bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–03–22
fifty-four papers selected by
Christian Frezza, Universität zu Köln
  1. Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
  2. Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
  3. Do metabolic fluxes change with age?
  4. Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
  5. Proteasome-guided haem signalling axis contributes to T cell exhaustion.
  6. Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
  7. Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
  8. DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
  9. Catabolism of extracellular glutathione supplies cysteine to support tumours.
  10. Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
  11. Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
  12. Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.
  13. Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
  14. MFF budding from mitochondria regulates melanosome size and maturation.
  15. Pan-cancer evolution signatures link clonal expansion to dynamic changes in the tumor immune microenvironment.
  16. Celcomen: spatial causal disentanglement for single-cell and tissue perturbation modeling.
  17. Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells.
  18. Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.
  19. Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
  20. Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
  21. INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis.
  22. Dissecting Metabolic Rewiring and Gene-Metabolite Interactions by Utilizing Untargeted Metabolomics and Single-Gene Knockouts in the Model Microorganism E. coli.
  23. Oxidizing to optimize stemness and antitumor immunity.
  24. Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
  25. Integrin-dependent neutrophil slowing reduces lung perfusion and supports metastasis in a model of breast cancer.
  26. Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.
  27. Masked mitochondria slip into cells to treat disease in mice.
  28. Fundamental mechanism of ferroptosis: Three unanswered questions.
  29. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  30. FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression.
  31. Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.
  32. Mitochondrial Precursor Overaccumulation Stress.
  33. AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3.
  34. Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
  35. Oxysterols at the crossroads of cholesterol metabolism and cancer.
  36. Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.
  37. Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes.
  38. Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors.
  39. AI is programmed to hijack human empathy - we must resist that.
  40. p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration in human cancer cells.
  41. Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
  42. Spatial Regulation of the Plant Circadian Clock.
  43. L-2-hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression.
  44. AARS1-mediated lactylation of STAT1 drives immune evasion.
  45. ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
  46. Hepatic GAPDH prevents excessive fasting-induced steatosis via serine-dependent inhibition of diacylglycerol synthesis.
  47. Seeing lipids where they live.
  48. Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement.
  49. Inosine promotes erythrocyte metabolic reprogramming and restores oxygen release for rejuvenation via 2,3-BPG-PNP axis.
  50. A review of peroxisome biology: Potential implications for cardiac physiology and pathology.
  51. Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
  52. Beyond the Tumor Mass: From Initiating Clones to Overt Isocitrate Dehydrogenase-Mutant Gliomas.
  53. Age-related B cell dysfunction at the aging-cancer nexus: from shared manifestations to therapeutic potential.
  54. Mitochondria acidify lysosomes through membrane contacts.
  1. Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00185-3. [Epub ahead of print]45(4): 117107
    Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
    Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.
      Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.
    Keywords:  CP: cancer; CP: metabolism; GPT2; MYC; alanine metabolism; liver cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117107
  2. Nat Metab. 2026 Mar 19.
    Python metabolomics uncovers a conserved postprandial metabolite and gut-brain feeding pathway.
    Shuke Xiao, Mengjie Wang, Thomas G Martin, Barry Scott, Xing Fang, Xinming Liu, Yongjie Yang, Sipei Fu, Steven D Truong, Jack F Gugel, Gregory L Maas, Marcus P Mullen, Jennifer Hampton Hill, Veronica L Li, Andrew L Markhard, Mingming Zhao, Wei Qi, Saranya C Reghupaty, Meng Zhao, Jan Spaas, Wei Wei, Trine Moholdt, John A Hawley, Christian T Voldstedlund, Erik A Richter, Xiaoke Chen, Katrin J Svensson, Daniel Bernstein, Leslie A Leinwand, Yong Xu, Jonathan Z Long.
      Most mammals consume small and frequent meals. By contrast, pythons are ambush predators that exhibit extreme feeding and fasting patterns and provide a unique model for uncovering molecular mediators of the postprandial response1-3. Using untargeted metabolomics, we show that circulating levels of the metabolite para-tyramine-O-sulphate (pTOS) are increased more than 1,000-fold in pythons after a single meal. In pythons, pTOS production occurs in a microbiome-dependent manner via sequential decarboxylation and sulphation of dietary tyrosine. In both pythons and mice, pTOS administration activates a neural population in the ventromedial hypothalamus (VMH). In mice, these VMH neurons are required for the anorexigenic effects of pTOS. Chronic administration of pTOS to diet-induced obese male mice suppresses food intake and body weight. pTOS is also present in human blood, where its levels are increased after a meal. Together, these data uncover a conserved postprandial anorexigenic metabolite that links nutrient intake to energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01485-0
  3. Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]
    Do metabolic fluxes change with age?
    Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.
      Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.
    Keywords:  age-associated diseases; aging; autophagy; geroscience; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2026.01.013
  4. J Biol Chem. 2026 Mar 12. pii: S0021-9258(26)00237-1. [Epub ahead of print] 111367
    Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
    Karen Slattery, Gearóid Conlon, Ethan Collins, Derek P Nolan, Clair M Gardiner, Geraldine M O'Connor.
      Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111367
  5. Nature. 2026 Mar 18.
    Proteasome-guided haem signalling axis contributes to T cell exhaustion.
    Yingxi Xu, Yangtao Shangguan, Yu-Ming Chuang, Tzu-Hsuan Chang, Wenbing Liu, Jhan-Jie Peng, Josep Garnica, Leling Xie, Pei-Chun Hsueh, Mei-Chun Lin, Yi-Hao Wang, Karina Lobo Hajdu, Yibo Wu, Maryam Akrami, Chen Wang, Anna Kohl, Alfred Zippelius, Wei Qi, Min Wang, Bugi Ratno Budiarto, Shih-Yu Chen, Zhengtao Xiao, Panagiota Vardaka, Rahul Roychoudhuri, Zhiliang Bai, Rong Fan, Santiago Carmona, Yi-Ru Yu, Christoph Scheiermann, Jianxiang Wang, Ping-Chih Ho.
      The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-026-10250-y
  6. Nat Metab. 2026 Mar 18.
    Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
    Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.
      Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.
    DOI:  https://doi.org/10.1038/s42255-026-01484-1
  7. Trends Cancer. 2026 Mar 16. pii: S2405-8033(26)00004-X. [Epub ahead of print]
    Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
    Mustafa Sibai, Martin Zacharias, Nicholas McGranahan, Mariam Jamal-Hanjani, Eduard Porta-Pardo.
      The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from 'ecological buffering' by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.004
  8. Nat Metab. 2026 Mar 20.
    DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
    Alaa Madi, Hui Shi, Min Su, Ahmed Mady, Boqiong Lv, Haiyan Wang, Bing Yang, Zhenni Yan, Xiaomeng Jin, Lingling Wu, Mengyue Lv, Marvin Hering, Sicong Ma, Alessa Mieg, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora Knabe, Gernot Poschet, Karsten Richter, Nikolai Schleußner, Rene-Filip Jackstadt, Sonja Loges, F Nina Papavasiliou, Xi Wang, Jingxia Wu, Guoliang Cui.
      Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s42255-026-01462-7
  9. Nature. 2026 Mar 18.
    Catabolism of extracellular glutathione supplies cysteine to support tumours.
    Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Fatemeh Alimohammadi, Amal Afzal Khan, Veronica C Gomes, Bradley Smith, Jennifer J Twardowski, Bradley N Mills, Kevin A Welle, Sina Ghaemmaghami, Zhuoran Zhou, Yuhan Gan, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Guillaume Cognet, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Stephano S Mello, Brian J Altman, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.
      Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
    DOI:  https://doi.org/10.1038/s41586-026-10268-2
  10. Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]
    Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
    Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cell.2026.02.017
  11. Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096
    Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
    Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.
      Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.
    Keywords:  CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117096
  12. Nat Cell Biol. 2026 Mar 16.
    Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.
    Lennart Hoffmann, Marlen Duchmann, Katina Lazarow, Yun-Hsuan Huang, Fabian Lukas, Wen-Ting Lo, Regina Feil, Christopher Schmied, Martin Lehmann, John E Lunn, Ilaria Piazza, Jens P von Kries, Volker Haucke, Tanja Maritzen.
      Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signalling. The best understood adhesion structures are focal adhesions (FAs). In spite of their importance, our knowledge of upstream factors that integrate FA dynamics with other cellular processes, such as metabolism, remains fragmentary. Using a genome-wide screen, we identify aldolase A, a key glycolytic enzyme that converts fructose-1,6-bisphosphate (FBP), as a regulatory switch that links metabolic flux to FA assembly and cell morphogenesis. We show that cellular FBP serves as a signalling metabolite, which transmits information about the metabolic cell state to the actin-based machinery for cell adhesion and protrusion. This mechanism involves FBP binding to the Rac1 inhibitor RCC2 and a concomitant elevation of Rac1 activity resulting in actin reorganization, increased FA assembly and elevated protrusive activity. Here we predict this mechanism to be crucial for processes ranging from development to cancer.
    DOI:  https://doi.org/10.1038/s41556-026-01911-1
  13. Genome Biol Evol. 2026 Mar 16. pii: evag067. [Epub ahead of print]
    Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
    Jess E Sterling, Kendra D Zwonitzer, Justin C Havird.
      Why do some species live for mere months, while others persist for centuries? A leading explanation implicates mitochondria. The mitochondrial theory of aging predicts that mitochondrial efficiency diminishes with age due to the accumulation of mutations within mitochondrial DNA (mtDNA). While experimental evidence for this theory is mixed, evolutionary analyses offer an ideal opportunity to determine if mitochondrial substitution rates are linked to longevity. Here, we explored the relationship between mtDNA evolution and species' lifespans across four clades-Aves, Actinopterygii, Bivalvia, and Sebastidae-using five normalization strategies. Across most methods, long-lived vertebrates showed reduced synonymous and nonsynonymous substitution rates, suggesting lower mtDNA mutation. However, we found that the strength and direction of these relationships varied drastically depending on the normalization approach used (i.e., correcting for divergence, generation time, and phylogeny). We also analyzed mtDNA mutation spectra and found similar patterns in long- and short-lived species, suggesting decreased rates of mtDNA mutations in long-lived species are not due to suppression of specific mutation processes, as predicted from the free-radical theory of aging. We also find little evidence for a relationship between selection on mitochondrial protein-coding genes and lifespan. Our results align with the idea that decreased mutation rates may help preserve mitochondrial integrity in long-lived vertebrate species, but that these species have not been selected to have particularly efficient OXPHOS or protection against a specific mitochondrial mutation process. Together, these findings underscore the critical link between mitochondrial stability and lifespan, and highlight the power of natural systems in this field.
    Keywords:  Mitochondrial DNA; comparative genomics; generation time; longevity; phylogenetic comparative methods; substitution rates
    DOI:  https://doi.org/10.1093/gbe/evag067
  14. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  15. Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00176-2. [Epub ahead of print]45(3): 117098
    Pan-cancer evolution signatures link clonal expansion to dynamic changes in the tumor immune microenvironment.
    Xinyu Yang, Wei Liu, Geoff Macintyre, Peter Van Loo, Florian Markowetz, Peter Bailey, Ke Yuan.
      Cancer is an evolutionary process characterized by profound intratumor heterogeneity (ITH), which can be quantified using in silico estimates of cancer cell fractions (CCFs) of tumor-specific somatic mutations. We demonstrate a data-driven approach based on CCF distributions to identify 4 robust pan-cancer evolutionary signatures from 4,146 tumors across 17 cancer types in The Cancer Genome Atlas (TCGA). These signatures define a continuum of cancer cell fractions reflecting neutral evolution, clonal expansion, and clonal fixation. Correlating evolutionary signatures with mutational and biological programs reveals that tumors enriched for clonal expansion and fixation are associated with immune evasion and distinct changes in the tumor immune microenvironment. Our analysis reveals a dynamic shift from adaptive to innate immune programs as tumors progress toward clonal fixation and escape immune surveillance, accompanied by the clonal expansion of driver genes modulating tumor-stroma interactions. These evolutionary dynamic subtypes are further associated with clinical outcomes and immunotherapy responses.
    Keywords:  CP: cancer; CP: genomics; cancer evolution; evolutionary dynamics; intratumor heterogeneity; machine learning; pan-cancer; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117098
  16. Nat Commun. 2026 Mar 18.
    Celcomen: spatial causal disentanglement for single-cell and tissue perturbation modeling.
    Stathis Megas, Daniel G Chen, Krzysztof Polanski, Hesam Asadollahzadeh, Moshe Eliasof, Carola-Bibiane Schönlieb, Sarah A Teichmann.
      Celcomen leverages a mathematical causality framework to disentangle intra- and inter-cellular gene regulation programs in spatial transcriptomics data through a generative graph neural network. It is a first step towards perturbation models of Virtual Tissues and can generate post-perturbation counterfactual spatial transcriptomics, thereby offering access to experimentally inaccessible samples. We validated its disentanglement, identifiability of causal structure, and counterfactual prediction capabilities through simulations and in clinically relevant human glioblastoma, human fetal spleen, and mouse lung cancer samples. Celcomen provides the means to model disease- and therapy-induced changes allowing for new insights into single-cell spatially resolved tissue responses.
    DOI:  https://doi.org/10.1038/s41467-026-69856-5
  17. Sci Rep. 2026 Mar 18.
    Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells.
    Bobak Parang, Liron Yoffe, Rabia Khan, Zhongchi Li, Michal J Nagiec, Eric E Gardner, Yiwey Shieh, Rachel S Heise, Ashish Saxena, Nasser Altorki, John Blenis.
      
    Keywords:  Drug-tolerant persister; EGFR-mutant; Lung cancer; Propionate metabolism
    DOI:  https://doi.org/10.1038/s41598-026-44451-2
  18. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2532814123
    Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.
    Evan R Abt, Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M Peña-Garcia, Lauryn Ruegg, Jami McLaughlin, Donghui Cheng, Nikolas G Balanis, Chia-Chun Chen, Yang Xu, Yi Xing, Sanaz Memarzadeh, Caius G Radu, Thomas G Graeber, Owen N Witte.
      Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.
    Keywords:  RB tumor suppressor; nucleotide metabolism; small cell cancer; synthetic lethality
    DOI:  https://doi.org/10.1073/pnas.2532814123
  19. Nat Commun. 2026 03 16. pii: 2532. [Epub ahead of print]17(1):
    Single-cell multi-omic analysis of mitochondrial mutational mosaicism and dynamics.
    Yu-Hsin Hsieh, Pauline Kautz, Lena Nitsch, Ambre M Giguelay, Janet Liebold, Veronika Dimitrova, Stephania Contreras Castillo, Freya Jungen, Gabor Zsurka, Genevieve Trombly, Markus Schuelke, Wolfram S Kunz, Caleb A Lareau, Leif S Ludwig.
      Mitochondrial DNA (mtDNA) mutations occur more frequently than nuclear mutations and are associated with various diseases. While single-cell sequencing enables mtDNA variant heteroplasmy analysis, a holistic view of mtDNA mutational landscapes in individual cells has remained limited. Here, we leverage mitochondrial single-cell ATAC-seq and mtDNA-hypermutated POLGD274A knock-in HEK293 cell lines to introduce two metrics-single-cell mtDNA mutations per million base pairs (scmtMPM) and heteroplasmy-weighted mitochondrial local constraint scores (scwMSS)-to capture cellular mutational loads and somatic mosaicism. We demonstrate that individual POLGD274A cells exhibit complex mutational landscapes, with pathogenic mutations and truncating variants only present at subthreshold levels, indicative of their negative selection. In human healthy donors and mitochondriopathy patients, we identify constrained mutations in complex I, highlighting previously unrecognized mtDNA mutational landscape heterogeneity present on the single-cell level. Overall, scmtMPM and scwMSS provide a framework to investigate fundamental properties of mitochondrial genetics, disease, and somatic mosaicism.
    DOI:  https://doi.org/10.1038/s41467-026-70399-y
  20. bioRxiv. 2026 Mar 03. pii: 2026.03.02.708949. [Epub ahead of print]
    Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
    Nithya Balasundaram, Ayşegül Erdem, Azeem Sharda, Veerle W Daniels, Phillip L Chea, Fleur Leguay, Youzhong Liu, Mark A Keibler, Charles Vidoudez, Andrew A Lane, Didier Vertommen, Hans Casteur, Michaël R Laurent, Sunia A Trauger, Gregory Stephanopoulos, David T Scadden, Nick van Gastel.
      Though cancer cells' altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.
    DOI:  https://doi.org/10.64898/2026.03.02.708949
  21. Nat Commun. 2026 Mar 15.
    INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis.
    Yuran Duan, Shuo Wang, Jianyu Liu, Wenxing Qin, Yuli Shen, Yueru Hou, Xue Sun, Yanni Lin, Zhiqiang Hu, Bofei Dong, Yanli Bi, Huang Yang, Min Li, Liwei Xiao, Qingang Wu, Xueli Bai, Yuhao Wang, Gaopeng Li, Yuan Ding, Zhengwei Mao, Yang Luo, Zhimin Lu, Tong Liu, Daqian Xu, Shijian Liu, Peng Zhan, Zheng Wang.
      Aerobic glycolysis supports tumor growth, but how tumor cells sense glucose to coordinate biosynthesis remains largely unclear. Here we show that in hepatocellular carcinoma cells, glucose-activated PKCε phosphorylates the purine synthesis enzyme ADSL, triggering its translocation to the endoplasmic reticulum. ADSL then promotes succination of INSIG1/2, which disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi, the activation of SREBP-1 and the transcription of downstream lipogenesis-related genes, proliferation of tumor cells, and tumorigenesis in mice. Through virtual screening, we identify Elsulfavirine, an approved HIV drug, which blocks ADSL-INSIG interaction and suppresses SREBP-1 activation induced by glucose. Combining Elsulfavirine with Lenvatinib synergistically inhibits tumor growth. Clinically, ADSL phosphorylation and INSIG succination correlate with SREBP-1 activation and poor prognosis in human HCC. In summary, these findings reveal a repurposing mechanism by which tumor cells coordinate glucose metabolism and lipogenesis via a moonlighting function of ADSL and underscore a repurposing strategy for liver cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-026-70583-0
  22. J Am Soc Mass Spectrom. 2026 Mar 16.
    Dissecting Metabolic Rewiring and Gene-Metabolite Interactions by Utilizing Untargeted Metabolomics and Single-Gene Knockouts in the Model Microorganism E. coli.
    Xinru Pang, Li Chen, Huan Zhang, Shiqi Zhang, Jiangjiang Zhu.
      Central carbon metabolism, comprising glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway (PPP), is essential for Escherichia coli survival and growth. While disruptions in these pathways are known to affect cellular physiology, the system-wide metabolite-level consequences of single-gene knockouts remain incompletely understood. Using untargeted LC-MS metabolomics, we systematically profiled E. coli knockouts of TCA core enzymes, isoforms, subunits, bypass routes, and TCA-associated pathways. Core TCA knockouts separated into two major metabolic clusters, with cluster 1 strains displaying strong divergence in amino acid metabolism and cluster 2 retaining partial similarity to the parent strain. Isoform-specific deletions revealed differential roles of aconitases (ΔacnA vs ΔacnB) and fumarases (ΔfumA vs ΔfumC), while subunit knockouts of 2-oxoglutarate dehydrogenase (ΔsucA, ΔsucB) and succinate dehydrogenase (ΔsdhA-D) produced localized but distinct metabolite shifts, particularly around glutamate- and 2-oxoglutarate-linked metabolism. Bypass enzyme deletions (ΔaceA, ΔaceB, ΔglcB, and ΔmaeB) disrupted carbohydrate- and redox-related metabolites, underscoring their role as metabolic safety nets. Importantly, knockouts also triggered off-target effects in glycolysis, PPP, and the electron transport chain, highlighting the interconnectivity of central carbon metabolism. Our systematic approach demonstrated the possibility of utilizing comprehensive and untargeted metabolomics to map gene-metabolite associations and decipher potential metabolic interlinks.
    Keywords:  Escherichia coli; central carbon metabolism; gene-metabolite interaction; metabolic rewiring; single-gene knockout model; untargeted metabolomics
    DOI:  https://doi.org/10.1021/jasms.5c00454
  23. Cell Chem Biol. 2026 Mar 19. pii: S2451-9456(26)00067-X. [Epub ahead of print]33(3): 280-281
    Oxidizing to optimize stemness and antitumor immunity.
    Julian J Lum.
      In this issue of Cell Chemical Biology, Pang et al.1 address the question of how effector CD8⁺ T cells acquire stem-like durability. They uncover a redox-driven metabolic program in which NQO1-mediated cycling of lawsone enhances pentose phosphate pathway, remodels mitochondrial function, and connects effector differentiation to sustained antitumor immunity.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.02.011
  24. Nat Commun. 2026 03 14. pii: 2487. [Epub ahead of print]17(1):
    Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
    Valentin Duhay, Miaomiao Tian, Klaudia Kosieradzka, Michael Ebner, Wen-Ting Lo, Michael Krauss, Henner-Linus Sprengel, Matthias Voss, Mara Riechmann, Jeffrey N Savas, Michael Schwake, Volker Haucke, Markus Damme.
      Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.
    DOI:  https://doi.org/10.1038/s41467-026-70345-y
  25. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00179-8. [Epub ahead of print]45(3): 117101
    Integrin-dependent neutrophil slowing reduces lung perfusion and supports metastasis in a model of breast cancer.
    Frédéric Fercoq, Gemma S Cairns, Victoria L Bridgeman, Marco De Donatis, John B G Mackey, Alessia Floerchinger, Amanda J McFarlane, Judith Secklehner, Ximena L Raffo-Iraolagoitia, Madeline Harrington, Lynn McGarry, Demi Brownlie, Declan Whyte, Lindsey W G Arnott, Colin Nixon, Robert Wiesheu, Anna Kilbey, Leah Brown, Sarwah Al-Khalidi, Jim C Norman, Edward W Roberts, Ilaria Malanchi, Karen Blyth, Seth B Coffelt, Leo M Carlin.
      Neutrophils are critical in establishing a tumor-cell-nurturing and immunosuppressive pulmonary "pre-metastatic" niche in breast cancer. The localization and behavior of these neutrophils is, however, not well described. Using multiplexed imaging to investigate the pre-metastatic lung in a spontaneously metastatic mammary cancer model, we uncover that neutrophils with impaired intravascular motility congest the capillaries of pre-metastatic lungs. Slowed neutrophil transit is reversed by activating β2 integrin with an antibody and can be recapitulated by treating non-tumor-bearing mice with G-CSF. Neutrophil congestion causes a reduction of intravenously injected microbeads in the lung, suggestive of lower perfusion. In a model where tumor cells are injected intravenously into mammary-cancer-bearing Rag1-deficient mice, we observe lower lung experimental metastasis burdens after activating β2 integrins. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries contributes to the pulmonary pre-metastatic niche.
    Keywords:  CP: cancer; CP: immunology; breast cancer; imaging; lung; metastasis; neutrophils
    DOI:  https://doi.org/10.1016/j.celrep.2026.117101
  26. Nat Commun. 2026 Mar 17.
    Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice.
    Xuhao Zhang, Yu Gao, Wenbo Hu, Yong Liang, Xiaozhe Yin, Xiangjun Shi, Hongjia Li, Huiping Liao, Jingya Guo, Xiaohong Yu, Mingzhao Zhu, Hua Peng, Wenyan Wang, Yang-Xin Fu.
      Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3+TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFNα-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFNα and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-026-70876-4
  27. Nature. 2026 Mar 19.
    Masked mitochondria slip into cells to treat disease in mice.
    Edward Chen.
      
    Keywords:  Cell biology; Gene therapy; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00869-2
  28. Ferroptosis Oxid Stress. 2026 ;pii: 202512. [Epub ahead of print]2(2):
    Fundamental mechanism of ferroptosis: Three unanswered questions.
    Hanna Feinsod, Brent R Stockwell.
      Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, has been extensively studied since its conceptualization in 2012 and has been suggested as a therapeutic target in many cancers and degenerative diseases. However, three fundamental questions remain unanswered about ferroptosis. First, the mechanisms by which cells execute death during ferroptosis remain elusive: The key role of lipid peroxides in triggering ferroptosis is established, but how this results in the death of a cell remains unclear. Second, the physiological role of ferroptosis throughout the human life cycle is unclear; currently, there is evidence for ferroptosis in early development, immunity, aging, and tumor suppression, but not in many other aspects of physiology. Third, and finally, the intersection between ferroptosis and other RCD modalities, such as apoptosis, necroptosis, pyroptosis, and autophagic cell death, is necessary for understanding how ferroptosis integrates into networks controlling cellular fate. Addressing these gaps in knowledge is essential for building a comprehensive understanding of this mode of cell death, as well as translating ferroptosis knowledge into effective therapeutics.
    Keywords:  Ferroptosis; ROS; iron; lipid; metabolism; peroxidation
    DOI:  https://doi.org/10.70401/fos.2026.0015
  29. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  30. Cell Death Discov. 2026 Mar 19.
    FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression.
    Zikai Guo, Hongxiao Jiang, Xu Wang, Ke Xuan, Huidong Zhong, Chengxi Liu, Mengkai Zhang, Zhichao Li, Weiren Huang, Yangyang Sun.
      Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of the von Hippel-Lindau (VHL) gene, leading to constitutive activation of hypoxia-inducible transcription factors (HIFs) and metabolic reprogramming toward aerobic glycolysis. Although core fucosylation catalysed by fucosyltransferase 8 (FUT8) is known to regulate receptor signaling and tumor malignancy, its role in metabolic regulation of ccRCC remains poorly defined. Here, we demonstrate that FUT8 knockdown significantly suppresses ccRCC proliferation and migration both in vitro and in vivo. Mechanistically, FUT8 enhances HIF-1α-driven glycolysis, increasing lactate production and promoting pan-lysine lactylation (pan-Kla). Specifically, FUT8 promotes pyruvate kinase M2 (PKM2) K115 lactylation, which boosts its enzymatic activity while reducing nuclear localization, thereby driving epithelial-mesenchymal transition and malignant progression. Collectively, our findings reveal the FUT8-HIF-1α-lactate-PKM2 axis as a key mechanism that links core fucosylation to metabolic reprogramming and malignant progression in ccRCC and highlights FUT8 as a promising therapeutic target.
    DOI:  https://doi.org/10.1038/s41420-026-03013-1
  31. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00162-2. [Epub ahead of print]45(3): 117084
    Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.
    Siyi Xie, Taiqi Chen, Linfeng Li, Chunyu Tan, Peng Jiang.
      Metabolic regulation is central to the tumor suppressor function of p53. By analyzing the human patients with autoimmune diseases, we found that p53 expression was significantly reduced in Treg cells, negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Treg function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration largely recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in patients with autoimmune diseases and correlates with poor efficacy of first-line therapies. Together, these findings reveal a direct connection between propionyl-CoA metabolism and histone modifications, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.
    Keywords:  CP: immunology; CP: metabolism; Treg cells; autoimmunity; histone propionylation; p53; propionyl-CoA anabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117084
  32. Annu Rev Biochem. 2026 Mar 20.
    Mitochondrial Precursor Overaccumulation Stress.
    Liam P Coyne, Xin Jie Chen.
      Damage to mitochondria imparts multifaceted cellular stress that extends beyond bioenergetic deficit. One newly emerged example is mitochondrial precursor overaccumulation stress (mPOS). mPOS is marked by impaired mitochondrial protein import, causing the toxic accumulation and aggregation of unimported mitochondrial precursor proteins in the cytosol. Analogous to the well-studied endoplasmic reticulum stress, which blocks proteins from leaving the cell, mPOS can impose a drastic proteostatic burden in the cytosol and closely interconnects with cell signaling pathways. Here, we review how researchers discovered mPOS and discuss its central importance in several major mitochondria-induced stress signaling pathways. We then focus on the emerging field of mPOS in cell demise and human disease, and we present recent evidence that mPOS can affect cell fitness and survival independent of bioenergetics. Looking forward, mPOS may provide a complementary or alternative pathogenic mechanism to bioenergetic deficit for classic mitochondriopathy and many aging-associated degenerative diseases involving mitochondrial stress.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-061016
  33. Reproduction. 2026 Mar 14. pii: xaag035. [Epub ahead of print]
    AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3.
    Hai-Hui Zhang, Zhi-Ling Zhang, Wei Xu.
      Premature ovarian insufficiency (POI) often arises from genetic causes, yet the pathogenic consequences of many variants remain undefined. The AARS2 R199C mutation has been repeatedly reported in patients, but its physiological effects were unknown. Here, we generated the first homozygous Aars2 R194C knock-in mouse to model this variant in vivo. Female knock-in mice showed irregular estrous cycles, reduced fecundity, altered endocrine profiles, and accelerated depletion of the primordial follicle pool, reproducing core features of POI. Mutant ovaries exhibited increased lysine lactylation of the metabolic enzymes pyruvate dehydrogenase alpha 1(PDHA1) and carnitine palmitoyltransferase 2(CPT2), accompanied by reduced activity and impaired mitochondrial respiration in granulosa cells. These metabolic defects were associated with sustained activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and premature follicle activation. Loss of the mitochondrial de-lactylase Sirtuin-3 mitigated these abnormalities, whereas pharmacological inhibition of pyruvate dehydrogenase and carnitine palmitoyltransferase in wild-type mice phenocopied key knock-in features. Together, these findings demonstrate that the Aars2 R194C/R199C mutation alone is sufficient to induce POI and establish a lactylation-driven metabolic mechanism underlying early follicle activation.
    Keywords:  AARS2; granulosa cells; lactylation; mitochondrial metabolism; premature ovarian insufficiency; primordial follicles
    DOI:  https://doi.org/10.1093/reprod/xaag035
  34. Biogerontology. 2026 Mar 15. pii: 71. [Epub ahead of print]27(2):
    Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
    Jyothi Priyanka Ghantasala, Timothy Wai, Writoban Basu Ball, Manjunatha Thondamal.
      Mitochondria provide energy and maintain homeostasis, and their dysfunction relates to aging. Disrupted structure and function of mitochondria are linked to age-related diseases, but the roles of many mitochondrial proteins in mitochondrial dynamics and aging remain unclear. We studied the role of the mitochondrial fission protein MTP-18 in mitochondrial dynamics and aging in C. elegans. Our data show that loss of mtp-18 increases longevity and stress resistance, alongside changes in key physiological processes. We tested whether mtp-18-mediated longevity is linked to the PI3K-dependent insulin/IGF-1 signaling (IIS) pathway. mtp-18-mediated longevity requires the Forkhead transcription factor DAF-16, a primary effector of the IIS pathway, but is not mediated by the canonical IIS cascade. We also observed unique interactions between mtp-18 and genes encoding components of the mobile electron carrier system in mitochondria, such as coenzyme Q and cytochrome c. Our study reveals that mtp-18 is an evolutionarily conserved, key aging regulator that maintains mitochondrial morphology. What sets this study apart from previous research is the identification of a novel mechanism by which MTP-18 affects these processes independently of the canonical IIS pathway, particularly through unique interactions with genes encoding components of the electron transport chain.
    Keywords:   C. elegans ; Electron transport chain; Insulin signlling pathway; Longevity; Mitochondrial fission; ROS
    DOI:  https://doi.org/10.1007/s10522-026-10415-2
  35. Semin Cancer Biol. 2026 Mar 14. pii: S1044-579X(26)00031-3. [Epub ahead of print]121 22-32
    Oxysterols at the crossroads of cholesterol metabolism and cancer.
    Julio Buñay, Silia Ayadi, Chloe Gressein, Philippe de Medina, Sandrine Silvente-Poirot, Marc Poirot.
      Oxysterols are enzymatically or non-enzymatically generated cholesterol derivatives that act as metabolic messengers at the interface of lipid homeostasis, nuclear receptor signaling, oxidative stress, and immunity. Their structural diversity endows them with highly selective biological activities: some function as ligands for LXRα/β, ERα, or GR; others regulate sterol trafficking, autophagy, redox equilibrium, and membrane organization. In cancer, this versatility translates into a dualistic influence on tumor biology. The oxysterol dendrogenin A activates differentiation programs, antioxidant defenses, and immunogenic pathways, whereas 27-hydroxycholesterol and oncosterone promote proliferation, endocrine resistance, and immune escape. The 5,6-epoxycholestanol pathway exemplifies this metabolic bifurcation: the same precursor may be routed toward dendrogenin A, supporting anticancer immunity, or toward OCDO, a glucocorticoid-like oncometabolite that suppresses cytotoxic lymphocytes and enhances tumor survival. A third axis, governed by CYP27A1, introduces additional complexity by hydroxylating the oncogenic oxysterol OCDO into an antiproliferative metabolite. These interlocking routes form a sterol-centered signaling network that integrates metabolic state with tumor progression and immune surveillance. Understanding how tumors rewire oxysterol metabolism, and how these lipid signals shape cellular plasticity and the tumor microenvironment, offers a promising framework for identifying metabolic vulnerabilities and designing sterol-based therapeutic strategies.
    Keywords:  Breast cancer; CYP27A1; ChEH; Cholesterol metabolism; DHCR7; Ferroptosis; GR; LXRβ; Lipid metabolic alterations; Oxysterols; Redox signaling
    DOI:  https://doi.org/10.1016/j.semcancer.2026.03.001
  36. EMBO J. 2026 Mar 20.
    Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.
    Varun Jayeshkumar Shah, Oliver Hartmann, Martin Wegner, Cristian Prieto-Garcia, Rubina Kazi, Viktoria von Heyl Zu Herrnsheim, Amin Wanli, Igor Mačinković, Bianka Bohnacker, Koraljka Husnjak, Dmitry Namgaladze, Mathias Rosenfeldt, Manuel Kaulich, Markus E Diefenbacher, Ivan Dikic.
      Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer dependencies, including ubiquitin ligase subunit KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated Nrf2 and upregulated Aldh3a1. This led to elevated reductive stress and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.
    Keywords:  CRISPR/Cas9; Keap1; NSCLC; Reductive Stress; Ubiquitin-Proteasome System
    DOI:  https://doi.org/10.1038/s44318-026-00737-9
  37. Cell Syst. 2026 Mar 18. pii: S2405-4712(25)00310-2. [Epub ahead of print]17(3): 101477
    Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes.
    Gregory J Brunette, Richard W Tourdot, Jinyu Wang, Darawalee Wangsa, David Pellman, Cheng-Zhong Zhang.
      Complex karyotype changes are widespread in cancer genomes. A major gap in cancer genome characterization is the resolution of rearranged chromosomes with chromosome-length continuity. Here, we describe a two-tiered approach to determine the segmental composition of rearranged chromosomes with haplotype resolution. First, we present refLinker, a bioinformatic method for robust determination of chromosomal haplotypes using cancer Hi-C data. By contrast with existing methods, refLinker is insensitive to the presence of large-scale DNA deletions, duplications, and high-level amplification in cancer genomes. Second, we demonstrate a computational strategy to determine the segmental structure of rearranged chromosomes using haplotype-specific Hi-C contacts. We apply these methods to breast cancer genomes and provide direct evidence for long-range transcriptional changes associated with rearrangements of the inactive X chromosome. Together, these results highlight refLinker's broad utility for studying the functional consequences of chromosomal rearrangements.
    Keywords:  X chromosome inactivation; cancer genome assembly; digital karyotype; haplotype phasing
    DOI:  https://doi.org/10.1016/j.cels.2025.101477
  38. Nat Commun. 2026 Mar 17.
    Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors.
    Carmen R Moncayo, Restuadi Restuadi, Guanying Zhang, Daniel Marks, Paula Ortega-Prieto, Emily Doherty, Nathalie Lambie, Chad Whilding, Ivan Andrew, Alex Montoya, Bhavik Patel, Katie Tyson, Betheney R Pennycook, Lauren Pendergast, Vincen Wu, Zoltan Takats, Nik Matthews, George R Young, Priyanka Verma, Pavel Shliaha, Laurence Game, Boris Lenhard, Iain McNeish, Christina Fotopoulou, Alexis R Barr, Paula Cunnea, Zoe Hall, Louise Fets.
      For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals enrichment of apoptotic and lysosomal signatures in high-drug regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with rucaparib-high cells demonstrating increased drug response relative to rucaparib-low. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content alters intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response.
    DOI:  https://doi.org/10.1038/s41467-026-70558-1
  39. Nature. 2026 Mar;651(8106): 559
    AI is programmed to hijack human empathy - we must resist that.
    Mustafa Suleyman.
      
    Keywords:  Computer science; Machine learning; Policy
    DOI:  https://doi.org/10.1038/d41586-026-00834-z
  40. Elife. 2026 Mar 17. pii: RP107538. [Epub ahead of print]14
    p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration in human cancer cells.
    Ravi Kumar, Simon Couly, Bruna R Muys, Xiao Ling Li, Ioannis Grammatikakis, Ragini Singh, Mary Guest, Xinyu Wen, Wei Tang, Stefan Ambs, Lisa M Jenkins, Erica C Pehrsson, Raj Chari, Tsung-Ping Su, Ashish Lal.
      The tumor suppressor p53 is a transcription factor that controls the expression of hundreds of genes. Emerging evidence indicates that the p53-induced RNA-binding protein ZMAT3 acts as a key splicing regulator that contributes to p53-dependent tumor suppression in vitro and in vivo. However, the mechanism by which ZMAT3 functions within the p53 pathway remains largely unclear. Here, we discovered a function of ZMAT3 in inhibiting transcription of HKDC1, a hexokinase that regulates glucose metabolism and mitochondrial respiration in human cancer cells. Quantitative proteomics revealed HKDC1 as the most significantly upregulated protein in ZMAT3-depleted colorectal cancer cells. ZMAT3 depletion resulted in increased mitochondrial respiration, which was rescued by simultaneous depletion of HKDC1, suggesting that HKDC1 is a critical downstream effector of ZMAT3. Unexpectedly, ZMAT3 did not bind to HKDC1 RNA or DNA; however, proteomic analysis of the ZMAT3 interactome identified its interaction with the oncogenic transcription factor JUN. ZMAT3 depletion enhanced JUN binding to the HKDC1 locus, leading to increased HKDC1 transcription that was rescued upon JUN depletion, suggesting that JUN activates HKDC1 transcription in ZMAT3-depleted cells. Collectively, these findings uncover a mechanism by which ZMAT3 regulates transcription through JUN and demonstrate that HKDC1 is a key component of the ZMAT3-regulated transcriptome in the context of mitochondrial respiration regulation.
    Keywords:  HKDC1; JUN; ZMAT3; cancer biology; chromosomes; gene expression; human; mitochondrial respiration; p53; transcription factors
    DOI:  https://doi.org/10.7554/eLife.107538
  41. Eur J Neurosci. 2026 Mar;63(6): e70463
    Mobile Powerhouses: Mitochondria Transfer via Tunnelling Nanotubes in Brain Health and Neurodegenerative Diseases.
    Anna Henrich, Hannah Scheiblich.
      Mitochondria are central regulators of cellular metabolism, calcium homeostasis and survival. Owing to the brain's exceptional energy demand, mitochondrial dysfunction is tightly linked to neurodegenerative and neuroinflammatory disorders. Recent evidence challenges the traditional view of mitochondria as strictly cell-autonomous organelles, revealing that they can be exchanged between cells via intercellular transfer by extracellular vesicles, gap junctions or tunnelling nanotubes (TNTs) as part of an adaptive mechanism of metabolic support and signalling. Among the pathways mediating this intercellular exchange, TNTs-thin, actin-rich cytoplasmic bridges-have emerged as key conduits for mitochondrial transfer in the nervous system. TNTs enable bidirectional exchange of mitochondria between neurons, glia and vascular cells, thereby promoting bioenergetic recovery after injury and modulating immune and inflammatory responses. This review summarizes current evidence for TNT-mediated mitochondrial transfer in the brain and highlights the underlying molecular mechanisms that coordinate mitochondrial movement, including cytoskeletal dynamics, mitochondrial trafficking machinery and stress-induced signalling cascades. While mitochondrial donation can restore metabolic balance and promote neuroprotection, it may also facilitate the spread of pathological proteins, contributing to disease progression. Understanding the underlying molecular mechanism of TNT-mediated mitochondrial transfer provides a new framework for exploring metabolic communication and cellular resilience in the brain. By emphasizing emerging conceptual and mechanistic insights, we outline how advancing this field could pave the way for the development of innovative therapeutic strategies for neurodegenerative and neuroinflammatory disorders.
    Keywords:  Miro1/2; actin dynamics; cell–cell connectivity; cytoskeletal remodelling; intercellular communication
    DOI:  https://doi.org/10.1111/ejn.70463
  42. Annu Rev Plant Biol. 2026 Mar 16.
    Spatial Regulation of the Plant Circadian Clock.
    Ho-Wei Wu, James C W Locke.
      The plant circadian clock enables the precise timing of physiological processes across the day-night cycle by generating endogenous 24-h rhythms in gene expression. In Arabidopsis, an iteration between experiments and modeling has uncovered a core oscillator comprising interlocked transcriptional feedback loops. However, emerging techniques now reveal that circadian dynamics vary across organs, tissues, and even individual cells, highlighting the need for spatially resolved clock models. In this review, we explore evidence for spatial variation in clock regulation, including differences in sensitivity to environmental cues, the timing of clock components, and the nature of downstream outputs. We discuss how local cellular rhythms are coordinated to achieve robust organism-level timing and consider how spatial regulation of the clock may contribute to the control of diverse developmental processes.
    DOI:  https://doi.org/10.1146/annurev-arplant-083123-102431
  43. J Clin Invest. 2026 Mar 17. pii: e197010. [Epub ahead of print]
    L-2-hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression.
    Wen Gu, Xun Wang, Ashley Solmonson, Ling Cai, Yi Xiao, Alpaslan Tasdogan, Jordan Franklin, Yuannyu Zhang, Hua Zhang, Aundrea K Westfall, Ashley Rowe, Hetali Trivedi, Brandon Faubert, Zheng Wu, Jessica Sudderth, Lauren G Zacharias, Bushra Afroze, Ilya Bezprozvanny, Sunil Sudarshan, Feng Cai, Samuel K McBrayer, Thomas P Mathews, Ralph J DeBerardinis.
      High levels of L- and D-2-hydroxyglutarate (2HG), the reduced forms of α-ketoglutarate (αKG), are implicated in neurodevelopmental disorders and cancer by modulating αKG-dependent dioxygenases involved in histone, DNA and RNA demethylation. L-2HG dehydrogenase (L2HGDH) deficiency, a rare autosomal recessive inborn error of metabolism associated with systemic L-2HG elevation, causes progressive neurological disability and increased brain tumor risk of unclear mechanism. Using an isogenic, patient-derived induced pluripotent stem cell (iPSC) system, we examined the impact of L2HGDH deficiency on neural progenitor cell (NPC) function and neuronal differentiation. L2HGDH deficiency caused L-2HG accumulation, NPC hyperproliferation, increased clonogenicity, and defective neuronal differentiation in 2D cultures and cortical spheroids. Editing the L2HGDH locus to wild-type reversed these effects. Inhibiting glutaminase reduced L-2HG levels and induced neuronal differentiation. L-2HG-dependent inhibition of KDM5 histone demethylases led to widespread retention of H3K4me2/3, markers of active gene expression, with prominent enrichment at the MYC locus and elevated MYC expression across multiple neural cell types. Despite broadly altered histone methylation, genetically or pharmacologically normalizing MYC completely restored neuronal differentiation. These data indicated that a primary metabolic disturbance activated MYC to favor self-renewal and suppress neuronal lineage commitment.
    Keywords:  Clinical Research; Development; Epigenetics; Human stem cells; Metabolism; Neurodevelopment
    DOI:  https://doi.org/10.1172/JCI197010
  44. Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00172-5. [Epub ahead of print]45(3): 117094
    AARS1-mediated lactylation of STAT1 drives immune evasion.
    Yu Du, Meilin He, Yixin Xu, Tongguan Tian, Yuefan Zhou, Yan Zhang, Haifei Fu, Jiaxi Li, Lei Lv, Yanping Xu.
      Lactate accumulates in large amounts in tumor cells due to the Warburg effect. However, the role of lactate-mediated lactylation, a post-translational modification, in regulating tumor immunity remains unclear. Here, we report that lactate-driven lactylation of STAT1 K193 inhibits interferon (IFN)-γ signaling pathway-mediated tumor immunity. Mechanistically, AARS1 lactylates STAT1 K193 and inhibits its binding to JAK2 and phosphorylation, thereby disrupting tumor responsiveness to IFN-γ, which leads to a reduction in the expression of downstream chemokines, including CXCL9, CXCL10, and CXCL11, ultimately facilitating immune escape of the tumor. Furthermore, we developed a cell-penetrating peptide, K193-pe, that can competitively inhibit STAT1 K193 lactylation and re-sensitize tumor cells to IFN-γ signaling, thus enhancing CD8+ T cell recruitment and improving the efficacy of immune checkpoint blockade therapy. Collectively, this study elucidates the functional significance of STAT1 K193 lactylation in tumor immunity and suggests that targeted inhibition of this modification, when paired with immunotherapy, may offer a viable treatment strategy.
    Keywords:  AARS1; CP: cancer; CP: immunology; IFN-γ; K193-pe; STAT1; immune evasion; lactylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117094
  45. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2534066123
    ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.
    Ziqi Zou, Jiajie Zhou, Yanhua Lu, Yuting Huang, Linru Zhou, Xiaoyu Wang, Jiahui Chen, Hengrui Tian, Xinnuo Ge, Chenyao Guo, Weiran Yao, Xiaosheng Zheng, Jia He, Yue Du, Yiting Zhou, Yinjing Song, Wei Luo, Qingqing Wang, Jun-Ping Liu, Meng Xia.
      Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.
    Keywords:  ATP13A2 mutation; NLRP3 inflammasome; Parkinson’s disease; macrophage; neuroinflammation
    DOI:  https://doi.org/10.1073/pnas.2534066123
  46. Cell Death Differ. 2026 Mar 17.
    Hepatic GAPDH prevents excessive fasting-induced steatosis via serine-dependent inhibition of diacylglycerol synthesis.
    Yihao Zhou, Yan Yuan, Yunhao Xie, Jiajian Shi, Hejun Song, Yuxia Liu, Jiao Wang, Pei Fan, Tongcan Cui, Hong Chen, Xiaolu Zhao, Xinran Liu, Kun Huang, Ling Zheng.
      Fasting-induced metabolic remodeling is a fundamental process maintaining systemic homeostasis, with profound implications for metabolic disease interventions. During fasting, liver establishes a regulatory network centered on gluconeogenesis that integrates major fuels to keep physiological energy homeostasis. Here, we report that GAPDH, a key enzyme in both glycolysis and gluconeogenesis, senses fasting stress in the liver. Compared to wildtype controls, hepatocyte Gapdh deficiency (GapAlb) mice show comparable blood glucose, decreased amino acid levels and aggravated lipid accumulation in the liver after overnight fasting. Mechanistically, Gapdh depletion decreases serine levels, and serine supplementation inhibits PA-DAG (phosphatidic acid-diacylglycerols) axis by downregulating Lipin1 (a phosphohydrolase in DAG synthesis) upon overnight fasting. Furthermore, knockdown of Lipin1 rescued the effects observed in fasted GapAlb mice. Similarly, GapAlb mice showed enhanced hepatic lipid accumulation under ketogenic diets, and serine supplementation abolished these effects. Together, we find hepatic GAPDH as a central hub in glucose-amino acid-fat metabolism during nutritional limitation.
    DOI:  https://doi.org/10.1038/s41418-026-01706-9
  47. Nat Cell Biol. 2026 Mar 20.
    Seeing lipids where they live.
    Aubrey Weigel.
      
    DOI:  https://doi.org/10.1038/s41556-026-01919-7
  48. bioRxiv. 2026 Mar 03. pii: 2026.03.01.708869. [Epub ahead of print]
    Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement.
    Siran Liu, Heidi J Elsaesser, Rene Quevedo, Diala Abd-Rabbo, Bruna C Bertol, Wenxi Xu, Melissa Yi Ran Liu, Sabelo Lukhele, Sara Lamorte, Tracy L McGaha, David G Brooks.
      Type I interferon (IFN-I) and interferon-γ (IFNγ) are central regulators of antiviral immunity, yet how they cooperatively govern CD8 T cell fate during chronic infection remains unresolved. Here, we uncover a previously unrecognized, spatially encoded interferon circuit that actively constrains progenitor exhausted CD8 T cells (Tpex) during chronic LCMV infection. Persistent IFN-I signaling indirectly restricts Tpex expansion by enforcing their sequestration within PDL1-rich B cell niches of lymphoid tissue and by suppressing T cell-derived IFNγ. Blockade of IFN-I signaling enables Tpex migration into T cell zones of splenic follicles driving IFNγ production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFNγ blockade disrupts this feedback, promoting coordinated niche redistribution of Tpex and checkpoint remodeling that drives robust Tpex expansion. Single-cell transcriptomics reveal that this layered IFN-I-IFNγ interplay establishes a regulatory balance that constrains Tpex proliferation while preserving effector-like transcriptional programs in their progeny effector CD8 T cells, ultimately preventing premature terminal differentiation. Thus, interferons orchestrate the coordinated T cell-myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection.
    DOI:  https://doi.org/10.64898/2026.03.01.708869
  49. Cell Discov. 2026 Mar 17. pii: 19. [Epub ahead of print]12(1):
    Inosine promotes erythrocyte metabolic reprogramming and restores oxygen release for rejuvenation via 2,3-BPG-PNP axis.
    Wuping Liu, Zhaoyu Yang, Changhan Chen, Fang Yu, Mengzhi Wu, Zhouzhou Yao, Yuhua Fan, Tingting Xie, Linlin Wan, Tiansheng Chou, Xianjing Feng, Hao Qi, Yuyu Chou, Juan Zhao, Juan Liu, Zhiyu Yang, Yujin Zhang, Rodney E Kellems, Yang Xia.
      Aging-related diseases are aggravated by tissue hypoxia; however, the underlying mechanism remains unknown. Here, we report that the oxygen (O2) release capacity of red blood cells (RBCs) gradually decreases with age and is closely associated with aging-related tissue dysfunction. Metabolomic profiling of human and mouse RBCs and genetic studies in mice revealed that the reduction in 2,3-bisphosphoglyceric acid (2,3-BPG) content mediated by a decrease in bisphosphoglycerate mutase (BPGM) activity is a metabolic checkpoint underlying decreased RBC O2 release capability and dysfunction with advancing age. When glucose metabolism is impaired, erythroid inosine, transported by equilibrative nucleoside transporter 1 and converted to ribose 1-phosphate by increased purine nucleoside phosphorylase (PNP) activity, is an important compensatory fuel for RBCs during aging. In a preclinical study, inosine supplementation successfully alleviated the age-dependent reduction in BPGM activity that mediates glucose metabolic impairment, decreased O2 delivery, and tissue dysfunction. Finally, we unexpectedly discovered that 2,3-BPG acts as an inhibitor of PNP in RBCs by competing with the phosphate (Pi)-binding domain and interacting with residues serine 33 and alanine 116. Our studies revealed that impaired glucose metabolic reprogramming resulting from decreased BPGM activity underlies RBC bioenergetic decline and is a novel hallmark of aging. As 2,3-BPG levels decrease during aging, its inhibitory effect on PNP is reduced, resulting in increased PNP activity and inosine catabolism as an alternative fuel, suggesting that inosine is a potential rejuvenating therapy.
    DOI:  https://doi.org/10.1038/s41421-026-00877-6
  50. J Mol Cell Cardiol. 2026 Mar 18. pii: S0022-2828(26)00041-6. [Epub ahead of print]
    A review of peroxisome biology: Potential implications for cardiac physiology and pathology.
    Pukjera J Rungreang, Sean Noudali, Erik A Blackwood, Yow Keat Tham.
      The human heart has often been described as the "metronome of life" beating continuously over 2.5 billion times across the average lifespan and consuming more than 6 kg of ATP daily. And, during both a healthy and diseased state, the heart predominately relies on the oxidation of fatty acids to fuel its contractile burden of supporting all other organ systems. While metabolic alterations and substrate utilization inflexibility have been well studied and are considered hallmarks of heart failure pathogenesis, the overwhelming majority of these investigations have focused on the health and function of the mitochondria in cardiac myocytes; for good reason given the mitochondria is the location of oxidative phosphorylation complexes that, although debated, can form respiratory super complexes to generate ATP in conjunction with the electron transport chain and TCA cycle. However, there exists a potentially overlooked supporting organelle crucial for fatty acid oxidation - the peroxisome. In addition to serving as the site of long chain fatty acid breakdown into acyl-CoA for transport into the mitochondria, the peroxisome supports cellular viability and function via several critical mechanisms (e.g. plasmalogen synthesis and reactive oxygen species quenching). Despite this, only recently have published reports started to appreciate the potential significance of peroxisomes in cardiovascular physiology. In this review, we aim to provide a global perspective on peroxisomes to include their lifecycle and function gathered mostly from seminal studies in extracardiac tissues and highlight functional roles for peroxisomes directly in the context of cardiac physiology and pathology from more recent literature.
    Keywords:  Heart; Lipid metabolism; Peroxisome; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.03.003
  51. Cancer Res. 2026 Mar 16.
    Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
    Sanjiban Nath, Debanik Choudhury, Alice Amitrano, Konstantinos Konstantopoulos.
      The mechanical properties of cells and tissues have emerged as important biophysical markers for distinguishing between healthy and diseased states. In cancer, mechanical heterogeneity spans multiple scales, from tissue-level variations to substantial differences between individual tumor cells. The prevailing notion is that metastatic cancer cells are typically elastically softer than their non-malignant counterparts, a feature attributed to their ability to deform, remodel their shape, and navigate dense extracellular matrices and constricting blood vessels. However, cells are not purely elastic materials, but instead they exhibit viscoelastic behavior, in which deformation depends not only on instantaneous stiffness but also on time-dependent internal flow. In this context, Gensbittel and colleagues find that cellular viscosity, rather than elasticity, is a key determinant of cancer cell dissemination and extravasation, providing new insights into the mechanical underpinnings of cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1081
  52. DNA Cell Biol. 2026 Mar 20. 10445498261435336
    Beyond the Tumor Mass: From Initiating Clones to Overt Isocitrate Dehydrogenase-Mutant Gliomas.
    Jung Won Park, Jeong Ho Lee, Seok-Gu Kang.
      Isocitrate dehydrogenase (IDH)-mutant gliomas are primary malignant brain tumors defined by recurrent mutations in IDH1/2 genes and characterized by distinct molecular subtypes and relatively favorable clinical outcomes. Although these mutations represent early and defining events, recent data suggest that IDH1 mutant glial progenitor cells can reside within the histologically normal-appearing peritumoral cortex, indicating that cells harboring the founding driver mutation can persist beyond the tumor mass while retaining nonmalignant features. These observations challenge a purely gene-centric view of gliomagenesis. In this essay, we review emerging data supporting a multistep and context-dependent model in which the mutant IDH enzyme establishes an epigenetically altered cellular state, with subsequent genetic alterations and lineage-specific constraints that shape malignant progression. We further discuss the conceptual distinction between the "cell-of-mutation" and the "cell-of-origin" and consider how temporal stratification of tumor evolution may inform stage-specific therapeutic strategies along the transition from initiating clones beyond the tumor mass to overt tumors.
    Keywords:  IDH-mutant gliomas; cell-of-mutation; cell-of-origin; multistep tumorigenesis
    DOI:  https://doi.org/10.1177/10445498261435336
  53. Cancer Lett. 2026 Mar 16. pii: S0304-3835(26)00199-0. [Epub ahead of print] 218436
    Age-related B cell dysfunction at the aging-cancer nexus: from shared manifestations to therapeutic potential.
    Luo-Tian Liu, Han Wang, Si-Wei Zhang, Zhi-Ming Shao, Yi-Zhou Jiang.
      Aging and cancer are intricately linked through complex, bidirectional interactions, with immune remodeling representing a central point of convergence. Although studies of immune aging have largely centered on T cells, accumulating evidence indicates that B cells also undergo significant functional or phenotypic alterations during aging and tumorigenesis. Here, we introduce the concept of age-related B cell dysfunction to encompass a spectrum of changes that include impaired germinal center response, decline in B cell diversity, expansion of pro-inflammatory phenotypes, and increased autoreactivity. Aging and cancer share fundamental biological hallmarks, including genomic instability, epigenetic reprogramming, chronic inflammation, and dysbiosis, that profoundly reshape immune cell states. In this review, we synthesize emerging mechanistic evidence linking these processes to maladaptive B cell programs across tissues and tumor contexts, and discuss how such alterations influence tumor evolution, responses to therapy, and treatment-related toxicities. Finally, we highlight emerging strategies targeting age-related dysfunctional B cells in cancer, illustrating how insights from biology of aging and tumor immunology could inform future translational approaches.
    Keywords:  Aging; Anti-tumor strategy; B cell dysfunction; Cancer
    DOI:  https://doi.org/10.1016/j.canlet.2026.218436
  54. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112
    Mitochondria acidify lysosomes through membrane contacts.
    Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.
      The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.
    Keywords:  CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux
    DOI:  https://doi.org/10.1016/j.celrep.2026.117112
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒22 at 5:45.