shenglin Huang, Xin Hu, Xiaoxiang Guan, Xichun Hu, Jian Zhang.
      Triple-negative breast cancer (TNBC) brain metastases (BrMs) remain a therapeutic challenge. We depict the discrepancies between primary tumors and BrMs, and examine patient-matched cerebrospinal fluid and plasma to provide detailed profiles of BrMs' metabolic microenvironment. High-throughput in vivo loss of function CRISPR screens identify NDUFB9 (NADH: Ubiquinone Oxidoreductase Subunit B9) as a brain-specific metabolic vulnerability. NDUFB9-knockout selectively inhibits the BrMs outgrowth without affecting extracranial metastases. Mechanistically, TNBC cells exhibit an imbalance between aspartate upstream supply and downstream biosynthetic demand. NDUFB9-knockout disrupts mitochondrial complex I and reduces intracellular aspartate, but this alone is insufficient to inhibit TNBC proliferation. Instead, the lower asparagine concentration in the brain microenvironment induces compensatory upregulation of asparagine synthetase, which further diverts aspartate toward asparagine biosynthesis. This dual-hit mechanism exhausts the aspartate pool and restricts nucleotide biosynthesis, thereby selectively suppressing BrM outgrowth. Our findings uncover a therapeutic strategy for TNBC BrMs.
    DOI:  https://doi.org/10.1038/s41467-026-72927-2
  21. bioRxiv. 2026 Apr 24. pii: 2026.04.22.720193. [Epub ahead of print]
    Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
    Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.
      The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans . Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
    DOI:  https://doi.org/10.64898/2026.04.22.720193
  22. bioRxiv. 2026 Apr 25. pii: 2026.04.23.720276. [Epub ahead of print]
    Mitochondrial mechanics nucleates axonal jamming and swelling.
    Patrick S Noerr, Ahmed A Abushawish, Gulcin Pekkurnaz, Padmini Rangamani.
      Neuronal function requires precise spatial organization of mitochondria to meet localized energetic demand. However, the physical constraints governing mitochondrial transport in axons remain poorly defined. Bidirectional motor-driven trafficking inherently introduces the potential for collisions, but the implications of these interactions for transport failure and structural damage are not understood. Here, we develop an agent-based model that couples mitochondrial motility, morphology, and lifecycle dynamics to a deformable axonal boundary. We show that mitochondrial traffic jams emerge from a force balance between active propulsion and steric interactions, and that their severity is governed by organelle shape and mechanical properties. Elongated, mechanically rigid mitochondria remain aligned and are transported rapidly, whereas flexible, low-aspect-ratio mitochondria are prone to jamming and accumulation. Incorporating fission and fusion dynamics reveals that fission amplifies transport disruption by generating collision-prone populations, while fusion restores transport by producing anisotropic structures that navigate crowded environments more efficiently. Importantly, we find that sustained jamming generates mechanical stress on the axonal membrane, leading to deformation and swelling. Together, these results establish a physical framework linking mitochondrial dynamics to axonal integrity and provide testable predictions for how dysregulated fission-fusion balance can drive transport failure and structural pathology in neurons.
    Significance: 2Axonal deformation is implicated in myriad neurodegenerative conditions. Mitochondrial transport disruption is inextricably linked to axonal deformation and disease progression. Mechanistic understanding of the interplay between mitochondrial transport and axon stability remains opaque. Here, we developed an agent-based model of mitochondrial transport through axons. We found that mitochondria, driven to-ward presynapses for energy supply and toward the soma for repositioning or recycling, can collide, jam, and accumulate within axonal segments. The severity of jamming is sensitive to mitochondrial density as well as mechanical and morphological properties. Further, we found a balance between lifecycle dynamics including fission and fusion is paramount to maintaining homeostatic transport. Lastly, we predict that accumulated mitochondria can deform the axonal membrane, thereby elucidating a direct mechanical link between mitochondrial transport disruption and axonal deformation.
    DOI:  https://doi.org/10.64898/2026.04.23.720276
  23. Nature. 2026 May 06.
    Expanding the human proteome with microproteins and peptideins.
    Eric W Deutsch, Leron W Kok, Jonathan M Mudge, Cristian F Valls, Irwin Jungreis, Jorge Ruiz-Orera, Zhi Sun, Ulrike Kusebauch, Ivo Fierro-Monti, Jennifer G Abelin, M Mar Alba, Julie L Aspden, Sreejan Bandyopadhyay, Kaushik Banerjee, Pavel V Baranov, Ariel A Bazzini, Francis Bourassa, Elspeth A Bruford, Lorenzo Calviello, Steven A Carr, Anne-Ruxandra Carvunis, Sonia Chothani, Jim Clauwaert, Kellie Dean, Pouya Faridi, Adam Frankish, Amy Goodale, Thomas Green, Norbert Hubner, Nicholas T Ingolia, Manolis Kellis, Michele Magrane, Maria Jesus Martin, Thomas F Martinez, Gerben Menschaert, Uwe Ohler, Sandra Orchard, Alisa Potter, Owen J L Rackham, Matthew G Rees, David E Root, Jennifer A Roth, Xavier Roucou, Fernando J Sialana, Sarah A Slavoff, Michał I Świrski, Jack A S Tierney, Félix-Antoine Trifiro, Eivind Valen, Valeriia Vasylieva, Aaron Wacholder, Shengbo Wang, Li Wang, Jonathan S Weissman, Wei Wu, Zhi Xie, Jyoti S Choudhary, Michal Bassani-Sternberg, Juan Antonio Vizcaíno, Nicola Ternette, Marie A Brunet, Robert L Moritz, John R Prensner, Sebastiaan van Heesch.
      A major scientific drive is to characterize the protein-coding genome, which is a primary basis for studying human health. But the fundamental question remains of what has been missed in previous analyses. Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states1-3, with major implications for biomedical science. However, a key gap in knowledge has been which ncORFs produce small microproteins or alternative protein molecules that contribute to the human proteome. Here we report the collaborative efforts of the TransCODE Consortium4 to produce a consensus landscape of protein-level evidence for ncORFs. We show that about 25% of a set of 7,264 ncORFs gives rise to detectable peptides in a large-scale analysis of 95,520 proteomics experiments. We develop an annotation framework for ncORF-encoded microproteins as human proteins and codify the new conceptual model of 'peptideins' as microproteins that have indeterminate potential as functional proteins. To probe the biological implications of peptideins, we create an evolutionary analysis approach, termed ORF relative branch length (ORBL), and determine that evolutionary constraint is common and associates with observation of ncORF-derived peptides. We then characterize a pan-essential cellular phenotype for one peptidein from the OLMALINC long non-coding RNA. Overall, we generate public research tools supported by GENCODE and PeptideAtlas and advance biomedical discovery for understudied components of the human proteome.
    DOI:  https://doi.org/10.1038/s41586-026-10459-x
  24. Cancer Lett. 2026 May 04. pii: S0304-3835(26)00325-3. [Epub ahead of print] 218562
    Cigarette smoke induces FASN-dependent fatty acid metabolic rewiring to drive bladder cancer progression.
    Chandra Sekhar Amara, Danthasinghe Waduge Badrajee Piyarathna, Abu Hena Mostafa Kamal, Yuen San Chan, Karthik Reddy Kami Reddy, Chandra Shekar R Ambati, Mohammed Khurshidul Hassan, Pratik Shriwas, Tanmay Gandhi, Antrix Jain, Tanja Gangnus, Pooja Popli, Roshan Borkar, Sung Wook Kang, Silvia L Summers, Vasanta Putluri, Sandra L Grimm, Sharan Venkatesh, Ningxin Song, Erin H Seeley, Jenna Hedlich-Dwyer, Shu-Hsia Chen, Nupam P Mahajan, Abhinav K Jain, Lacey Elizabeth Dobrolecki, Gabrielle A Wells, Hugo Villanueva, Jenny Li, Xuefeng Liu, Roni J Bollag, Anna Malovannaya, Sung Yun Jung, Hyun-Sung Lee, Irfan A Asangani, Martha K Terris, Chad J Creighton, Leomar Y Ballester, Balasubramanyam Karanam, Suyu Liu, MinJae Lee, Rajeeva R Raju, M Minhaj Siddiqui, Livia S Eberlin, Ramakrishna Kommagani, Arun Sreekumar, Jianjun Gao, Nicolas L Young, H Courtney Hodges, Cristian Coarfa, Natalie R Gassman, Seth P Lerner, Yair Lotan, Nagireddy Putluri.
      Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via FASN. Genetic and pharmacological inhibition of FASN significantly reduced tumor growth in a Chicken embryo Chorio-allantoic Membrane model exposed to smoke. FASN inhibitors such as TVB-2640, currently in clinical trials, may represent an effective therapeutic strategy for smokers with bladder cancer exhibiting high FASN levels.
    Keywords:  Bladder Cancer; Cigarette Smoke; DNA damage and repair; FASN; Fatty acid metabolism
    DOI:  https://doi.org/10.1016/j.canlet.2026.218562
  25. bioRxiv. 2026 Apr 27. pii: 2026.04.24.720406. [Epub ahead of print]
    Selective Editing and Functionalization of the Mammalian Lipidome.
    Binyou Wang, Lukas Lüthy, Logan Tenney, Leo Qi, Takeshi Harayama, Kim Ekroos, Johannes Morstein.
      Lipids exhibit extraordinary molecular diversity, yet tools to selectively manipulate defined lipid classes in living cells are lacking. Here we show that lipid tail structure biases metabolic fate, enabling the design of synthetic lipid analogs with programmable metabolic selectivity. This approach enables selective cellular production of distinct lipid species or subclasses, including types of neutral lipids, phospholipids, sphingolipids, and ether lipids, without genetic or enzymatic perturbation. We further couple metabolic selectivity to chemical functionalization using bifunctional lipids, in which one modification directs metabolic flux and a second enables bioorthogonal tagging. Using this strategy, we achieve selective in situ labeling of different lipid pools in living cells. Together, our work establishes a chemical biology strategy that enables unprecedented precision in modulating, functionalizing, and rewiring the mammalian lipidome.
    DOI:  https://doi.org/10.64898/2026.04.24.720406
  26. Nat Commun. 2026 May 02.
    PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer.
    Zehua Li, Cong Fu, Kartik Sehgal, Ann Marie Egloff, Tran C Thai, Omar Avila Monge, Cun Lan Chuong, Yaiza Senent, Maia Shea Lineberry, Benjamin K Eschle, Koji Haratani, Elena V Ivanova, Marco Campisi, Navin R Mahadevan, John D Quadarella, Patrick C Gedeon, Jonathan D Schoenfeld, Michihisa Kono, Caroline G Fahey, Chayapatou Chayawatto, Kenneth Ngo, Cloud P Paweletz, Prafulla C Gokhale, Robert T Manguso, Ravindra Uppaluri, David A Barbie.
      cGAS-STING signaling can promote antitumor immunity, and tumor cell STING is suppressed in a variety of cancer subtypes that resist immune checkpoint blockade. Although STING agonists have failed clinical trials, precision approaches targeting restoration of tumor cell STING expression have yet to be explored. Here, we report that head and neck squamous cell cancer (HNSCC) exhibits a mechanism of STING suppression related to upregulation of protein tyrosine phosphatase non-receptor (PTPN) type 2 (PTPN2) that is also evident in other cancers. PTPN2 inhibition (PTPN2i) increases HNSCC tumor cell STING by restoring IFNγ-STAT1-mediated induction of STING mRNA. This restores sensitivity to STING agonism and natural killer cell activation, suppressing tumor growth in an immune cell-dependent manner in anti-PD-1 refractory syngeneic HNSCC mouse tumor models in female mice. Together, these findings demonstrate that PTPN2i can unleash STING agonist response, providing a rationale for the evaluation of this therapeutic combination in HNSCC and potentially other cancer types.
    DOI:  https://doi.org/10.1038/s41467-026-72372-1
  27. Nat Methods. 2026 May 07.
    FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
    Jianpeng Ao, Jiaze Yin, Haonan Lin, Guangrui Ding, Youchen Guan, Marzia Savini, Bethany Weinberg, Dashan Dong, Qing Xia, Zhongyue Guo, Bowen Liu, Biwen Gao, Ji-Xin Cheng, Meng C Wang.
      Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis and organismal physiopathology. Despite the importance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here we report a fluorescence-detected mid-infrared photothermal microscope (FILM) implemented with optical boxcar demodulation, artificial intelligence-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. In addition, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.
    DOI:  https://doi.org/10.1038/s41592-026-03090-1
  28. Elife. 2026 May 07. pii: e111373. [Epub ahead of print]15
    How membranes shape up for lipid transfer.
    Takashi Hirashima, Toshiya Endo.
      The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.
    Keywords:  biochemistry; cardiolipin; chemical biology; lipid transport; mitochondria; none; phosphatidic acid
    DOI:  https://doi.org/10.7554/eLife.111373
  29. Nat Commun. 2026 May 05.
    Global mitochondrial connectivity map reveals the landscape of yeast functional assemblies and conserved protein communities.
    Matthew Jessulat, Sadhna Phanse, Hiroyuki Aoki, Kirsten Broderick, Qingzhou Zhang, Inês Gomes Castro, Noelle Alexa Novales, Sakib Abrar Hossain, Tatiana Saccon, Mohamed Taha Moutaoufik, Thomson Patrick Joseph, Shahreen Amin, Larrisa Hoell, Zoran Minic, Yury Bykov, Noga Preminger, Sahily Gonzalez Crespo, Jamie Snider, Ashkan Golshani, Igor Stagljar, Jose R Rodriguez-Medina, Catherine F Clarke, Maya Schuldiner, Mohan Babu.
      Mitochondria are essential organelles whose functions depend on coordinated multiprotein complexes, yet their composition and organization remain incomplete. Here, we present a large-scale map of mitochondrial protein complexes by integrating affinity purification of 740 endogenously GFP-tagged mitochondrial proteins with biochemical co-fractionation of mitochondrial extracts from yeast (Saccharomyces cerevisiae) grown under respiratory conditions. Mass spectrometry identifies 13,716 high-confidence protein associations and defines 556 heteromeric complexes, many previously unknown. These assemblies reveal factors involved in coenzyme Q6 biosynthesis, membrane contact sites, phospholipid transport, and coordination with the MICOS complex during respiration. We further link 538 assemblies to 294 candidate human disease genes and construct a conservation map of 852,146 predicted mitochondrial interactions across 271 genomes, and validate key predictions in human cell lines and mouse brain tissue. Together, this work provides a comprehensive mitochondrial interactome, assigning functions to poorly characterized proteins, and offering insights into mitochondrial biology and disease-associated assemblies.
    DOI:  https://doi.org/10.1038/s41467-026-72525-2
  30. Immunometabolism (Cobham). 2026 Apr;8(2): e00079
    Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction.
    Zikuan Song, Christian Frezza.
      Immune checkpoint inhibitor therapies induce metabolic dysfunction. A study by Wu et al now pinpoints macrophage programmed cell death protein 1 (PD-1) as a key molecular mediator of the anti-PD-1 treatment-triggered exacerbation of systemic metabolic disorders. Macrophage PD-1 blockade disrupts the moonlighting function of PD-1 in suppressing endoplasmic reticulum stress-mediated inflammatory responses, thereby impairing adipose tissue thermogenesis, reducing energy expenditure, and ultimately leading to systemic metabolic dysfunction.
    Keywords:  cancer; immunity; macrophages; metabolism; programmed cell death protein 1
    DOI:  https://doi.org/10.1097/IN9.0000000000000079
  31. Am J Physiol Renal Physiol. 2026 May 06.
    Loss of Proximal Tubule Lactate Dehydrogenase A (LDHA) Exacerbates Nephrotoxic Acute Kidney Injury Through Metabolic Dysregulation.
    Yan Lu, Anna A Zmijewska, Yanfeng Zhang, Gunars Osis, Matthew D Cheung, Landon Wilson, Yanlin Jiang, Sudeepthi Vejendla, Amie Traylor, Stephen Barnes, James F George, Anupam Agarwal.
      Acute kidney injury (AKI) involves abrupt loss of kidney function driven in part by proximal tubule metabolic stress, yet the role of glycolytic regulation in tubular injury susceptibility remains unclear. Lactate dehydrogenase A (LDHA) is a key regulator of glycolytic flux and redox balance, but its function in proximal tubules during AKI is poorly defined. In this work, we use a cisplatin-induced AKI model to investigate the role of proximal tubule LDHA in regulating metabolic responses and injury severity. Proximal tubule-specific LDHA knockout mice (PEPCKCreLDHAΔ/Δ) and LDHAflox/flox controls were subjected to cisplatin-induced AKI. Untargeted metabolomics of kidney cortex and single-nucleus RNA sequencing (snRNA-seq) were performed to define metabolic and cell-specific transcriptional responses. Loss of proximal tubular LDHA exacerbated cisplatin-induced AKI, as evidenced by worsened kidney function and tubular injury, accompanied by increased expression of inflammatory markers following injury. The analysis also showed a distinct metabolic profile at baseline in LDHA-deficient kidneys, which became more pronounced after cisplatin exposure, with coordinated changes in purine and nucleotide metabolism, energy-related metabolites, and pathways linked to redox balance and mitochondrial function. snRNA-seq revealed intrinsic transcriptional changes within proximal tubule cells at baseline and after injury, reflecting cellular stress and metabolic remodeling without strong activation of classic inflammatory gene programs. Together, these findings identify proximal tubular LDHA as a key regulator of metabolic flexibility and injury tolerance in cisplatin-induced AKI, and suggest that disrupted coordination of glycolytic and nucleotide metabolism increases tubular vulnerability, highlighting metabolic regulation as a potential therapeutic target.
    Keywords:  acute kidney injury; cisplatin; lactate dehydrogenase; metabolism
    DOI:  https://doi.org/10.1152/ajprenal.00048.2026
  32. bioRxiv. 2026 Apr 27. pii: 2026.04.23.720365. [Epub ahead of print]
    MOSAIC: a longitudinal phenotypic clock to dissect organismal aging trajectories in C. elegans.
    Alexandre Pierre Vaudano, Marie Pierron, Lazar Stojkovíc, Mathieu Membrez, Morgane Bourgeois, Christopher Neal, Myriam Chimen, Lina Verbakel, Matteo Cornaglia, Florence Solari, Laurent Mouchiroud.
      Interventions that extend lifespan do not necessarily preserve healthspan, the portion of life spent in good health. This disconnect has intensified interest in biological aging clocks as quantitative proxies of organismal health. However, most existing clocks rely on invasive or endpoint measurements, providing static estimates that capture biological age at a single time point and offer limited insight into aging trajectories - the dynamic patterns through which physiological resilience and functional capacity change within individuals over time. Here we combine standardized, high-frequency imaging of individual Caenorhabditis elegans across the lifespan with machine learning to develop MOSAIC (Modular Organismal Signature of Aging In C. elegans ), a non-invasive phenotypic clock that estimates biological age longitudinally at single-organism resolution. Leveraging ∼3'750 animals, ∼230'000 observations and 29 phenotypic features, MOSAIC predicts biological age with high accuracy and resolves organism-wide aging trajectories at high temporal resolution. Beyond age prediction, MOSAIC decomposes biological age into contributions from distinct physiological modules, enabling mechanistic interpretation of organismal decline. Applying MOSAIC to natural lifespan variation, dietary restriction, longevity mutants and pharmacological interventions reveals that lifespan extension can emerge through distinct, time-dependent phenotypic trajectories rather than a uniform slowing of aging. Interventions with similar effects on longevity produce divergent biological-age trajectories and distinct combinations of younger and older traits, highlighting context-dependent physiological trade-offs. MOSAIC provides a scalable, non-invasive framework to repeatedly quantify biological age across the lifespan and to compare interventions based on how they reshape aging trajectories.
    DOI:  https://doi.org/10.64898/2026.04.23.720365
  33. Nat Struct Mol Biol. 2026 May 07.
    Membrane insertion of mitochondrial-encoded proteins regulates ribosome decoding speed.
    Thomas Schöndorf, Valentyn Petrychenko, Ilgin Kotan, Drishan Dahal, Natalia Napieraj, Luis Daniel Cruz-Zaragoza, Cong Wang, Oliver Urbach, Tanja Gall, Sven Dennerlein, Günter Kramer, Niels Fischer, Peter Rehling.
      The human mitochondrial genome encodes 13 subunits of the oxidative phosphorylation system essential for energy metabolism to drive cellular activities. Translation of 11 mRNAs by membrane-bound ribosomes is coupled to insertion of the nascent polypeptides into the inner membrane aided by the OXA1L insertase. To this end, the mechanism of membrane insertion of nascent polypeptides and the functional link to the translation process are not sufficiently understood. Here, we applied ribosome profiling to assess translation dynamics in combination with cryo-electron microscopy analysis of a COX1 ribosome-nascent chain complex to visualize cotranslational folding of the nascent chain. We find that the membrane topology of the translation product impacts translation speed and that positioning of amphipathic helices in the ribosome vestibule induces structural changes, correlating with translation pausing events. Thus, our findings reveal a link between translation process and folding and membrane insertion of nascent polypeptides at the inner mitochondrial membrane.
    DOI:  https://doi.org/10.1038/s41594-026-01803-w
  34. bioRxiv. 2026 Apr 27. pii: 2026.04.24.720727. [Epub ahead of print]
    TFAM organizes DNA into compact higher order structures.
    Sashi R Weerawarana, Wei Tian, Karolin Luger.
      TFAM (Transcription Factor A, Mitochondrial) is an essential human protein that plays two key roles in mitochondrial DNA (mtDNA) homeostasis. TFAM acts as a transcription factor that specifically binds to promoter regions, but it is also solely responsible for organizing mtDNA into nucleoids by nonspecifically covering the entire genome. Many studies have addressed TFAM in transcription regulation, but its role as a genome organizing entity is not well characterized. The current understanding of how TFAM compacts DNA into nucleoids is based on crystal structures of a TFAM monomer bound to short fragments of DNA (22-28 bp). However, this does not adequately reflect the biological role of TFAM in organizing the nucleoid where multiple TFAM molecules oligomerize on the 16.5 kb genome to form the nucleoid. Here, we present a biochemical and structural analysis of TFAM oligomerization on longer DNA. Our results show that TFAM compacts longer segments of DNA into higher order complexes that are homogenous yet exhibit continuous conformational dynamics.
    Significance statement: Mutations or damage to mitochondrial DNA (mtDNA) severely impairs cellular respiration and is implicated in many human diseases and aging. 'Transcription Factor A, Mitochondrial' (TFAM) is an essential protein that is solely responsible for packaging mtDNA into nucleoids thereby shielding it from DNA damage. Despite its importance, the mechanism by which this is accomplished is poorly understood. Here, we use biochemistry to show that TFAM oligomerizes on DNA to form compact, homogenous higher order structures in solution. We also examined these complexes at a low resolution using cryo-EM, suggesting an organizational unit of mtDNA. This work reveals there may be a regular organization to mitochondrial nucleoids, providing the basis for further understanding mtDNA compaction by TFAM.
    DOI:  https://doi.org/10.64898/2026.04.24.720727
  35. Life Metab. 2026 Jun;5(3): loag009
    Circadian biology and exercise: the time to move.
    Zhihui Zhang, John A Hawley, Min-Dian Li.
      Exercise performance in endurance- and power-based events is time-of-day dependent in both humans and rodents. Accordingly, there has been growing interest in determining whether there is an optimal time of day for physical activity that can amplify the well-known benefits of exercise on metabolic health in humans. Here, we discuss critical features of circadian biology that underpin many of the physiological responses to the timing of exercise. Recent studies indicate that the circadian clock regulates exercise capacity through the coordination of tissue-specific physiological responses, including fuel metabolism and mitochondrial biogenesis. Synchronized actions between circadian clocks and clock-output pathways residing in the skeletal muscle and other tissues are likely to explain how external time-of-day cues influence exercise performance and physiological responses to exercise. Understanding the circadian biology of exercise will provide the foundation on which future individualized exercise protocols are prescribed to improve metabolic health outcomes at both individual and population levels.
    Keywords:  circadian clock; circadian rhythm; exercise; exercise training; metabolic health; skeletal muscle
    DOI:  https://doi.org/10.1093/lifemeta/loag009
  36. bioRxiv. 2026 Apr 20. pii: 2026.04.20.719537. [Epub ahead of print]
    MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.
    Anastasia Rumyantseva, Alissa Wilhalm, William Carter, Trevor S Tippetts, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart undergoes a rapid metabolic transition from fetal glycolysis to oxidative phosphorylation, requiring coordinated metabolic remodeling. Mechanisms driving this transition remain unclear. Here, we demonstrate that sufficient mitochondrial S-adenosylmethionine (mitoSAM), imported via the solute carrier Slc25a26 , is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.
    DOI:  https://doi.org/10.64898/2026.04.20.719537
  37. Sci Adv. 2026 May 08. 12(19): eaea8724
    A redox-sensitive phosphatase regulates glycolysis as a metabolic switch in the bacterial inner membrane.
    Lei Zheng, Wei Niu, Xianfa Xie, Trung Vu, Guangwei Du.
      Microorganisms rapidly adjust their metabolism to survive fluctuating environmental conditions, but how they coordinate glycolytic control with redox signals remains unclear. We found that the membrane phosphatase PgpA acts as a redox-sensitive switch to regulate glycolytic flux in Escherichia coli. PgpA dephosphorylates key glycolytic intermediates, glyceraldehyde-3-phosphate and glycerol-3-phosphate, to modulate central metabolism. This activity is controlled by a reversible disulfide bond that forms an inactive dimer under oxidative stress and restores activity when reduced. This redox-dependent regulation enables E. coli to fine-tune metabolism in response to changes in nutrients and oxygen availability. PgpA inactivation increases glucose uptake and promotes metabolism, while constitutive activation impairs growth under anaerobic conditions. We also found that PgpA influences redox homeostasis by regulating glutathione biosynthesis. These findings reveal a negative feedback mechanism in which PgpA integrates glycolysis with redox balance, serving as a central regulator of bacterial metabolic homeostasis in response to environmental changes.
    DOI:  https://doi.org/10.1126/sciadv.aea8724
  38. Cancer Discov. 2026 May 05.
    The evolution of polyclonal competition in aging hematopoiesis.
    Nathaniel V Mon Père, Francesco Terenzi, Benjamin Werner.
      Clonal hematopoiesis (CH) - the expansion of genetic variants in blood - is a prime example of somatic evolution. Although it often precedes malignant transformation, many aspects of this process remain unknown. We show that a model of polyclonal competition, in which selectively-advantaged clones continually appear and compete, explains observed CH dynamics throughout human life. We quantify the fitness distribution and occurrence rate of clonal expansions using either variant trajectories or HSC genetic heterogeneity. Inferences on both data converge. Approximately three fit clones enter the HSC pool per year, yet rarely more than five achieve >1.5% frequency throughout life. The fittest clones emerge predominantly later in life in accordance with a multistep evolutionary process. DNMT3A-variants were enriched for single-hit clones, whereas TET2, ASXL1, JAK2, SF3B1, and SRSF2 showed enrichment for multi-hit evolution. These findings suggest precursors of hematological malignancies are identifiable prior to transformation and may facilitate early intervention strategies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0990
  39. Cell Rep. 2026 May 07. pii: S2211-1247(26)00435-3. [Epub ahead of print]45(5): 117357
    Loss of pyruvate carboxylase suppresses lethality in propionic acidemia.
    Jasmine Encarnacion, Susanna Scafidi, Michael J Wolfgang.
      Inborn errors in propionyl-CoA carboxylase cause life-threatening propionic acidemia. To understand the contribution of propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific Pcca knockout mouse models. The inducible whole-body loss of Pcca results in acute metabolic decompensation like the inborn error. The liver-specific loss of Pcca recapitulates these adverse effects, demonstrating the centrality of the liver to systemic disease. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Strikingly, the lethality of Pcca knockout (KO) mice is reversed by simultaneously inhibiting pyruvate carboxylase (Pcx). Most metabolites suspected as deleterious in propionic acidemia are exacerbated in liver-specific Pcca;Pcx double KO mice with the exception of methylcitrate, suggesting a role of this metabolite in systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism is critical to mitigate the adverse effects from alternative propionyl-CoA metabolic pathways.
    Keywords:  CP: metabolism; TCA cycle; citrate; fatty acid; inborn error; knockout; liver; metabolism; propionate; propionyl-CoA; propionylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117357
  40. EMBO J. 2026 May 07.
    SLX4IP limits replication stress globally and at ALT telomeres.
    Jessica Spindler, Francesca Pandolfo, Anna Eva Koch, Priscilla Piccirillo, Drew Jordahl, Nikhil Venkatesh, Dhruthi Suresh, K R Ylvisaker, Anita Jopkiewicz, Johanna Bihler, Sandra Buschbaum, Marcel Morgenstern, Katherine A Overmyer, Estelle Vincendeau, Joshua J Coon, Pei-Chi Wei, Robert Hänsel-Hertsch, Kavi P M Mehta, Stephanie Panier.
      Faithful DNA replication is essential for genome stability, yet replication forks face constant stress. The Bloom syndrome helicase (BLM) safeguards fork integrity, but excessive BLM activity can itself induce replication stress. We identify SLX4IP as a genome-wide regulator that restrains BLM to maintain replication fork stability. SLX4IP localizes broadly across chromatin with recruitment enhanced under replication stress. Loss of SLX4IP slows replication forks, remodels the replisome, and generates post-replicative single-stranded DNA gaps that are accompanied by elevated nuclear ADP ribose, reflecting compromised replication integrity. These defects are driven by dysregulated BLM activity, establishing SLX4IP as a negative regulator of BLM-dependent replication stress. At ALT telomeres, SLX4IP deficiency triggers ATR signaling, telomere fragility, and accumulation of ALT-associated PML bodies. Here, SLX4IP functions in parallel with FANCM to restrain BLM at ALT telomeres, with co-depletion of SLX4IP and FANCM causing synthetic lethality in ALT-positive cells, a phenotype fully rescued by BLM loss. Together, our results define SLX4IP as a critical genome-wide regulator of replication fork integrity and reveal SLX4IP as a potential vulnerability in ALT-positive cancers.
    DOI:  https://doi.org/10.1038/s44318-026-00790-4
  41. EMBO J. 2026 May 05.
    Cytosolic DNA inhibits rDNA transcription by retaining the RNA polymerase I transcription machinery.
    Yinfeng Xu, Qian Wang, Chuying Qian, Sheng Lu, Zhengfu He, Wei Liu, Wei Wan.
      Cytosolic DNA, derived from cellular damage or microbial infection, functions as a pivotal trigger for the host innate immune responses by activating intracellular DNA-sensing machinery, including the cGAS-STING pathway. However, whether cytosolic DNA is involved in DNA-sensing pathway-independent biological processes remains largely unknown. Here, we show that cytosolic DNA interacts with UBTF and POLR1A, two essential components of the RNA polymerase I transcription machinery, and sequesters these two proteins in the cytoplasm. This retention decreases nuclear UBTF and POLR1A, inhibits rDNA transcription, suppresses protein synthesis, and curtails cell proliferation. Furthermore, we demonstrate that STING-induced autophagy specifically eliminates cytosolic DNA and restores nuclear UBTF and POLR1A, thereby abolishing the inhibitory effects of cytosolic DNA on rDNA transcription, protein synthesis, and cell proliferation. Thus, our findings uncover a novel role of cytosolic DNA in rDNA transcription, suggesting that cytosolic DNA not only activates immune responses but also interferes with cell metabolism.
    DOI:  https://doi.org/10.1038/s44318-026-00792-2
  42. bioRxiv. 2026 Apr 26. pii: 2026.04.22.720272. [Epub ahead of print]
    Paternal folate deficiency reveals meiosis as a metabolic sensing window in the male germline.
    Jasmine M Esparza, Rohan V Kumar, Mengwen Hu, Yasuhisa Munakata, Saanvi Jain, Akihiko Sakashita, So Maezawa, Richard M Schultz, Satoshi H Namekawa.
      Folate-dependent one-carbon metabolism supplies methyl donors required for chromatin modification, yet how metabolic conditions shape epigenome establishment in the male germline remains poorly understood. Here, using a folate-deficient mouse model, we identify meiotic prophase I as a metabolically sensitive window in the male germline. By integrating in vivo germline analysis with bulk and single-cell transcriptomic and epigenomic profiling, we show that folate deficiency disturbs transcriptional programs in pachytene spermatocytes and preferentially perturbs CpG island (CGI)-associated promoters, which are characterized by bivalent H3K4me3 and H3K27me3 during meiosis. Consistent with this selective vulnerability, active chromatin marks, including H3K4me3 and H3K27ac, are markedly reduced at CGI-associated promoters under folate-deficient conditions. Notably, loci that later exhibit altered H3K4me3 enrichment in mature sperm show earlier chromatin perturbations during meiosis, suggesting that these sperm epigenomic alterations may originate during meiotic development. Together, these findings establish a mechanistic link between paternal folate deficiency and dynamic epigenomic remodeling of CGI-associated chromatin in the male germline.
    DOI:  https://doi.org/10.64898/2026.04.22.720272
  43. Cell. 2026 May 05. pii: S0092-8674(26)00332-6. [Epub ahead of print]
    Disrupted molecular glue complex drives RAS inhibitor resistance.
    Ben Sang, Ling Feng Ye, Zheng Fu, Yasin Pourfarjam, Antonio Cuevas-Navarro, Shijie Fan, Feng Hu, Aaliyah Washington, Diego J Rodriguez, Alberto Vides, Sumit Kar, Ethan Ahler, Kevin K Lin, Aparna Hegde, Jacqueline A M Smith, Brian M Wolpin, Salman R Punekar, Alexander I Spira, Ignacio Garrido-Laguna, David S Hong, Arvin C Dar, Rona Yaeger, Kathryn C Arbour, Piro Lito.
      Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases. Structural and functional analyses revealed that acquired mutations confer resistance by disrupting interactions essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.
    Keywords:  RAF; RAS; RAS inhibitor; acquired resistance; cancer; clinical resistance; daraxonrasib; molecular glues; targeted therapy; tri-complex inhibitor
    DOI:  https://doi.org/10.1016/j.cell.2026.03.031
  44. Science. 2026 May 07. eaec8514
    TranscriptFormer: A generative cell atlas across 1.5 billion years of evolution.
    James D Pearce, Sara E Simmonds, Gita Mahmoudabadi, Lakshmi Krishnan, Giovanni Palla, Ana-Maria Istrate, Alexander Tarashansky, Benjamin Nelson, Omar Valenzuela, Donghui Li, Stephen R Quake, Theofanis Karaletsos.
      Single-cell transcriptomics is revolutionizing our understanding of cellular diversity, yet comparing transcriptional programs across the tree of life remains challenging. We developed TranscriptFormer, a family of generative foundation models trained on up to 112 million cells spanning 1.53 billion years of evolution across 12 species. We demonstrate state-of-the-art performance on cell type classification, even for species separated over 685 million years of evolution, and zero-shot disease state identification in human cells. Developmental trajectories, phylogenetic relationships and cellular hierarchies emerge naturally in TranscriptFormer's representations without any explicit training on these annotations. This work establishes a powerful framework for quantitative single-cell analysis and comparative cellular biology, thus demonstrating that universal principles of cellular organization can be learned and predicted across the tree of life.
    DOI:  https://doi.org/10.1126/science.aec8514
  45. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
  46. Nature. 2026 May 06.
    Non-invasive profiling of the tumour microenvironment with spatial ecotypes.
    Wubing Zhang, Erin L Brown, Abul Usmani, Noah Earland, Minji Kang, Chibuzor Olelewe, Anushka Viswanathan, Pradeep S Chauhan, Chloé B Steen, Hyun Soo Jeon, Susanna Avagyan, Irfan Alahi, Nicholas P Semenkovich, Janella C Schwab, Chloe M Sachs, Faridi Qaium, Peter K Harris, Qingyuan Cai, Andrew J Gentles, James Knight, Rondell P Graham, Antonietta Bacchiocchi, Peter C Lucas, Ryan C Fields, Mario Sznol, Ruth Halaban, David Y Chen, Aadel A Chaudhuri, Aaron M Newman.
      Multicellular programs in the tumour microenvironment (TME) drive cancer pathogenesis and response to therapy but remain challenging to identify and profile clinically1-3. Here, we present a machine-learning framework for multi-analyte profiling of spatially dependent cell states and multicellular ecosystems, termed spatial ecotypes (SEs). By integrating over 10 million single-cell and spot-level spatial transcriptomes from diverse human carcinomas and melanomas, we identified nine SEs with broad conservation, each of which has unique biology, geospatial features and clinical outcome associations, including several linked to immunotherapy response. Notably, SEs were distinguishable by DNA methylation profiling and were recoverable from plasma cell-free DNA (cfDNA) using deep learning. In cfDNA from nearly 100 patients with melanoma, SE levels exhibited striking associations with immunotherapy response. Our data reveal fundamental units of TME organization and demonstrate a multimodal platform for profiling solid and liquid TMEs, with implications for improved risk stratification and therapy personalization.
    DOI:  https://doi.org/10.1038/s41586-026-10452-4
  47. Am J Physiol Cell Physiol. 2026 May 08.
    The role of glycolysis in inflammation.
    Ethan T Dehantschutter, Cormac T Taylor.
      A characteristic feature of inflamed tissue is hypoxia, which arises from elevated oxygen consumption and impaired perfusion. Inflammation is accompanied by metabolic reprogramming enabling immune and non-immune cells to meet increased bioenergetic and biosynthetic demands. Glycolysis is among the most ancient and fundamental metabolic pathways in biology. Hypoxia reduces mitochondrial oxidative phosphorylation, driving cells towards a reliance on glycolysis to sustain ATP production. This requires an increase in flux through the glycolytic pathway, which is mediated through rapid allosteric regulation of glycolytic enzymes, transcriptional upregulation of glucose transporters and glycolytic enzymes, and the formation of glycolytic enzyme complexes. In immune cells such as macrophages, neutrophils, and lymphocytes, enhanced glycolytic flux determines effector functions including, but not limited to, cytokine production, phagocytosis, migration, and antimicrobial activity, as well as maintaining bioenergetic homeostasis. Similarly, non-immune cells within inflamed tissues, including epithelial cells and stromal cells, utilize glycolysis to influence barrier function, tissue remodelling, and inflammation. In this review, we summarize our current understanding of how hypoxia drives glycolytic reprogramming during inflammation, examine the cell-type-specific impact of this, and discuss the therapeutic potential of targeting glycolytic pathways for inflammatory diseases.
    DOI:  https://doi.org/10.1152/ajpcell.00113.2026
  48. Cell Rep. 2026 May 05. pii: S2211-1247(26)00402-X. [Epub ahead of print]45(5): 117324
    Tissue-specific tolerance mechanisms and lymph node co-drainage shape T cell immunity in the upper digestive system and pancreatic cancer progression.
    Yixuan D Zhou, Peter Wang, Emily Schaffer, Macy R Komnick, Hailey Brown, Gwen M Taylor, Kay L Fiske, Colin Sheehan, Terence S Dermody, Alexander Muir, Daria Esterházy.
      The liver, pancreas, and duodenum share lymph nodes (LNs), providing a unique system to examine how tissue origin of self-antigens shapes T cell fate. Comparing mice expressing ovalbumin (OVA) from distinct subcellular compartments, we found that cytosolic OVA from the liver or pancreas, but not gut, was immunologically ignored. High-dose hepatic-secreted OVA triggered antigen-specific T cell deletion, whereas secreted pancreatic and intestinal OVA induced regulatory T (Treg) cells, revealing immunological ignorance, clonal deletion, and Treg cell generation as tissue-specific tolerance mechanisms. Of these, LN co-drainage only influenced Treg cell induction, establishing gut-pancreas-liver axes: intestinal viral infection rendered hepatocyte- and exocrine pancreas-specific T cells inflammatory and liver injury promoted pancreas- and gut-directed responses. These self-reactive T cells caused tissue destruction but enhanced pancreatic tumor control when neoantigen OVA was secreted, but not cytosolic. Thus, LN co-drainage and tissue-specific tolerance mechanisms jointly shape immune homeostasis and disease susceptibility in the upper digestive system.
    Keywords:  CP: cancer; CP: immunology; T cell responses; inter-organ communication; lymph nodes; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117324
  49. Nat Commun. 2026 May 06.
    Non-enzymatic coupling of protometabolic reactions with a prebiotic redox cofactor.
    David González-Martínez, Noemí Nogal, Iván de la Infanta, Pilar Ocón, Fernando Aguilar-Galindo, Javier Luis-Barrera, Andrés de la Escosura.
      One of the crucial questions about the origin of life is how the first metabolic networks emerged. Cofactors such as nicotinamide adenine dinucleotide (NAD⁺/NADH) are essential in modern metabolism, and their prebiotic analogues may have played a key role in the non-enzymatic coupling of protometabolic reactions. In this study we explore the potential of prebiotically plausible pyridinium/1,4-dihydropyridine pairs as reversible redox cofactors capable of linking catabolic and anabolic transformations. Using pyruvate as a model substrate, we demonstrate that one such pair can simultaneously mediate oxidative decarboxylation and reductive amination without enzymes. This redox activity extends to other α-ketoacids, producing key metabolites and amino acids such as succinate, acetate, formate, glutamate, alanine, and glycine. Structure-activity relationships highlight the importance of a carbamoyl group at the 3-position and suitable N-substitution for redox efficiency and stability, offering a physicochemical rationale for the natural selection of the nicotinamide ring. Electrochemical analyses and density functional theory (DFT) calculations provide mechanistic insights into the redox behaviour and reaction pathways of these cofactors. Our results suggest that simple redox-active molecules could have enabled early protometabolic coupling, helping bridge the gap between prebiotic chemistry and biological evolution.
    DOI:  https://doi.org/10.1038/s41467-026-72707-y
  50. J Cell Sci. 2026 May 07. pii: jcs.264913. [Epub ahead of print]
    A screening pipeline to characterize stress-induced enzymes uncovers a cellular function for the poorly characterized alcohol dehydrogenase Bdh2.
    Dunya Edilbi, Rosario Valenti, Benjamin Dubreuil, Yeynit Asraf, Yoav Peleg, Shira Albeck, Sergey Malitsky, Maxim Itkin, Maya Schuldiner.
      Cells possess intricate metabolic networks comprised of hundreds of enzymes. Despite extensive research, many of these enzymes remain uncharacterized. Identifying the function of these enzymes is crucial for advancing our understanding of cellular metabolism. However, multiple enzymes are not active in standard conditions, making them challenging to study. To overcome this challenge, we created a pipeline to track the upregulation of enzymes at the protein level during diverse growth conditions, suggesting a requirement for their activity in these conditions. To do this, we assembled a collection of ∼180 of yeast strains, each containing an uncharacterized putative enzyme fused to a fluorophore and under the regulation of its own promoter. By subjecting the collection to 42 diverse environments, we identified the biologically relevant conditions for the upregulation of 16 proteins. We focused on one such putative alcohol dehydrogenase, Bdh2, whose expression was upregulated during nutrient-limited conditions, and functionally characterized it. More broadly, our discovery pipeline lays the foundation for uncovering new stress-induced enzymes. This has implications in the cell biology of metabolism and biotechnology.
    Keywords:  Alcohol dehydrogenase; Cell metabolism; Enzymes; Metabolites; Metabolomics; Stress conditions
    DOI:  https://doi.org/10.1242/jcs.264913
  51. Nat Rev Immunol. 2026 May 08.
    Calibrating T cell responsiveness through interactions with self.
    Judith N Mandl, Heather J Melichar, Byron B Au-Yeung, Johannes Textor, Ludger Klein.
      During an immune response, T cells face one of the most consequential decisions of their lifespan upon recognition of a ligand they have not previously encountered: whether to exit the naive basal state, undergo clonal expansion and acquire effector functions. This process is often portrayed as a binary switch, in which naive cells from a highly diverse repertoire transition from an 'off' state to an 'on' state. However, this digital view overlooks the crucial prior information that T cells integrate through T cell receptor (TCR) interactions with self-peptide-MHC (self-pMHC). During thymic selection, immature T cells encounter a unique self-pMHC ligandome that shapes their development. After maturation, naive T cells continue to engage self-ligands as they patrol secondary lymphoid organs. Here we review evidence that these encounters with self-peptides are not only essential for T cell survival but also have lasting consequences that dynamically tune T cell function when called into action. The naive off state, therefore, is neither fixed nor functionally neutral. We argue that a deeper understanding of an individual's self-peptide repertoire is crucial for deciphering TCR self and non-self discrimination and for effectively harnessing T cell responses to foreign antigens.
    DOI:  https://doi.org/10.1038/s41577-026-01305-2
  52. bioRxiv. 2026 Apr 22. pii: 2026.04.20.718782. [Epub ahead of print]
    Ketone ester supplementation in aged mice reduces activation of B cell subsets.
    Ariel Adkisson-Floro, Ritesh Tiwari, Mitsunori Nomura, Rebeccah R Riley, Ryan Kwok, Durai Sellegounder, Mir M Khalid, Herbert G Kasler, John C Newman, Eric Verdin.
      Aging in the immune system results in increased susceptibility to infections, exacerbated autoimmunity, and reduced responsiveness to vaccines. However, there are no current established interventions for immune aging. Ketogenic diets and fasting have been researched as interventions against other aspects of aging and age-related diseases, and they work in part by increasing circulating levels of ketone bodies, which have anti-inflammatory properties and can boost T cell function. Exogenous ketones, such as ketone esters, are currently being studied as a more accessible approach to obtain the benefits of ketone bodies through direct supplementation. Here, we investigated whether ketone ester supplementation improves immune function during aging. Aged (19-month-old) C57BL/6JN mice were given a diet supplemented with the ketone ester or a control diet for 15 weeks. We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. In spite of this decrease in activation, mice on the ketone ester diet showed no impairment in antibody production after nitrophenyl-ovalbumin immunization. The ketone ester diet also inhibited glucose dependence and translation of age-associated B cells, likely through inhibition of mTOR signaling via ketone bodies. Our study elucidates the effect of ketone esters on B cells in the context of aging and unveils a new immunoregulatory role of ketone bodies on B cells.
    DOI:  https://doi.org/10.64898/2026.04.20.718782
  53. J Am Chem Soc. 2026 May 08.
    Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.
    Sofia Badolato, Sarah C Rossmann, Joana Pereira, Hyunho Kim, Ville R I Kaila.
      The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts, its long-range energy transduction principles remain much debated. Here, we study the molecular principles of proton transport by engineering the antiporter modules of Complex I. By combining directed mutagenesis with time-resolved spectroscopy and molecular dynamics (MD) simulations, we identify conserved residues along the proton channels that control the rate of proton transfer across proteoliposome membranes. The antiporter modules catalyze this tightly regulated proton transport by transient water wires that follow intrinsic electric fields along the proton channels. Based on MD simulations, we identify conserved gating sites, established by nonpolar residues, which modulate the hydration and electric field effects underlying the proton transport upon mutation. On a general level, our findings highlight how the modular energy-transduction machinery of Complex I employs a combination of electrostatic and conformational coupling principles to catalyze long-range proton transport, with distinct similarities to other enzymes.
    DOI:  https://doi.org/10.1021/jacs.6c05956
  54. Circulation. 2026 May 05. 153(18): 1421-1435
    Vascular Aging.
    Ruoqi Wang, Stephen Y Chan, Toren Finkel.
      Vascular aging is a central determinant of healthy life span, not only influencing the susceptibility to cardiovascular diseases but also shaping the risk of systemic decline across multiple organs. It is driven by a variety of age-related factors, including cellular senescence, chronic inflammation, loss of proteostasis, mitochondrial dysfunction, genomic instability, epigenetic remodeling, and stem cell exhaustion. These processes interact with the unique mechanical and metabolic environment of the vasculature to create a distinctive pathological trajectory, manifested in part as arterial stiffening, impaired barrier integrity, and dysregulated vasomotor control. Recent advances in single-cell omics and cross-organ molecular clocks have revealed the heterogeneity and organ specificity of aging, underscoring the need for integrative frameworks that connect vascular biology with overall health. Meanwhile, the development of diverse therapeutic strategies-ranging from senolytic and immune-mediated clearance to metabolic and mitochondrial interventions-highlights the translational potential of targeting the aging vasculature. Looking ahead, multimodal biomarkers and precision medicine may transform vascular aging from an inevitable process into a modifiable determinant of health span.
    Keywords:  DNA damage; aging; inflammation; mitochondria; stem cells
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.075567
  55. EMBO J. 2026 May 02.
    Spatial metabolomics: design, pitfalls and data interpretation.
    Prasad Phapale.
      
    DOI:  https://doi.org/10.1038/s44318-026-00797-x
  56. Nat Commun. 2026 05 07. pii: 4195. [Epub ahead of print]17(1):
    Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
    Maria E Gierisch, Enrica Barchi, Mirco Marogna, Moritz H Wallnöfer, Maria Ankarcrona, Luana Naia, Florian A Salomons, Nico P Dantuma.
      The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we conduct a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter. Genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, are enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A leads to dissociation of the aggregation-prone substrate from mitochondria, which is accompanied by enhanced ubiquitin-dependent proteasomal degradation. The presence of an aggregation-prone, amphipathic helix that localizes the reporter to mitochondria is crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhances degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose that mitochondria serve as a holdout compartment for aggregation-prone proteins. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72783-0
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