bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–04–27
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.
  2. Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
  3. Career pathways, part 17.
  4. Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
  5. Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition.
  6. Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
  7. The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma.
  8. α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
  9. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
  10. Mitochondrial transfer drives immune evasion in tumor microenvironment.
  11. DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
  12. Metabolites in tumour interstitial fluid directly suppress T cells.
  13. Circulating glycerate predicts resilience to fructose-induced hepatic steatosis.
  14. Origin and evolution of mitochondrial inner membrane composition.
  15. TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
  16. Targeting PIKfyve-driven lipid metabolism in pancreatic cancer.
  17. A host-pathogen metabolic synchrony that facilitates disease tolerance.
  18. Mitochondrial DNA signals driving immune responses: Why, How, Where?
  19. ZBP1 senses splicing aberration through Z-RNA to promote cell death.
  20. Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function.
  21. Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
  22. Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity.
  23. PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.
  24. Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
  25. Tumor-Infiltrating Clonal Hematopoiesis.
  26. IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.
  27. Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases.
  28. A protein tunnel that shuttles lipids around the cell.
  29. TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
  30. Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.
  31. Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan.
  32. MAVS is a sensor of fumarate during antiviral immunity.
  33. Glucose sensing and the unfolded protein response.
  34. Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.
  35. Challenges in Spatial Metabolomics and Proteomics for Functional Tissue Unit and Single-Cell Resolution.
  36. Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
  37. Evolutionary paths towards metastasis.
  38. Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.
  39. Cold memories control whole-body thermoregulatory responses.
  40. Metabolic origin and significance of 3-methylglutaryl CoA.
  41. New insights into tryptophan metabolism in cancer.
  42. YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
  43. Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network.
  44. Transcriptome-wide analysis of differential expression in perturbation atlases.
  45. Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
  46. B cell-derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor-mediated signaling.
  47. Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
  48. TNFα Mediated Subcellular Heterogeneity of Succinate Dehydrogenase Activity in Human Airway Smooth Muscle Cells.
  49. Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse.
  50. Human de novo mutation rates from a four-generation pedigree reference.
  1. Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596
    Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.
    Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.
      Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.
    Keywords:  CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115596
  2. Nat Metab. 2025 Apr;7(4): 823-841
    Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
    Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.
      Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01265-2
  3. Nat Metab. 2025 Apr 21.
    Career pathways, part 17.
    Leah Gates, Benjamin P Weaver.
      
    DOI:  https://doi.org/10.1038/s42255-025-01288-9
  4. Nat Cell Biol. 2025 Apr 21.
    Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
    Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.
      Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.
    DOI:  https://doi.org/10.1038/s41556-025-01655-4
  5. Neuron. 2025 Apr 14. pii: S0896-6273(25)00247-8. [Epub ahead of print]
    Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition.
    Sung Min Son, Farah H Siddiqi, Ana Lopez, Rizwan Ansari, Sylwia D Tyrkalska, So Jung Park, Tilo Kunath, Emmanouil Metzakopian, Angeleen Fleming, David C Rubinsztein.
      Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson's disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity increases acetyl-CoA levels, which activate p300. Second, ACLY activation increases LKB1 acetylation, which inhibits AMPK, leading to increased cytoplasmic and decreased nuclear p300. This lowers histone acetylation and increases acetylation of cytoplasmic p300 substrates, like raptor, which causes mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, thereby impairing autophagy. ACLY inhibitors rescue pathological phenotypes in PD neurons, organoids, zebrafish, and mouse models, suggesting that this pathway is a core feature of α-Syn toxicity and that ACLY may be a suitable therapeutic target.
    Keywords:  ACLY; AMPK; Parkinson's disease; acetyl-CoA; acetylation; alpha-synuclein; autophagy; mTORC1; nucleocytoplasmic shuttling of p300
    DOI:  https://doi.org/10.1016/j.neuron.2025.03.028
  6. Curr Biol. 2025 Apr 21. pii: S0960-9822(25)00296-9. [Epub ahead of print]35(8): R287-R290
    Cell biology: Mitochondrial protease degrades unoccupied translocases upon import stress.
    Mohamed A Eldeeb, Michael Shahid, Edward A Fon.
      Dysregulation of mitochondrial protein import induces significant cellular stress. Yet, our understanding of the dialogue between mitochondrial import, the stress it can trigger, and counteracting mechanisms remains incomplete. A recent study unveils how the mitochondrial protease YME1L1 degrades unoccupied mitochondrial translocases during mitochondrial import stress.
    DOI:  https://doi.org/10.1016/j.cub.2025.03.011
  7. Cell Death Discov. 2025 Apr 19. 11(1): 186
    The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma.
    Yifan Zhang, Shengli Zhang, Hongbin Sun, Luwei Xu.
      Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regions-a feature increasingly recognized as a determinant of therapeutic resistance. Our review systematically deciphers the molecular architecture of RCC metabolism, elucidating how VHL/HIF axis mutations, mTOR pathway dysregulation, and epigenetic modifiers converge to reshape glucose flux, lipid droplet biogenesis, and amino acid catabolism. We present novel insights into spatial metabolic zonation within RCC tumors, where pseudohypoxic niches engage in lactate shuttling and cholesterol efflux to adjacent vasculature, creating pro-angiogenic and immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes in de novo lipogenesis and glutamine metabolism, while proposing biomarker-driven strategies to overcome compensatory pathway activation. We highlight the synergy between glutaminase inhibitors and PD-1 blockade in reinvigorating CD8+ T cell function, and the role of lipid-loaded cancer-associated fibroblasts in shielding tumors from ferroptosis. Finally, we outline a translational roadmap integrating multi-omics profiling, functional metabolomics, and spatial biology to match metabolic vulnerabilities with precision therapies.
    DOI:  https://doi.org/10.1038/s41420-025-02479-9
  8. Nat Cell Biol. 2025 Apr 23.
    α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
    Karlien Van Nerum, Anne Wenzel, Lidia Argemi-Muntadas, Eleni Kafkia, Antar Drews, Ida Sophie Brun, Viktoria Lavro, Annina Roelofsen, Nikolaos Stamidis, Sandra Bages Arnal, Cheng Zhao, Simone di Sanzo, Moritz Völker-Albert, Sophie Petropoulos, Thomas Moritz, Jan Jakub Żylicz.
      Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.
    DOI:  https://doi.org/10.1038/s41556-025-01658-1
  9. Nature. 2025 Apr 23.
    Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer.
    Guangsheng Pei, Jimin Min, Kimal I Rajapakshe, Vittorio Branchi, Yunhe Liu, Benson Chellakkan Selvanesan, Fredrik Thege, Dorsay Sadeghian, Daiwei Zhang, Kyung Serk Cho, Yanshuo Chu, Enyu Dai, Guangchun Han, Mingyao Li, Cassian Yee, Kazuki Takahashi, Bharti Garg, Herve Tiriac, Vincent Bernard, Alexander Semaan, Jean L Grem, Thomas C Caffrey, Jared K Burks, Andrew M Lowy, Andrew J Aguirre, Paul M Grandgenett, Michael A Hollingsworth, Paola A Guerrero, Linghua Wang, Anirban Maitra.
      Patients with treatment-refractory pancreatic cancer often succumb to systemic metastases1-3; however, the transcriptomic heterogeneity that underlies therapeutic recalcitrance remains understudied, particularly in a spatial context. Here we construct high-resolution maps of lineage states, clonal architecture and the tumour microenvironment (TME) using spatially resolved transcriptomics from 55 samples of primary tumour and metastases (liver, lung and peritoneum) collected from rapid autopsies of 13 people. We observe discernible transcriptomic shifts in cancer-cell lineage states as tumours transition from primary sites to organ-specific metastases, with the most pronounced intra-patient distinctions between liver and lung. Phylogenetic trees constructed from inferred copy number variations in primary and metastatic loci in each patient highlight diverse patient-specific evolutionary trajectories and clonal dissemination. We show that multiple tumour lineage states co-exist in each tissue, including concurrent metastatic foci in the same organ. Agnostic to tissue site, lineage states correlate with distinct TME features, such as the spatial proximity of TGFB1-expressing myofibroblastic cancer-associated fibroblasts (myCAFs) to aggressive 'basal-like' cancer cells, but not to cells in the 'classical' or 'intermediate' states. These findings were validated through orthogonal and cross-species analyses using mouse tissues and patient-derived organoids. Notably, basal-like cancer cells aligned with myCAFs correlate with plasma-cell exclusion from the tumour milieu, and neighbouring cell analyses suggest that CXCR4-CXCL12 signalling is the underlying basis for observed immune exclusion. Collectively, our findings underscore the profound transcriptomic heterogeneity and microenvironmental dynamics that characterize treatment-refractory pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41586-025-08927-x
  10. Trends Cancer. 2025 Apr 22. pii: S2405-8033(25)00094-9. [Epub ahead of print]
    Mitochondrial transfer drives immune evasion in tumor microenvironment.
    Qiang Cai, Xiaojun Cai, Quazi T H Shubhra.
      Tumors subvert T cell metabolism through diverse mechanisms. Ikeda et al. reveal mitochondrial transfer as a tumor-driven immune evasion strategy, where cancer cells deliver dysfunctional mitochondria to T cells, impairing metabolism and inducing exhaustion. These findings highlight mitochondrial dynamics as a promising therapeutic target to improve immunotherapy outcomes.
    Keywords:  T cell exhaustion; cancer immunotherapy; mitochondrial transfer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.002
  11. Nat Commun. 2025 Apr 24. 16(1): 3867
    DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
    Da Teng, Kenneth D Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R Avritt, Lei Gu, John M Asara, Yaqing Zhang, Bin Zheng.
      The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-59307-y
  12. Nat Cell Biol. 2025 Apr 21.
    Metabolites in tumour interstitial fluid directly suppress T cells.
      
    DOI:  https://doi.org/10.1038/s41556-025-01652-7
  13. Cell Metab. 2025 Apr 12. pii: S1550-4131(25)00209-8. [Epub ahead of print]
    Circulating glycerate predicts resilience to fructose-induced hepatic steatosis.
    Cuauhtemoc B Ramirez, In Sook Ahn, Varvara I Rubtsova, Ingrid Cely, Johnny Le, Joohwan Kim, Sunhee Jung, Miranda E Kelly, Yeojin Kim, Hosung Bae, Won-Suk Song, Yasmine H Alam, Guanglin Zhang, Graciel Diamante, Alina Chao, Lauren Hoffner, Alexis Anica, Izabelle Le, Miranda L Lopez, Ian J Tamburini, Elena M Moyer, Ariel Tsai, Qin Yang, Xing Dai, Daniele Piomelli, Gina Lee, Xia Yang, Cholsoon Jang.
      Excessive intake of dietary fructose increases the risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), cirrhosis, and cancers. However, what host factors determine disease vulnerability is incompletely understood. Here, we leverage genetically divergent mouse strains, mass spectrometry-based metabolomics, and in vivo isotope tracing, identifying circulating glycerate as a biomarker that predicts resilience to fructose-induced hepatic steatosis in both sexes. We found that the surge of circulating glycerate after an oral fructose provision reflects strong small-intestinal fructose catabolism. Such fructose clearance by the small intestine is linked to a weaker induction of hepatic de novo lipogenesis and steatosis upon chronic fructose exposure across strains. These data indicate the potential utility of an oral fructose tolerance test and circulating glycerate measurements to predict an individual's susceptibility to fructose-elicited steatotic liver and provide personalized dietary recommendations.
    Keywords:  MASLD; fructose; in vivo isotope tracing; liquid chromatography spectrometry
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.017
  14. J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):
    Origin and evolution of mitochondrial inner membrane composition.
    Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.
      Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.
    Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.263780
  15. J Cell Biol. 2025 May 05. pii: e202503004. [Epub ahead of print]224(5):
    TMBIM-2 links neuronal mitochondrial stress to systemic adaptation via calcium signaling.
    Yu Sun, Terytty Yang Li.
      Mitochondrial function is critical for neuronal activity and systemic metabolic adaptation. In this issue, Li et al. (https://doi.org/10.1083/jcb.202408050) identify TMBIM-2 as a key regulator of calcium dynamics, coordinating the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt), pathogen-induced aversive learning, and aging.
    DOI:  https://doi.org/10.1083/jcb.202503004
  16. Nature. 2025 Apr 23.
    Targeting PIKfyve-driven lipid metabolism in pancreatic cancer.
    Caleb Cheng, Jing Hu, Rahul Mannan, Tongchen He, Rupam Bhattacharyya, Brian Magnuson, Jasmine P Wisniewski, Sydney Peters, Saadia A Karim, David J MacLean, Hüseyin Karabürk, Li Zhang, Nicholas J Rossiter, Yang Zheng, Lanbo Xiao, Chungen Li, Dominik Awad, Somnath Mahapatra, Yi Bao, Yuping Zhang, Xuhong Cao, Zhen Wang, Rohit Mehra, Pietro Morlacchi, Vaibhav Sahai, Marina Pasca di Magliano, Yatrik M Shah, Lois S Weisman, Jennifer P Morton, Ke Ding, Yuanyuan Qiao, Costas A Lyssiotis, Arul M Chinnaiyan.
      Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS-MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS-MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.
    DOI:  https://doi.org/10.1038/s41586-025-08917-z
  17. Nat Commun. 2025 Apr 19. 16(1): 3729
    A host-pathogen metabolic synchrony that facilitates disease tolerance.
    Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.
      Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.
    DOI:  https://doi.org/10.1038/s41467-025-59134-1
  18. Cell Commun Signal. 2025 Apr 22. 23(1): 192
    Mitochondrial DNA signals driving immune responses: Why, How, Where?
    Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.
      There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
    Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12964-025-02042-0
  19. Mol Cell. 2025 Apr 15. pii: S1097-2765(25)00299-0. [Epub ahead of print]
    ZBP1 senses splicing aberration through Z-RNA to promote cell death.
    Zhang-Hua Yang, Puqi Wu, Bo-Xin Zhang, Cong-Rong Yang, Jia Huang, Lei Wu, Shuang-Hui Guo, Yuenan Zhou, Yuanhui Mao, Yafei Yin, Xiurong Wu, Pu Cheng, Baizhou Li, Rongbin Zhou, Han-Ming Shen, Sheng Nie, Zhi-Yu Cai, Wei Mo.
      RNA splicing, a highly regulated process performed by the spliceosome, is essential for eukaryotic gene expression and cellular function. Numerous cellular stresses, including oncogenic insults, dysregulate RNA splicing, often provoking inflammatory responses and cell death. However, the molecular signals generated by splicing aberrations and the mechanism by which cells sense and respond to these signals remain poorly understood. Here, we demonstrate that spliceosome inhibition induces the widespread formation of left-handed Z-form double-stranded RNA (Z-RNA), predominantly derived from mis-spliced exonic and intronic RNA transcripts in the nucleus. These Z-RNAs are exported to the cytoplasm in a RanGTP-dependent manner. Cytosolic sensing of accumulated Z-RNA by the host sensor Z-DNA-binding protein 1 (ZBP1) initiates cell death, primarily through RIPK3-MLKL-dependent necroptosis. Together, these findings reveal a previously uncharacterized mechanism in which ZBP1-mediated detection of Z-RNA serves as a critical response to global RNA splicing perturbations, ultimately triggering inflammatory cell death.
    Keywords:  Z-RNA; ZBP1; necroptosis; spliceosome; splicing aberration
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.023
  20. Nat Cell Biol. 2025 Apr 21.
    Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function.
    Yupeng Wang, Drew Wilfahrt, Patrick Jonker, Konstantinos Lontos, Chufan Cai, Benjamin Cameron, Bingxian Xie, Ronal M Peralta, Emerson R Schoedel, William G Gunn, Roya AminiTabrizi, Hardik Shah, Dayana B Rivadeneira, Alexander Muir, Greg M Delgoffe.
      Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41556-025-01650-9
  21. Cell Rep. 2025 Apr 21. pii: S2211-1247(25)00381-X. [Epub ahead of print]44(5): 115610
    Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells.
    Benjamin A S Willett, Scott B Thompson, Vincent Chen, Anza Dareshouri, Conner L Jackson, Tonya Brunetti, Angelo D'Alessandro, Jared Klarquist, Travis Nemkov, Ross M Kedl.
      Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.
    Keywords:  CD8; CP: Immunology; Mitofusins; Opa1; T cell; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.115610
  22. Science. 2025 Apr 25. 388(6745): eadr3026
    Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity.
    David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Qiang Liu, Kazukuni Hayashi, Bo Yu, Ryan Lee, Catherine Zhang, Xiuli An, Jayakumar Rajadas, Nathan E Reticker-Flynn, Erinn B Rankin, Edgar G Engleman.
      Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
    DOI:  https://doi.org/10.1126/science.adr3026
  23. Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2426338122
    PPARα regulates ER-lipid droplet protein Calsyntenin-3β to promote ketogenesis in hepatocytes.
    Lauren F Uchiyama, Alexander Nguyen, Kevin Qian, Liujuan Cui, Khoi T Pham, Xu Xiao, Yajing Gao, Yuta Shimanaka, Marcus J Tol, Laurent Vergnes, Karen Reue, Peter Tontonoz.
      Ketogenesis requires fatty acid flux from intracellular (lipid droplets) and extrahepatic (adipose tissue) lipid stores to hepatocyte mitochondria. However, whether interorganelle contact sites regulate this process is unknown. Recent studies have revealed a role for Calsyntenin-3β (CLSTN3β), an endoplasmic reticulum-lipid droplet contact site protein, in the control of lipid utilization in adipose tissue. Here, we show that Clstn3b expression is induced in the liver by the nuclear receptor PPARα in settings of high lipid utilization, including fasting and ketogenic diet feeding. Hepatocyte-specific loss of CLSTN3β in mice impairs ketogenesis independent of changes in PPARα activation. Conversely, hepatic overexpression of CLSTN3β promotes ketogenesis in mice. Mechanistically, CLSTN3β affects LD-mitochondria crosstalk, as evidenced by changes in fatty acid oxidation, lipid-dependent mitochondrial respiration, and the mitochondrial integrated stress response. These findings define a function for CLSTN3β-dependent membrane contacts in hepatic lipid utilization and ketogenesis.
    Keywords:  hepatocyte; ketogenesis; ketogenic diet; lipid metabolism
    DOI:  https://doi.org/10.1073/pnas.2426338122
  24. Sci Adv. 2025 Apr 25. 11(17): eadv4410
    Conformational plasticity of mitochondrial VDAC2 controls the kinetics of its interaction with cytosolic proteins.
    William M Rosencrans, Harisankar Khuntia, Motahareh Ghahari Larimi, Radhakrishnan Mahalakshmi, Tsyr-Yan Yu, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The voltage-dependent anion channel (VDAC) is a key conduit of the mitochondrial outer membrane for water-soluble metabolites and ions. Among the three mammalian isoforms, VDAC2 is unique because of its embryonic lethality upon knockout. Using single-molecule electrophysiology, we investigate the biophysical properties that distinguish VDAC2 from VDAC1 and VDAC3. Unlike the latter, VDAC2 exhibits dynamic switching between multiple high-conductance, anion-selective substates. Using α-synuclein (αSyn)-a known VDAC1 cytosolic regulator-we found that higher-conductance substates correlate with increased on-rates of αSyn-VDAC2 interaction but shorter blockage times, maintaining a consistent equilibrium constant across all substates. This suggests that αSyn detects VDAC2's dynamic structural variations before final binding. We explored the dependence of VDAC2's unique amino-terminal extension and cysteines on substate behavior, finding that both structural elements modulate substate occurrence. The discovered conformational flexibility enables VDAC2 recognition by diverse binding partners, explaining its critical physiological role via dynamical adaptation to mitochondrial metabolic conditions.
    DOI:  https://doi.org/10.1126/sciadv.adv4410
  25. N Engl J Med. 2025 Apr 24. 392(16): 1594-1608
    Tumor-Infiltrating Clonal Hematopoiesis.
    Oriol Pich, Elsa Bernard, Maria Zagorulya, Andrew Rowan, Constandina Pospori, Ramy Slama, Hector Huerga Encabo, Jennifer O'Sullivan, Despoina Papazoglou, Panayiotis Anastasiou, Chrysante S Iliakis, Sally-Ann Clark, Krijn K Dijkstra, Vittorio Barbè, Chris Bailey, Aaron J Stonestrom, Katey S S Enfield, Mary Green, Charlotte K Brierley, Alastair Magness, David R Pearce, Robert E Hynds, Rija Zaidi, Jayant K Rane, Ángel F Álvarez-Prado, Kerstin Thol, Rachel Scott, Supreet Kaur Bola, Elena Hoxha, Steve K Harris, Karl S Peggs, Sergio A Quezada, Allan Hackshaw, Simone Zaccaria, Johanna A Joyce, Ilaria Malanchi, Michael F Berger, Mariam Jamal-Hanjani, Andreas Wack, Julian Downward, William Grey, Cristina Lo Celso, Eva Grönroos, Charles M Rudin, Adam J Mead, Dominique Bonnet, Elli Papaemmanuil, Charles Swanton.
       BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.
    METHODS: We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.
    RESULTS: Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.
    CONCLUSIONS: TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
    DOI:  https://doi.org/10.1056/NEJMoa2413361
  26. Nat Commun. 2025 Apr 24. 16(1): 3874
    IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.
    Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur.
      Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an anti-tumor immune response which is important for viral efficacy. Mutant IDH (IDHR132H) gliomas are incapable of reductive carboxylation and hence ferroptosis. Pharmacological blockade of IDHR132H induces ferroptosis and anti-tumor immunity. This study provides a rationale to use an IDHR132H inhibitor to treat high grade IDH-mutant glioma patients undergoing oHSV treatment.
    DOI:  https://doi.org/10.1038/s41467-025-58911-2
  27. Annu Rev Immunol. 2025 Apr;43(1): 313-342
    Genetic Regulation of Cell Death: Insights from Autoinflammatory Diseases.
    Hirotsugu Oda, Alessandro Annibaldi, Daniel L Kastner, Ivona Aksentijevich.
      Metazoans have evolved innate antimicrobial defenses that promote cellular survival and proliferation. Countering the inevitable molecular mechanisms by which microbes sabotage these pathways, multicellular organisms rely on an alternative, perhaps more ancient, strategy that is the immune equivalent of suicide bombing: Infection triggers cell death programs that summon localized or even systemic inflammation. The study of human genetics has now unveiled a level of complexity that refutes the naive view that cell death is merely a blunt instrument or an evolutionary afterthought. To the contrary, findings from patients with rare diseases teach us that cell death-induced inflammation is a sophisticated, tightly choreographed process. We herein review the emerging body of evidence describing a group of illnesses-inborn errors of cell death, which define many of the molecular building blocks and regulatory elements controlling cell death-induced inflammation in humans-and provide a possible road map to countering this process across the spectrum of rare and common illnesses.
    Keywords:  IECDs; NF-κB; TNF; apoptosis; autoinflammatory diseases; cell death; inborn errors of cell death; mutations; necroptosis; ubiquitylation
    DOI:  https://doi.org/10.1146/annurev-immunol-090222-105848
  28. Nature. 2025 Apr 23.
    A protein tunnel that shuttles lipids around the cell.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-01167-z
  29. Nat Chem Biol. 2025 Apr 22.
    TOM20-driven E3 ligase recruitment regulates mitochondrial dynamics through PLD6.
    Anat Raiff, Shidong Zhao, Aizat Bekturova, Colin Zenge, Shir Mazor, Xinyan Chen, Wenwen Ru, Yaara Makaros, Tslil Ast, Alban Ordureau, Chao Xu, Itay Koren.
      Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41589-025-01894-4
  30. Gut. 2025 Apr 23. pii: gutjnl-2025-335220. [Epub ahead of print]
    Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.
    Yihui Chen, Riccardo Ballarò, Marta Sans, Fredrik Ivar Thege, Mingxin Zuo, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, J Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal I Rajapakshe, Hamid K Rudsari, Mark W Hurd, Ricardo A León-Letelier, Hiroyuki Katayama, Edwin Ostrin, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Samir M Hanash, Robert A Wolff, Paolo A Guerrero, Michael Kim, C Max Schmidt, Anirban Maitra, Johannes F Fahrmann.
       BACKGROUND: We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).
    OBJECTIVE: We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.
    DESIGN: Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.
    RESULTS: MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.
    CONCLUSION: Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.
    Keywords:  METABOLOMICS; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-335220
  31. Nat Genet. 2025 Apr 21.
    Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan.
    Siqi Chen, Ruiyang Liu, Chia-Kuei Mo, Michael C Wendl, Andrew Houston, Preet Lal, Yanyan Zhao, Wagma Caravan, Andrew T Shinkle, Atieh Abedin-Do, Nataly Naser Al Deen, Kazuhito Sato, Xiang Li, André Luiz N Targino da Costa, Yize Li, Alla Karpova, John M Herndon, Maxim N Artyomov, Joshua B Rubin, Sanjay Jain, Xue Li, Sheila A Stewart, Li Ding, Feng Chen.
      There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.
    DOI:  https://doi.org/10.1038/s41588-025-02161-x
  32. Nat Microbiol. 2025 Apr 23.
    MAVS is a sensor of fumarate during antiviral immunity.
    Yukun Min, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1038/s41564-025-01991-z
  33. FEBS J. 2025 Apr 24.
    Glucose sensing and the unfolded protein response.
    Mabel Cruz-Rodríguez, Eric Chevet, Cristina Muñoz-Pinedo.
      The unfolded protein response (UPR) is activated primarily upon alteration of protein folding in the endoplasmic reticulum (ER). This occurs under physiological situations that cause an abrupt increase in protein synthesis, or under redox and metabolic stresses. Among the latter, hyperglycemia and glucose scarcity have been identified as major modulators of UPR signaling. Indeed, the first mammalian UPR effector, the glucose-regulated protein 78, also known as BiP, was identified in response to glucose deprivation. Tunicamycin, arguably the most commonly used drug to induce ER stress responses in vitro and in vivo, is an inhibitor of N-glycosylation. We compile here evidence that the UPR is activated upon physiological and pathological conditions that alter glucose levels and that this is mostly mediated by alterations of protein N-glycosylation, ATP levels, or redox balance. The three branches of the UPR transduced by PERK/ATF4, IRE1/XBP1s, and ATF6, as well as non-canonical ER sensors such as SCAP/SREBP, sense ER protein glycosylation status driven by glucose and other glucose-derived metabolites. The outcomes of UPR activation range from restoring protein N-glycosylation and protein folding flux to stimulating autophagy, organelle recycling, and mitochondrial respiration, and in some cases, cell death. Anabolic responses to glucose levels are also stimulated by glucose through components of the UPR. Therefore, the UPR should be further studied as a potential biomarker and mediator of glucose-associated diseases.
    Keywords:  ATF6; IRE1; PERK; glucose; glycosylation; nutrient sensing; starvation; unfolded protein response
    DOI:  https://doi.org/10.1111/febs.70113
  34. EMBO Mol Med. 2025 Apr 22.
    Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies.
    Sara Clerici, Alessandra Boletta.
      Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies. Besides this common manifestation, however, the renal ciliopathies present with profoundly different phenotypes, resulting in either polycystic kidney disease (PKD) or nephronophthisis (NPH) phenotypes. The past decade has seen a surge of studies highlighting metabolic reprogramming as a major feature of PKD, with a distinct involvement of mitochondrial dysfunction. This discovery has brought forward the development of novel therapeutic approaches. More recent evidence suggests that primary cilia modulate the mitochondrial production of energy in response to environmental cues. Here, we summarize the evidence available to date and propose a more general involvement of metabolic and mitochondrial alterations in the renal ciliopathies that might in principle help defining the profoundly different, and potentially opposite, manifestations observed.
    Keywords:  Cilia; Ciliopathies; Kidney Cysts; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1038/s44321-025-00239-x
  35. Semin Nephrol. 2025 Apr 21. pii: S0270-9295(25)00020-8. [Epub ahead of print] 151583
    Challenges in Spatial Metabolomics and Proteomics for Functional Tissue Unit and Single-Cell Resolution.
    Kevin J Zemaitis, Ljiliana Paša-Tolić.
      In the last decade, advanced developments of mass spectrometry-based assays have made spatial measurements of hundreds of metabolites and thousands of proteins not only possible, but routine. The information obtained from such mass spectrometry imaging experiments traces metabolic events and helps decipher feedback loops across anatomical regions, connecting genetic and metabolic networks that define phenotypes. Herein we overview developments in the field over the past decade, highlighting several case studies demonstrating direct measurement of metabolites, proteins, and proteoforms from thinly sliced tissues at the level of functional tissue units, approaching single-cell levels. Much of this work is feasible due to multidisciplinary team science, and we offer brief perspectives on paths forward and the challenges that persist with adoption and application of these spatial omics techniques at the single-cell level on mammalian kidneys. Data analysis and reanalysis still pose issues that plague spatial omics, but many mass spectrometry imaging platforms are commercially available. With greater harmonization across platforms and rigorous quality control, greater adoption of these platforms will undoubtedly provide major insights in complex diseases. Semin Nephrol 36:x-xx © 20xx Elsevier Inc. All rights reserved.
    Keywords:  Mass spectrometry; metabolomics; multimodal analyses; proteomics; spatial omics
    DOI:  https://doi.org/10.1016/j.semnephrol.2025.151583
  36. Mol Cell. 2025 Apr 18. pii: S1097-2765(25)00304-1. [Epub ahead of print]
    Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
    Xinyu Wang, Amin Jiang, Quan Meng, Tao Jiang, Huaide Lu, Xiaohan Geng, Zikuo Song, Xinyao Hu, Zhu Yu, Wencong Xu, Chao Ning, Yajing Lin, Dong Li.
      Membrane remodeling is essential for numerous cellular functions. Although liquid-liquid phase separation (LLPS) of intrinsically disordered region (IDR)-rich proteins could drive dramatic membrane remodeling of artificial giant unilamellar vesicles, it remains elusive whether LLPS-mediated membrane-remodeling functions in live cells and what role it plays in specific bioprocesses. Here, we show that three IDR-rich integral transmembrane fusion proteins (MFPs), generated by chromosomal translocations, can lead to de novo remodeling of their located membranous organelles. Taking FUS-CREB3L2, prevalent in low-grade fibromyxoid sarcoma (LGFMS), as a proof of concept, we recorded super-resolution long-time imaging of endoplasmic reticulum (ER) remodeling dynamics as accumulating FUS-CREB3L2, meanwhile causing spontaneous ER stress to hijack the X-box-binding protein 1 (XBP1) pathway. We further reveal the underlying mechanisms of how FUS-CREB3L2 transduces its tumorigenic signals and aberrant LLPS effects from the ER membrane into the nucleus autonomously, which activates hundreds of LGFMS-specific genes de novo compared with CREB3L2, thus sufficiently reprogramming the cells into an LGFMS-like status.
    Keywords:  ER stress; FUS-CREB3L2; fusion proteins; membrane remodeling; phase separation; spontaneous regulated intramembrane proteolysis
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.001
  37. Nat Rev Cancer. 2025 Apr 22.
    Evolutionary paths towards metastasis.
    Kamila Naxerova.
      The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness - a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.
    DOI:  https://doi.org/10.1038/s41568-025-00814-x
  38. Cell Death Differ. 2025 Apr 20.
    Age-associated reduction in ER-Mitochondrial contacts impairs mitochondrial lipid metabolism and autophagosome formation in the heart.
    Weilong Hong, Xue Zeng, Ruiyan Ma, Yu Tian, Huimin Miu, Xiaoping Ran, Rui Song, Zhenchun Luo, Dapeng Ju, Daqing Ma, Milad Ashrafizadeh, Sujit Kumar Bhutia, João Conde, Gautam Sethi, He Huang, Chenyang Duan.
      The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.
    DOI:  https://doi.org/10.1038/s41418-025-01511-w
  39. Nature. 2025 Apr 23.
    Cold memories control whole-body thermoregulatory responses.
    Andrea Muñoz Zamora, Aaron Douglas, Paul B Conway, Esteban Urrieta, Taylor Moniz, James D O'Leary, Lydia Marks, Christine A Denny, Clara Ortega-de San Luis, Lydia Lynch, Tomás J Ryan.
      Environmental thermal challenges trigger the brain to coordinate both autonomic and behavioural responses to maintain optimal body temperature1-4. It is unknown how temperature information is precisely stored and retrieved in the brain and how it is converted into a physiological response. Here we investigated whether memories could control whole-body metabolism by training mice to remember a thermal challenge. Mice were conditioned to associate a context with a specific temperature by combining thermoregulatory Pavlovian conditioning with engram-labelling technology, optogenetics and chemogenetics. We report that if mice are returned to an environment in which they previously experienced a 4 °C cold challenge, they increase their metabolic rates regardless of the actual environmental temperature. Furthermore, we show that mice have increased hypothalamic activity when they are exposed to the cold, and that a specific network emerges between the hippocampus and the hypothalamus during the recall of a cold memory. Both natural retrieval and artificial reactivation of cold-sensitive memory engrams in the hippocampus mimic the physiological responses that are seen during a cold challenge. These ensembles are necessary for cold-memory retrieval. These findings show that retrieval of a cold memory causes whole-body autonomic and behavioural responses that enable mice to maintain thermal homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-08902-6
  40. Clin Chim Acta. 2025 Apr 17. pii: S0009-8981(25)00199-8. [Epub ahead of print] 120320
    Metabolic origin and significance of 3-methylglutaryl CoA.
    Elizabeth A Jennings, Zane H Abi-Rached, Robert O Ryan.
      3-Methylglutaryl (3MG) CoA is not part of any biochemical pathway, yet its byproducts, 3MG carnitine and 3MG acid, are disease biomarkers. Both compounds are excreted in HMG CoA lyase deficiency, while 3MG aciduria occurs in inborn errors of metabolism (IEM) associated with compromised mitochondrial energy metabolism. In one such disorder (i.e., TMEM70 deficiency), 3MG carnitine is also present. Moreover, in a number of chronic and acute maladies, elevated levels of 3MG carnitine are present. The precursor of 3MG CoA istrans-3-methylglutaconyl (3MGC) CoA. Whentrans-3MGC CoA levels rise, a portion of this metabolite pool is reduced to 3MG CoA, potentially via a side reaction involving glutaryl CoA dehydrogenase (GCDH), which normally catalyzes the oxidative decarboxylation of glutaryl CoA to crotonyl CoA and CO2. This reaction occurs via a two-step process wherein glutaryl CoA is initially oxidized to glutaconyl CoA, coupled to reduction of the enzyme's FAD prosthetic group. Enzyme-bound glutaconyl CoA is then decarboxylated to the reaction product, crotonyl CoA. Before GCDH can accept another glutaryl CoA the flavin prosthetic group must be oxidized to FAD by donating electrons to electron transferring flavoprotein (ETF). However, genetic- or disease-induced defects in electron transport chain function can impede this reaction. We propose thattrans-3MGC CoA is a substrate for reduced GCDH and, when glutaryl CoA andtrans-3MGC CoA are present, GCDH is able to bypass ETF and cycle between oxidized and reduced states, producing crotonyl CoA and CO2from glutaryl CoA, and 3MG CoA fromtrans-3MGC CoA.
    Keywords:  3-methylglutaric acid; 3-methylglutaryl carnitine; Biomarker; Glutaryl CoA dehydrogenase; Mitochondria
    DOI:  https://doi.org/10.1016/j.cca.2025.120320
  41. Trends Cancer. 2025 Apr 23. pii: S2405-8033(25)00076-7. [Epub ahead of print]
    New insights into tryptophan metabolism in cancer.
    Zhe Qi Liu, M Teresa Ciudad, Tracy L McGaha.
      Tryptophan (Trp) is an essential amino acid and key intermediate in a range of biological processes. Early studies identified altered Trp utilization in cancer cells favoring cancer survival and growth. Seminal findings linking Trp metabolism and suppression of immunity led to an explosion of interest ultimately culminating in clinical trials targeting these pathways in melanoma. The failure of these trials led to a clinical retreat in this approach; however, recent insights into the complex interplay of the various Trp circuits and between tumor cells, immune cells, and the microbiota have shown that reconsideration of Trp metabolism is needed. Here, we discuss recent developments in our understanding of Trp metabolism and apparent contradictions in the field. We also discuss adaptations that occur when Trp pathways are manipulated, which may impact therapy responses.
    Keywords:  kynurenine; metabolism; microbiome; tryptophan; tumor immunity
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.008
  42. J Inherit Metab Dis. 2025 May;48(3): e70029
    YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.
    Anthi Demetriadou, Olga Grafakou, Theodoros Georgiou, Daniela Burska, Anna Malekkou, Jana Krizova, Efstathia Paramera, Gavriella Mavrikiou, Maria Dionysiou, Athina Theodosiou, Carolina Sismani, Violetta Anastasiadou, Ioannis Ioannou, Evangelos Papakonstantinou, Hana Hansikova, Anthi Drousiotou, Petros P Petrou.
      3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.
    Keywords:  3‐methylglutaconic aciduria; YME1L1; inherited metabolic disorders; mitochondrial disorders; mitochondrial dysfunction; mitochondrial fragmentation
    DOI:  https://doi.org/10.1002/jimd.70029
  43. Cell Death Differ. 2025 Apr 22.
    Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network.
    Anthony M Boutelle, Aicha R Mabene, David Yao, Haiqing Xu, Mengxiong Wang, Yuning J Tang, Steven S Lopez, Sauradeep Sinha, Janos Demeter, Ran Cheng, Brooks A Benard, Edel M McCrea, Liz J Valente, Alexandros P Drainas, Martin Fischer, Ravindra Majeti, Dmitri A Petrov, Peter K Jackson, Fan Yang, Monte M Winslow, Michael C Bassik, Laura D Attardi.
      TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.
    DOI:  https://doi.org/10.1038/s41418-025-01513-8
  44. Nat Genet. 2025 Apr 21.
    Transcriptome-wide analysis of differential expression in perturbation atlases.
    Ajay Nadig, Joseph M Replogle, Angela N Pogson, Mukundh Murthy, Steven A McCarroll, Jonathan S Weissman, Elise B Robinson, Luke J O'Connor.
      Single-cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are noisy, and many effects may go undetected. Here we introduce transcriptome-wide analysis of differential expression (TRADE)-a statistical model for the distribution of true differential expression effects that accounts for estimation error appropriately. TRADE estimates the 'transcriptome-wide impact', which quantifies the total effect of a perturbation across the transcriptome. Analyzing several large Perturb-seq datasets, we show that many transcriptional effects remain undetected in standard analyses but emerge in aggregate using TRADE. A typical gene perturbation affects an estimated 45 genes, whereas a typical essential gene affects over 500. We find moderate consistency of perturbation effects across cell types, identify perturbations where transcriptional responses vary qualitatively across dosage levels and clarify the relationship between genetic and transcriptomic correlations across neuropsychiatric disorders.
    DOI:  https://doi.org/10.1038/s41588-025-02169-3
  45. PLoS Genet. 2025 Apr 25. 21(4): e1011678
    Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
    Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei.
      Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011678
  46. Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2501960122
    B cell-derived acetylcholine mitigates skin inflammation in mice through α9 nicotinic acetylcholine receptor-mediated signaling.
    Erica Foffi, Francesco Rugolo, Nisha Ramamurthy, Jillian Haight, Simone Helke, Annick You-Ten, Chantal Tobin, Soode Moghadas Jafari, Andrew J Elia, Thorsten Berger, Eleonora Candi, Gerry Melino, Tak W Mak.
      Chronic inflammatory skin disorders are characterized by keratinocyte hyperproliferation and hyperactivation as well as immune cell infiltration. We investigated whether immune cell-derived acetylcholine (ACh) is a modulator of skin inflammation in mice. Here, we identify skin epithelial B cells as a key source of ACh that damps down inflammation. We used imiquimod (IMQ) to induce inflammatory skin disease (ISD) in mice lacking ACh production specifically in B cells (ChATfl/fl;Mb1-Cre mice). Increased keratinocyte proliferation, epidermal thickening, and elevated levels of proinflammatory cytokines resulted. ACh binding to α9 nicotinic ACh receptor (encoded by Chrna9) expressed on wild-type mouse keratinocytes reduced their proliferation. Chrna9-deficient mice exhibited the same exacerbated ISD phenotype as ChATfl/fl;Mb1-Cre mice following IMQ induction. Our data suggest that B cell-derived ACh maintains skin homeostasis by modulating keratinocyte turnover and controlling immune-related inflammation. Therapeutic manipulation of this cholinergic pathway might mitigate both keratinocyte dysfunction and immune dysregulation in human patients, potentially pointing to treatments for ISDs such as psoriasis and related disorders.
    Keywords:  B lymphocytes; acetylcholine; inflammation; psoriasis; skin
    DOI:  https://doi.org/10.1073/pnas.2501960122
  47. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00380-8. [Epub ahead of print]44(5): 115609
    Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
    Netherlands Brain Bank
      Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.
    Keywords:  ARCH; CH; CHIP; CP: Immunology; CP: Neuroscience; DNMT3A R882H; HSC; brain macrophages; clonal hematopoiesis; microglia; monocytes
    DOI:  https://doi.org/10.1016/j.celrep.2025.115609
  48. Am J Physiol Lung Cell Mol Physiol. 2025 Apr 23.
    TNFα Mediated Subcellular Heterogeneity of Succinate Dehydrogenase Activity in Human Airway Smooth Muscle Cells.
    Sanjana Mahadev Bhat, Claire C Creighton, Gary C Sieck.
      Tumor necrosis factor α (TNFα) is a proinflammatory cytokine which mediates acute inflammatory effects in response to allergens, pollutants, and respiratory infections. Previously, we reported that TNFα increased maximum O2 consumption rate (OCR) and mitochondrial volume density (MVD) in human airway smooth muscle (hASM) cells. However, TNFα decreased maximum OCR when normalized to mitochondrial volume. Additionally, TNFα altered mitochondrial distribution and motility within hASM cells. Although high-resolution respirometry is valuable for assessing mitochondrial function, it overlooks mitochondrial structural and functional heterogeneity within cells. Therefore, a direct measurement of cellular mitochondrial function provides valuable information. Previously, we developed a confocal-based quantitative histochemical technique to determine the maximum velocity of the succinate dehydrogenase (SDH) reaction (SDHmax) in single cells and observed that cellular SDHmax corresponds with MVD. Therefore, we hypothesized that TNFα decreases SDHmax per mitochondrion in hASM cells. The hASM cells were treated with TNFα (20 ng/mL, 6 h and 24 h) or untreated (time-matched control). Using 3D confocal imaging of labeled mitochondria and a concentric shell method for analysis, we quantified MVD, mitochondrial complexity index (MCI) and SDHmax relative to the nuclear membrane. Within each shell, SDHmax and MVD peaked in the perinuclear compartments and decreased toward the distal compartments of the cell. When normalized to mitochondrial volume, SDHmax decreased in the perinuclear compartments compared to distal compartments. TNFα caused a significant shift in mitochondrial morphometry and function compared to control. In conclusion, mitochondria within individual cells exhibit distinct morphological and functional heterogeneity, which is disrupted during acute inflammation.
    Keywords:  Airway Inflammation; Mitochondria; Mitochondrial Function; Succinate Dehydrogenase; TNFα
    DOI:  https://doi.org/10.1152/ajplung.00396.2024
  49. Sci Signal. 2025 Apr 22. 18(883): eado3473
    Re-epithelialization of cancer cells increases autophagy and DNA damage: Implications for breast cancer dormancy and relapse.
    Diana Drago-Garcia, Suvendu Giri, Rishita Chatterjee, Arturo Simoni-Nieves, Maha Abedrabbo, Alessandro Genna, Mary Luz Uribe Rios, Moshit Lindzen, Arunachalam Sekar, Nitin Gupta, Noa Aharoni, Tithi Bhandari, Agalyan Mayalagu, Luisa Schwarzmüller, Nooraldeen Tarade, Rong Zhu, Harsha-Raj Mohan-Raju, Feride Karatekin, Francesco Roncato, Yaniv Eyal-Lubling, Tal Keidar, Yam Nof, Nishanth Belugali Nataraj, Karin Shira Bernshtein, Bettina Wagner, Nishanth Ulhas Nair, Neel Sanghvi, Ronen Alon, Rony Seger, Eli Pikarsky, Sara Donzelli, Giovanni Blandino, Stefan Wiemann, Sima Lev, Ron Prywes, Dalit Barkan, Oscar M Rueda, Carlos Caldas, Eytan Ruppin, Yosef Shiloh, Maik Dahlhoff, Yosef Yarden.
      Cellular plasticity mediates tissue development as well as cancer growth and progression. In breast cancer, a shift to a more epithelial phenotype (epithelialization) underlies a state of reversible cell growth arrest called tumor dormancy, which enables drug resistance, tumor recurrence, and metastasis. Here, we explored the mechanisms driving epithelialization and dormancy in aggressive mesenchymal-like breast cancer cells in three-dimensional cultures. Overexpressing either of the epithelial lineage-associated transcription factors OVOL1 or OVOL2 suppressed cell proliferation and migration and promoted transition to an epithelial morphology. The expression of OVOL1 (and of OVOL2 to a lesser extent) was regulated by steroid hormones and growth factors and was more abundant in tumors than in normal mammary cells. An uncharacterized and indirect target of OVOL1/2, C1ORF116, exhibited genetic and epigenetic aberrations in breast tumors, and its expression correlated with poor prognosis in patients. We further found that C1ORF116 was an autophagy receptor that directed the degradation of antioxidant proteins, including thioredoxin. Through C1ORF116 and unidentified mediators, OVOL1 expression dysregulated both redox homeostasis (in association with increased ROS, decreased glutathione, and redistribution of the transcription factor NRF2) and DNA damage and repair (in association with increased DNA oxidation and double-strand breaks and an altered interplay among the kinases p38-MAPK, ATM, and others). Because these effects, as they accumulate in cells, can promote metastasis and dormancy escape, the findings suggest that OVOLs not only promote dormancy entry and maintenance in breast cancer but also may ultimately drive dormancy exit and tumor recurrence.
    DOI:  https://doi.org/10.1126/scisignal.ado3473
  50. Nature. 2025 Apr 23.
    Human de novo mutation rates from a four-generation pedigree reference.
    David Porubsky, Harriet Dashnow, Thomas A Sasani, Glennis A Logsdon, Pille Hallast, Michelle D Noyes, Zev N Kronenberg, Tom Mokveld, Nidhi Koundinya, Cillian Nolan, Cody J Steely, Andrea Guarracino, Egor Dolzhenko, William T Harvey, William J Rowell, Kirill Grigorev, Thomas J Nicholas, Michael E Goldberg, Keisuke K Oshima, Jiadong Lin, Peter Ebert, W Scott Watkins, Tiffany Y Leung, Vincent C T Hanlon, Sean McGee, Brent S Pedersen, Hannah C Happ, Hyeonsoo Jeong, Katherine M Munson, Kendra Hoekzema, Daniel D Chan, Yanni Wang, Jordan Knuth, Gage H Garcia, Cairbre Fanslow, Christine Lambert, Charles Lee, Joshua D Smith, Shawn Levy, Christopher E Mason, Erik Garrison, Peter M Lansdorp, Deborah W Neklason, Lynn B Jorde, Aaron R Quinlan, Michael A Eberle, Evan E Eichler.
      Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98-206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4 kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.
    DOI:  https://doi.org/10.1038/s41586-025-08922-2
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