bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–07–06
57 papers selected by
Christian Frezza, Universität zu Köln
  1. Subclonal immune evasion in non-small cell lung cancer.
  2. Cellular metabolite sensors: Arginine? It's in the bag!
  3. A constricted mitochondrial morphology formed during respiration.
  4. Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
  5. Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
  6. RNA-binding proteins as versatile metabolic regulators.
  7. mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
  8. Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.
  9. Triglycerides are an important fuel reserve for synapse function in the brain.
  10. PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
  11. MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions.
  12. Chemosensor receptors are lipid-detecting regulators of macrophage function in cancer.
  13. Circadian metabolism in myeloid cells.
  14. Moonlighting functions of phosphoglycerate dehydrogenase in cancer.
  15. A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
  16. Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
  17. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  18. Cysteine allostery and autoinhibition govern human STING oligomer functionality.
  19. Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
  20. The Somatic Mosaicism across Human Tissues Network.
  21. BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma.
  22. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  23. Imaging cancer metabolism using magnetic resonance.
  24. Tumor-Intrinsic and Microenvironmental Determinants of Impaired Antitumor Immunity in Chromophobe Renal Cell Carcinoma.
  25. Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers.
  26. FAF2 is a bifunctional regulator of peroxisomal homeostasis and saturated lipid responses.
  27. Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.
  28. Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
  29. Beyond glucose and Warburg: finding the sweet spot in cancer metabolism models.
  30. Publisher Correction: Metabolic adaptations direct cell fate during tissue regeneration.
  31. WSTF nuclear autophagy regulates chronic but not acute inflammation.
  32. Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
  33. The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.
  34. Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.
  35. The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells.
  36. Pan-cancer immune and stromal deconvolution predicts clinical outcomes and mutation profiles.
  37. Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.
  38. Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
  39. Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation.
  40. Ageing is linked to inflammation - but only in the industrialized world.
  41. Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
  42. Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory.
  43. You are what you eat: autophagy guides CD8+ T cell function through metabolism.
  44. Muscle needs NAD, but how much?
  45. The long-term effects of chemotherapy on normal blood cells.
  46. Regulation of adipogenesis by nucleotides.
  47. A high-fiber diet mimics aging-related signatures of caloric restriction in mammals.
  48. Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
  49. Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
  50. Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.
  51. Presentation of immunoregulatory sialoglycans on T cells is divergent between mice and humans.
  52. Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
  53. The metabolic costs of meiotic drive.
  54. The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
  55. Condensin II activation by M18BP1.
  56. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  57. Regulation of inflammatory processes by caspases.
  1. Cancer Cell. 2025 Jul 01. pii: S1535-6108(25)00262-4. [Epub ahead of print]
    Subclonal immune evasion in non-small cell lung cancer.
    TRACERx consortium
      Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.
    Keywords:  T cell; cancer evolution; immune escape; immune evasion; immunosurveillance; immunotherapy; intratumor heterogeneity; non-small cell lung cancer; organoids; tumor evolution; tumor immunology
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.012
  2. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00510-6. [Epub ahead of print]85(13): 2457-2459
    Cellular metabolite sensors: Arginine? It's in the bag!
    Thomas D Jackson, Jonathan M Palozzi, Pere Puigserver.
      In this issue of Molecular Cell, Chen et al.1 identify a novel arginine-sensing system, composed of the cytosolic proteins BAG2 and SAMD4B, which promotes cancer cell survival during arginine deficiency.
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.010
  3. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  4. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
    Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
    Laura Sophie Kremer, Guanbin Gao, Giovanni Rigoni, Roberta Filograna, Mara Mennuni, Rolf Wibom, Ákos Végvári, Camilla Koolmeister, Nils-Göran Larsson.
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  5. Nat Commun. 2025 Jul 01. 16(1): 5435
    Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  6. npj metabolic health and disease... 2025 Jan 13. 3(1): 1
    RNA-binding proteins as versatile metabolic regulators.
    Ellie Koletsou, Ina Huppertz.
      Metabolic shifts are a hallmark of numerous biological processes, including the differentiation of stem cells along a specific lineage and the activation of diverse cell types, such as immune cells. This review examines the intricate energy metabolic alterations that occur in diverse biological settings, from embryonic development to adult tissue homoeostasis and disease states. In particular, we emphasise the regulatory function of RNA-binding proteins (RBPs) in coordinating these metabolic shifts and examine how they modulate key pathways, such as glycolysis and oxidative phosphorylation, to meet the dynamic cellular energy demands. This review highlights the various mechanisms by which RBPs regulate these changes, ranging from active involvement in the post-transcriptional regulation of metabolically relevant genes to alteration of an RBP's function by specific RNAs, metabolites or growth factors. Finally, we consider how ageing and disease affect the function of RBPs and how RBPs can disrupt the delicate balance of metabolic regulation. Taken together, this review provides a comprehensive overview of the critical interplay between RBPs and metabolism and offers insights into potential therapeutic targets for regenerative medicine and age-related diseases.
    DOI:  https://doi.org/10.1038/s44324-024-00044-z
  7. Trends Cancer. 2025 Jul 02. pii: S2405-8033(25)00153-0. [Epub ahead of print]
    mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
    Israel Cañadas, Takahiko Murayama, Lorenzo Galluzzi.
      Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.
    Keywords:  NF-κB; PD-L1; SASP; STING; VDAC; prostate cancer
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.010
  8. ACS Chem Biol. 2025 Jul 02.
    Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.
    Stephen B Ruiz, Daniel E Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R Izawa-Ishiguro, Justin Cross, Daniel A Heller.
      Although ferroptosis resistance is prevalent among many cancer cell types, precisely how ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that phospholipase PAFAH2 regulates ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized phospholipids in KEAP1 mutant and NRF2-active cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly ferroptosis state characterized by the enrichment of key phospholipids previously identified to be important in ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in ferroptosis induction and abrogation of ferroptosis resistance across cancer types.
    DOI:  https://doi.org/10.1021/acschembio.5c00273
  9. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  10. Cancer Res. 2025 Jul 03.
    PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
    Beatriz Parejo-Alonso, David Barneda, Sara Maria David Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruiz-Cañas, Quan Zheng, Jiajia Tang, Matthias M Gaida, Ulf Schmitz, Pilar Irun, Laure Penin-Peyta, Shanthini Mary Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng-Lay Lin, Shenghui Huang, Ming-Hsin Yang, Angel Lanas, Bruno Sainz, Christoph Thiele, Christopher Heeschen, Patricia Sancho.
      The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3475
  11. npj metabolic health and disease... 2024 Mar 15. 2(1): 3
    MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions.
    Natalia Pardo-Lorente, Sara Sdelci.
      Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.
    DOI:  https://doi.org/10.1038/s44324-024-00005-6
  12. Nat Immunol. 2025 Jul;26(7): 1182-1197
    Chemosensor receptors are lipid-detecting regulators of macrophage function in cancer.
    Giulia Marelli, Nicolò Morina, Simone Puccio, Marta Iovino, Marta Pandini, Federica Portale, Mattia Carvetta, Divya Mishra, Elisabetta Diana, Greta Meregalli, Elvezia Paraboschi, Javier Cibella, Clelia Peano, Gianluca Basso, Gabriele De Simone, Chiara Camisaschi, Elena Magrini, Giulio Sartori, Elham Karimi, Piergiuseppe Colombo, Massimo Lazzeri, Paolo Casale, Lavinia Morosi, Giuseppe Martano, Rosanna Asselta, Eduardo Bonavita, Hiro Matsunami, Francesco Bertoni, Logan Walsh, Enrico Lugli, Diletta Di Mitri.
      Infiltration of macrophages into tumors is a hallmark of cancer progression, and re-educating tumor-associated macrophages (TAMs) toward an antitumor status is a promising immunotherapy strategy. However, the mechanisms through which cancer cells affect macrophage education are unclear, limiting the therapeutic potential of this approach. Here we conducted an unbiased genome-wide CRISPR screen of primary macrophages. Our study confirms the function of known regulators in TAM responses and reveals new insights into the behavior of these cells. We identify olfactory and vomeronasal receptors, or chemosensors, as important drivers of a tumor-supportive macrophage phenotype across multiple cancers. In vivo deletion of selected chemosensors in TAMs resulted in cancer regression and increased infiltration of tumor-reactive CD8+ T cells. In human prostate cancer tissues, palmitic acid bound to olfactory receptor 51E2 (OR51E2) expressed by TAMs, enhancing their protumor phenotype. Spatial lipidomics analysis further confirmed the presence of palmitic acid in close proximity to TAMs in prostate cancer, supporting the function of this lipid mediator in the tumor microenvironment. Overall, these data implicate chemosensors in macrophage sensing of the lipid-enriched milieu and highlight these receptors as possible therapeutic targets for enhancing antitumor immunity.
    DOI:  https://doi.org/10.1038/s41590-025-02191-x
  13. Life Metab. 2025 Aug;4(4): loaf018
    Circadian metabolism in myeloid cells.
    Yingxi Xu, Chen Wang, Ping-Chih Ho.
      Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets. Furthermore, mitochondrial dynamics, a key metabolic feature, are under circadian control and influence antigen presentation and effector functions. Here, we review the interplay between circadian clocks, metabolism, and myeloid immunity, discussing their therapeutic opportunities for optimizing vaccination, infection management, and immunotherapy.
    Keywords:  circadian rhythms; metabolism; myeloid cell
    DOI:  https://doi.org/10.1093/lifemeta/loaf018
  14. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00711-9. [Epub ahead of print]44(7): 115940
    Moonlighting functions of phosphoglycerate dehydrogenase in cancer.
    Chuanlong Wang, Sanqi An, Lingyang Zhao, Shuo Li, Jia Huang, Wenkai Ren.
      Phosphoglycerate dehydrogenase (PHGDH) is traditionally known for catalyzing the conversion of 3-phosphoglycerate (3-PG) to 3-phosphonooxypyruvate (3-PHP), a key step in the de novo synthesis of serine. However, recent studies have uncovered that PHGDH exhibits a wide range of non-canonical functions. In addition to its role in metabolic reactions within the glycolytic pathway, PHGDH also participates in the regulation of gene transcription and translation. These newly identified functions significantly alter our understanding of how PHGDH aberrantly regulates tumor cell fate. In this review, we summarize the mechanisms by which PHGDH promotes cancer progression through these non-canonical pathways, potentially offering new therapeutic avenues for cancer.
    Keywords:  CP: Cancer; CP: Metabolism; PHGDH; moonlighting enzyme; serine; tumor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115940
  15. Nat Aging. 2025 Jun 30.
    A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
    Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  16. Nat Commun. 2025 Jul 01. 16(1): 5850
    Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
    Aliyah Habashy, Christopher Acree, Keun-Young Kim, Ali Zahraei, Martin Dufresne, Sebastien Phan, Melanie Cutler, Emilee Patterson, Alexandra G Mulligan, Kristopher Burkewitz, Charles Robert Flynn, Louise Lantier, Thomas Deerinck, Owen P McGuinness, Jeffrey M Spraggins, Mark H Ellisman, Rafael Arrojo E Drigo.
      Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived 13C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose 13C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.
    DOI:  https://doi.org/10.1038/s41467-025-60994-w
  17. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  18. Nat Chem Biol. 2025 Jul 03.
    Cysteine allostery and autoinhibition govern human STING oligomer functionality.
    Rebecca Chan, Xujun Cao, Sabrina L Ergun, Evert Njomen, Stephen R Lynch, Christopher Ritchie, Benjamin Cravatt, Lingyin Li.
      The stimulator of interferon genes (STING) innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, no inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human STING activation are crucial for inhibition of downstream signaling. Here we report that C91 palmitoylation is not universally necessary for human STING signaling. Instead, evolutionarily-conserved C64 is basally palmitoylated and is crucial for preventing unproductive STING oligomerization. The effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at C148. Together, dynamic equilibria of these cysteine post-translational modifications allow proper STING ligand-binding domain self-assembly and scaffolding function. Given this complex landscape, we took inspiration from STING's natural autoinhibitory mechanism and identified an eight-amino-acid peptide that binds a defined pocket at the oligomerization interface, setting the stage for future therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-025-01951-y
  19. Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00708-9. [Epub ahead of print]44(7): 115937
    Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
    Zongyu Huang, Yanjun Liu, Ya Zeng, Jun Wang, Siyuan Sun, Chris Soon Heng Tan, Peng R Chen.
      Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.
    Keywords:  CP: Metabolism; CP: Molecular biology; cancer cell susceptibility; cuproptosis; mitochondrial thermal proteome; proximity labeling; pyruvate dehydrogenase aberrant activation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115937
  20. Nature. 2025 Jul;643(8070): 47-59
    The Somatic Mosaicism across Human Tissues Network.
    Somatic Mosaicism across Human Tissues Network
      From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09096-7
  21. Nat Commun. 2025 Jul 01. 16(1): 5834
    BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma.
    Rebecca M Mello, Diego Gomez Ceballos, Colby R Sandate, Sicong Wang, Celine Jouffe, Daniel Agudelo, Nina Henriette Uhlenhaut, Nicolas H Thomä, M Celeste Simon, Katja A Lamia.
      Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). The core circadian transcription factor BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 selectively reduces HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). BMAL1-HIF2α is more sensitive than ARNT-HIF2α is to suppression by PT2399, and the effectiveness of PT2399 for suppressing xenograft tumor growth in vivo depends on the time of day at which it is delivered. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 influences HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
    DOI:  https://doi.org/10.1038/s41467-025-60904-0
  22. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
  23. Npj imaging... 2024 Jan 11. 2(1): 1
    Imaging cancer metabolism using magnetic resonance.
    Kevin M Brindle.
      The challenge in clinical oncology is to select the most appropriate treatment for an individual patient. Transcriptome and metabolite profiling have revealed that tumours can display metabolic subtypes with different therapeutic vulnerabilities1-4. Metabolic imaging has the potential to distinguish these subtypes and therefore those treatment(s) that should be most effective. Moreover, since changes in tumour metabolism can occur early during treatment, metabolic imaging can also be used subsequently to detect early evidence of treatment response. In this Perspective I briefly review and discuss the relative advantages and disadvantages of magnetic resonance imaging of tumour metabolism using hyperpolarized 13C- and 2H-labelled substrates.
    DOI:  https://doi.org/10.1038/s44303-023-00004-0
  24. J Clin Oncol. 2025 Jul 02. JCO2500234
    Tumor-Intrinsic and Microenvironmental Determinants of Impaired Antitumor Immunity in Chromophobe Renal Cell Carcinoma.
    Chris Labaki, Eddy Saad, Katrine N Madsen, Charbel Hobeika, Kevin Bi, Michel Alchoueiry, Sabrina Camp, Yue Hou, Ziad Bakouny, Sayed Matar, Nourhan El Ahmar, Jackson Nyman, Long Zhang, Carmen Priolo, Rishabh Rout, Melissa Daou, Damir Khabibullin, Samer Salem, Nicholas Schindler, Renée Maria Saliby, Kevin Meli, J Connor Wells, Erica Pimenta, Kosuke Takemura, Jihye Park, Marc Eid, Karl Semaan, Jingxin Fu, Thomas Denize, Razane El Hajj Chehade, Marc Machaalani, Rashad Nawfal, Wassim Daoud Khatoun, Mustafa Saleh, Jad El Masri, Nina Rossa Haddad, Wenxin Xu, Bradley A McGregor, Michelle S Hirsch, Wanling Xie, Daniel Y C Heng, David F McDermott, Sabina Signoretti, Eliezer M Van Allen, Sachet A Shukla, Toni K Choueiri, Elizabeth P Henske, David A Braun.
       PURPOSE: While immune checkpoint inhibition (ICI) has transformed the management of many advanced renal cell carcinomas (RCCs), the determinants of effective antitumor immunity for chromophobe RCC (ChRCC) and renal oncocytic tumors remain an unmet clinical and scientific need.
    METHODS: Single-cell transcriptomic and T-cell receptor profiling was performed on tumor and adjacent normal tissue of patients with ChRCC and renal oncocytic neoplasms. Using machine learning, the cellular origin of renal oncocytic neoplasms was evaluated, with analysis of associated oncogenic pathways. Using immunohistochemistry, immune infiltration was analyzed in renal oncocytic neoplasms in comparison with clear cell RCC (ccRCC). Immune checkpoint expression, clonal expansion, and tumor specificity were compared between ChRCC and ccRCC. Using the International Metastatic RCC Database Consortium data set, clinical outcomes of patients with metastatic ChRCC (mChRCC) treated with first-line systemic regimens were compared with those of patients with ccRCC.
    RESULTS: We validated α-intercalated cells as the cellular origin of renal oncocytic neoplasms. We identified a downregulation of HLA class I molecules with enrichment of potentially targetable pathways including mammalian target of rapamycin and ferroptosis in ChRCC. The tumor microenvironment of ChRCC showed markedly decreased immune infiltration, with a pronounced depletion in tumor-infiltrating CD8+ T cells. ChRCC-infiltrating CD8+ T cells demonstrated lower immune checkpoint expression, diminished clonal expansion, and decreased tumor specificity. Clinical analysis identified poor survival outcomes selectively among patients with mChRCC treated with immune-based therapies.
    CONCLUSION: Immunogenomic analysis of ChRCC revealed profound depletion of T cells, with an immune phenotype marked by a lack of expression of immune checkpoints and poor tumor specificity, suggesting that the few T cells in these tumor types are likely nonspecific bystanders. This immune-cold environment hinders an effective response to immunotherapy and underscores the need for ChRCC-tailored treatments designed to improve tumor-specific T-cell infiltration into the microenvironment.
    DOI:  https://doi.org/10.1200/JCO-25-00234
  25. Nat Genet. 2025 Jul 04.
    Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers.
    Tim Arnoldus, Alex van Vliet, Onno B Bleijerveld, Adriaan F H de Groot, Qinglin Piao, Niek Blomberg, Désirée Schatton, Jing Dong, Susan E van Hal-van Veen, Rolf Harkes, Anita E Grootemaat, Natalie Proost, Birol Cabukusta, Christian Frezza, Marieke van de Ven, Nicole N van der Wel, Martin Giera, Maarten Altelaar, Daniel S Peeper.
      Synthetic lethal interactions (SLIs) based on genomic alterations in cancer have been therapeutically explored. We investigated the SLI space as a function of differential RNA expression in cancer and normal tissue. Computational analyses of functional genomic and gene expression resources uncovered a cancer-specific SLI between the paralogs cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2. The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which have low or absent CDS1 expression and account for roughly half of all cancers. Mechanistically, the CDS1-2 SLI is accompanied by disruption of lipid homeostasis, including accumulation of cholesterol esters and triglycerides, and apoptosis. Genome-wide CRISPR-Cas9 knockout screens in CDS1-negative cancer cells identify no common escape mechanism of death caused by CDS2 ablation, indicating the robustness of the SLI. Synthetic lethality is driven by CDS2 dosage and depends on catalytic activity. Thus, CDS2 may serve as a pharmacologically tractable target in mesenchymal-like cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02221-2
  26. Sci Adv. 2025 Jul 04. 11(27): eadu9104
    FAF2 is a bifunctional regulator of peroxisomal homeostasis and saturated lipid responses.
    Choah Kim, Katlyn R Gabriel, Dylan Boone, Matthew R Brown, Katherine Oppenheimer, Maria Kost-Alimova, Juan Lorenzo B Pablo, Anna Greka.
      Exposure to saturated fatty acids (SFAs), such as palmitic acid, can lead to cellular metabolic dysfunction known as lipotoxicity. Although canonical adaptive metabolic processes like lipid storage or desaturation are known cellular responses to saturated fat exposure, the link between SFA metabolism and organellar biology remains an area of active inquiry. We performed a genome-wide CRISPR knockout screen in human epithelial cells to identify modulators of SFA toxicity. The screen revealed peroxisomal proteins, especially those that affect ether lipid synthesis, as important regulators of lipotoxicity. We identified Fas-associated factor family member 2 (FAF2) as a critical bifunctional coregulator of peroxisomal and fatty acid biology. We further demonstrated the requirement of the ubiquitin-regulatory X (UBX) and UAS thioredoxin-like domains of FAF2 for peroxisomal protein abundance and SFA-induced cellular stress. Our work highlights the role of FAF2 in regulating peroxisomal abundance and function and the peroxisome as a key organelle in the cellular response to SFAs.
    DOI:  https://doi.org/10.1126/sciadv.adu9104
  27. Nat Aging. 2025 Jun 30.
    Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.
    Roméo S Blanc, Nidhi Shah, Sarah Hachmer, Noah A S Salama, Fanju W Meng, Alireza Mousaei, Gayatri Puri, Jeonghye Hannah Hwang, Elizabeth E Wacker, Benjamin A Yang, Carlos A Aguilar, Joe V Chakkalakal, John O Onukwufor, Patrick J Murphy, Laura M Calvi, F Jeffrey Dilworth, Robert T Dirksen.
      Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration.
    DOI:  https://doi.org/10.1038/s43587-025-00902-5
  28. J Clin Invest. 2025 Jul 01. pii: e185000. [Epub ahead of print]135(13):
    Mitofusin 2 controls mitochondrial and synaptic dynamics of suprachiasmatic VIP neurons and related circadian rhythms.
    Milan Stoiljkovic, Jae Eun Song, Hee-Kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph T Bass, Tamas L Horvath.
      Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide-expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
    Keywords:  Behavior; Cell biology; Metabolism; Mitochondria; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI185000
  29. npj metabolic health and disease... 2024 Sep 02. 2(1): 11
    Beyond glucose and Warburg: finding the sweet spot in cancer metabolism models.
    Nia G Hammond, Robert B Cameron, Brandon Faubert.
      Advances in cancer biology have highlighted metabolic reprogramming as an essential aspect of tumorigenesis and progression. However, recent efforts to study tumor metabolism in vivo have identified some disconnects between in vitro and in vivo biology. This is due, at least in part, to the simplified nature of cell culture models and highlights a growing need to utilize more physiologically relevant approaches to more accurately assess tumor metabolism. In this review, we outline the evolution of our understanding of cancer metabolism and discuss some discrepancies between in vitro and in vivo conditions. We describe how the development of physiological media, in combination with advanced culturing methods, can bridge the gap between in vitro and in vivo metabolism.
    DOI:  https://doi.org/10.1038/s44324-024-00017-2
  30. Nature. 2025 Jul 01.
    Publisher Correction: Metabolic adaptations direct cell fate during tissue regeneration.
    Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.
      
    DOI:  https://doi.org/10.1038/s41586-025-09294-3
  31. Nature. 2025 Jul 02.
    WSTF nuclear autophagy regulates chronic but not acute inflammation.
    Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.
      Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09234-1
  32. Nat Commun. 2025 Jul 01. 16(1): 5708
    Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
    Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun.
      The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal that Rev-erb suppresses fatty acid oxidation and promotes carbohydrate metabolism before sleep. Thus, the muscle-autonomous clock, not feeding or locomotor behaviors, dictates diurnal variations of muscle functions and time-dependent adaptations to training, which has broad implications in metabolic disorders and sports medicine as Rev-erb agonists are exercise mimetics or enhancers.
    DOI:  https://doi.org/10.1038/s41467-025-60520-y
  33. Nat Genet. 2025 Jul 04.
    The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.
    Pui Ying Chan, Diana Alexander, Ishan Mehta, Larissa Satiko Alcantara Sekimoto Matsuyama, Victoria Harle, Rebeca Olvera-León, Jun Sung Park, Fernanda G Arriaga-González, Louise van der Weyden, Saamin Cheema, Vivek Iyer, Victoria Offord, David Barneda, Phillip T Hawkins, Len Stephens, Zuza Kozik, Michael Woods, Kim Wong, Gabriel Balmus, Alessandro Vinceti, Nicola A Thompson, Martin Del Castillo Velasco-Herrera, Lodewyk Wessels, Joris van de Haar, Emanuel Gonçalves, Sanju Sinha, Martha Estefania Vázquez-Cruz, Luisa Bisceglia, Francesco Raimondi, Jyoti Choudhary, Sumeet Patiyal, Anjan Venkatesh, Francesco Iorio, Colm J Ryan, David J Adams.
      Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02222-1
  34. Mol Metab. 2025 Jun 26. pii: S2212-8778(25)00101-2. [Epub ahead of print] 102194
    Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.
    Caroline Bartman, Shengqi Hou, Fabian Correa, Yihui Shen, Victoria da Silva-Diz, Maya Aleksandrova, Daniel Herranz, Joshua D Rabinowitz, Andrew Intlekofer.
      Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.
    Keywords:  Immunometabolism; Isotope tracing; Metabolomics; Tissue metabolism; Whole-body metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2025.102194
  35. Cancer Metab. 2025 Jul 02. 13(1): 34
    The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells.
    Mohamed M A El Husseiny, Roland Nilsson.
       BACKGROUND: Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown.
    METHODS: Cancer cell lines were cultured with homocysteine in place of methionine, and growth responses were measured. Revertant cells capable of growing in homocysteine were generated through long-term culture with high B12 and analyzed using single-cell RNA-seq. Metabolite uptake/release was measured using isotope dilution and MTR activity was assessed using metabolic flux analysis (MFA). Functional rescue experiments were performed by overexpressing the B12-independent methionine synthase enzyme.
    RESULTS: We report evidence that methionine dependence is caused by low MTR activity secondary to a B12 deficiency. High levels of the B12 cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted "revertant" cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B12-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B12-dependent human enzyme had no effect.
    CONCLUSION: Methionine dependence in cancer can be driven by low MTR activity secondary to B12 deficiency, at least in the cell lines studied. This mechanistic insight resolves a long-standing question in cancer metabolism and may open new avenues for exploiting the phenomenon for cancer therapy.
    Keywords:  Cancer nutrition; Cobalamin; Methylation; One-carbon metabolism
    DOI:  https://doi.org/10.1186/s40170-025-00405-2
  36. Sci Rep. 2025 Jul 04. 15(1): 23921
    Pan-cancer immune and stromal deconvolution predicts clinical outcomes and mutation profiles.
    Cancer Genome Atlas Analysis Network
      Traditional gene expression deconvolution methods assess a limited number of cell types, therefore do not capture the full complexity of the tumor microenvironment (TME). Here, we integrate nine deconvolution tools to assess 79 TME cell types in 10,592 tumors across 33 different cancer types, creating the most comprehensive analysis of the TME. In total, we found 41 patterns of immune infiltration and stroma profiles, identifying heterogeneous yet unique TME portraits for each cancer and several new findings. Our findings indicate that leukocytes play a major role in distinguishing various tumor types, and that a shared immune-rich TME cluster predicts better survival in bladder cancer for luminal and basal squamous subtypes, as well as in melanoma for RAS-hotspot subtypes. Our detailed deconvolution and mutational correlation analyses uncover 35 therapeutic target and candidate response biomarkers hypotheses (including CASP8 and RAS pathway genes).
    Keywords:  Cell type estimation; Deconvolution; Immune cells; Integrated scores; Pan-cancer analysis; Somatic mutations; Stroma; Survival; Tumor microenvironment; Tumor progression; iScores
    DOI:  https://doi.org/10.1038/s41598-025-09075-y
  37. EMBO Mol Med. 2025 Jun 30.
    Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.
    Lucas Schoenfeldt, Patrick T Paine, Sara Picó, Nibrasul H Kamaludeen M, Grace B Phelps, Calida Mrabti, Gabriela Desdín-Micó, María Del Carmen Maza, Kevin Perez, Alejandro Ocampo.
      The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.
    Keywords:  Aging; Cellular Reprogramming; Chemical Reprogramming; Epigenetics; Lifespan
    DOI:  https://doi.org/10.1038/s44321-025-00265-9
  38. Nat Commun. 2025 Jul 01. 16(1): 5563
    Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
    Huiwang Zhan, Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long, Chris Janetopoulos, Chuan-Hsiang Huang, Peter N Devreotes.
      Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.
    DOI:  https://doi.org/10.1038/s41467-025-60596-6
  39. Nat Genet. 2025 Jul 01.
    Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation.
    Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Li Zhao, Joanne I Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney DiNardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi.
      The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy.
    DOI:  https://doi.org/10.1038/s41588-025-02235-w
  40. Nature. 2025 Jun 30.
    Ageing is linked to inflammation - but only in the industrialized world.
    Miryam Naddaf.
      
    Keywords:  Ageing; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-02085-w
  41. Cell Commun Signal. 2025 Jul 01. 23(1): 311
    Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
    Mincong Shu, Yuhan Liu, Jianbin Wang.
      Serine is a non-essential amino acid, serving as a precursor for other amino acids, lipids, and nucleotide synthesis. Its supply is ensured by two main mechanisms: exogenous uptake and endogenous synthesis. The serine synthesis pathway (SSP) connects glycolysis with the one-carbon cycle and plays an important role in cellular homeostasis by regulating substance synthesis, redox homeostasis, and gene expression. The de novo SSP involves three successive enzymatic reactions catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). Post-translational modifications (PTMs), as essential regulatory mechanisms of proteins, play pivotal roles in physiological and pathological processes. This review focuses on the regulatory mode of PTMs on PHGDH, PSAT1, and PSPH, including phosphorylation, ubiquitination, acetylation, methylation, S-palmitoylation, S-nitrosylation, deamidation, SUMOylation, and lactylation. We summarize how these PTMs participate in the metabolic reprogramming of SSP. It helps us better understand the molecular mechanisms and physiological significance of the PTM network in serine synthetic metabolism, providing guidance for subsequent research and development in the future.
    Keywords:  PHGDH; PSAT1; PSPH; Post-translational modification; Serine synthetic pathway
    DOI:  https://doi.org/10.1186/s12964-025-02327-4
  42. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00462-9. [Epub ahead of print]85(13): 2455-2457
    Metabolic compartmentalization via glycogenolysis-derived G1P bolsters T cell memory.
    Hao Shi, Hongbo Chi.
      In this issue of Molecular Cell, Zhou et al.1 show that glycogenolysis-derived glucose-1-phosphate enhances glucose-6-phosphate dehydrogenase oligomerization and activity, promoting the formation of a liquid-liquid phase separation compartment containing glycogen. This channels glycogenolysis-derived glucose-6-phosphate into the pentose phosphate pathway, supporting CD8+ memory T cell fitness and antitumor effects.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.023
  43. Immunometabolism (Cobham). 2025 Jul;7(3): e00064
    You are what you eat: autophagy guides CD8+ T cell function through metabolism.
    Caio Loureiro Salgado, Henrique Borges da Silva.
      The differentiation of naive CD8+ T cells into effector or memory populations requires dynamic remodeling of cellular metabolism and proteome composition. In a recent study published in Nature Immunology, Sinclair et al offer critical insights into the role of autophagy, particularly mitophagy, in regulating these processes during CD8+ T cell differentiation. Autophagy, a conserved catabolic mechanism, is traditionally associated with cellular homeostasis and survival during nutrient deprivation. In contrast, Sinclair et al reveal that, in the immune system, autophagy is not simply a survival mechanism but a fine-tuned regulator of CD8+ T cell metabolism and function, fine-tuning CD8+ T cell effector vs quiescence choices.
    Keywords:  CD8+ T cells; autophagy; cytotoxic T cell; mitophagy; naive T cells
    DOI:  https://doi.org/10.1097/IN9.0000000000000064
  44. Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456
    Muscle needs NAD, but how much?
    David W Frederick, Joseph P McGaunn, Joseph A Baur.
      Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.001
  45. Nat Genet. 2025 Jul 01.
    The long-term effects of chemotherapy on normal blood cells.
    Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan McDermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton.
      Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.
    DOI:  https://doi.org/10.1038/s41588-025-02234-x
  46. Biochem Soc Trans. 2025 Jun 30. 53(3): 687-697
    Regulation of adipogenesis by nucleotides.
    Julia A Pinette, Heather G Bryant, Jacob W Myers, Elma Zaganjor.
      The process by which multipotent cells commit to differentiate into distinct cell types, eventually forming functional tissues and organisms, has fascinated scientists for decades. Consequently, numerous studies have contributed to our understanding of how transcription factors and signaling molecules regulate differentiation. A growing area of interest in the field centers around the role of nutrients and metabolic pathways in cell fate determination. This review focuses on adipogenesis (also termed hyperplasia), the formation of adipocytes, which are key sensors of nutrient availability. We will examine recent findings that reshape our understanding of how nucleotide metabolism regulates adipogenesis.
    Keywords:  adipogenesis; lipid metabolism; metabolic regulation; mitochondria; purinergic signaling; white adipose tissue
    DOI:  https://doi.org/10.1042/BST20253045
  47. Nat Commun. 2025 Jul 01. 16(1): 5917
    A high-fiber diet mimics aging-related signatures of caloric restriction in mammals.
    Fangchao Hu, Lu Yu, Xingyu Tu, Rong Huang, Xinyue Yan, Liping Wang, Yang Wei, Xinlin Wei, Ziyun Wu.
      Caloric restriction (CR) delays aging-related hallmarks in various organisms by slowing growth and development while enhancing metabolic homeostasis. However, desirable diets that harness the metabolic benefits of CR without imposing food intake restrictions remain elusive. Here we evaluated the effects of a high-fiber diet we developed, in which 30% of the macronutrients in a standard diet are replaced with indigestible cellulose, compared to a CR control consisting of a nighttime-2h-restricted feeding regimen. Our findings show that the 2h-restricted feeding triggered a robust systemic response associated with the anti-aging benefits typically observed with CR. Intriguingly, the high-fiber diet did not reduce food intake but mimicked the aging-related signatures of CR in male mice from young to old age. These results indicate that the high-fiber diet confers promising benefits for metabolic homeostasis and represents a valuable candidate for further health and aging studies.
    DOI:  https://doi.org/10.1038/s41467-025-61046-z
  48. Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]
    Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
    Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.
      Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.
    Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing
    DOI:  https://doi.org/10.1016/j.tem.2025.05.005
  49. Trends Biochem Sci. 2025 Jun 27. pii: S0968-0004(25)00140-9. [Epub ahead of print]
    Cell-specific mitoproteomics reveals mitochondrial plasticity and applications.
    Domingos F M Neto, Rita de Cassia Monteiro-Batista, Adriano Nunes-Nesi, Wagner L Araújo.
      Understanding the tissue-specific mitochondrial proteome is essential for advancing understanding of plant biology. In a recent study, Boussardon et al. applied Isolation of Mitochondria Tagged in Specific Cell Types (IMTACT) to investigate mitoproteome dynamics during pollen development. Here, we explore the broader potential of high-purity mitochondrial isolation in elucidating specific roles across tissues and developmental stages.
    Keywords:  mitochondrial proteomics; plant stress; single cell mitochondria
    DOI:  https://doi.org/10.1016/j.tibs.2025.06.010
  50. Immunity. 2025 Jun 30. pii: S1074-7613(25)00275-4. [Epub ahead of print]
    Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.
    Megan L Clark, Kamen P Simeonov, Walter K Mowel, Michaël F Michieletto, Leonel Joannas, Jasmine M Wright, Isabel Erickson, Lexus R Johnson, Rakesh Krishnan, César de la Fuente-Núñez, Andy J Minn, Jorge Henao-Mejia.
      Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.
    Keywords:  STING; cGAS; complex IV; electron transport chain; immune checkpoint blockade; interferon-stimulated genes; mitochondria; tumor immunity; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2025.06.006
  51. Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00704-1. [Epub ahead of print]44(7): 115933
    Presentation of immunoregulatory sialoglycans on T cells is divergent between mice and humans.
    Fauzia N Izzati, Hani Choksi, Paolo Giuliana, Diala Abd-Rabbo, Heidi Elsaesser, Aled Blundell, Vanessa Affe, Vinicius Kannen, Zeinab Jame-Chenarboo, Edward N Schmidt, Meggie Kuypers, David B Avila, Eric S Y Chiu, Dzhangar Badmaev, Haissi Cui, Jason Matthews, Thierry Mallevaey, Matthew S Macauley, David G Brooks, Landon J Edgar.
      Glycans are emerging as important regulators of T cell function but remain poorly characterized across the functionally distinct populations that exist in vivo. Here, we couple single-cell analysis technologies with soluble lectins and chemical probes to interrogate glycosylation patterns on major T cell populations across mouse and human tissues. Our analysis focused on terminal glycan epitopes with immunomodulatory functions, including sialoglycan ligands for Siglecs. We demonstrate that glycosylation patterns are diverse across the resting murine T cell repertoire and dynamically remodeled in response to stimulation. Surprisingly, we find that human T cell populations do not share the same glycoprofiles or glycan remodeling dynamics as their murine counterparts. We show that these differences can be explained by divergent regulation of glycan biosynthesis pathways between the species. These results highlight fundamental glycophysiological differences between mouse and human T cells and reveal features that are critical to consider for glycan-targeted therapies.
    Keywords:  CP: Cell biology; CP: Immunology; T cells; adaptive immunity; glycan biosynthesis; glycocalyx; glycosylation; sialic acid
    DOI:  https://doi.org/10.1016/j.celrep.2025.115933
  52. J Cell Biol. 2025 Aug 04. pii: e202407209. [Epub ahead of print]224(8):
    Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
    Sunyoung Hwang, William Russo, Jaylah Cormier, Jillian Johnson, Sara Martin, Marica Rosaria Ippolito, Sara Cordone, Rui Li, Lihua Julie Zhu, Stefano Santaguida, Eduardo M Torres.
      Lipid synthesis must be precisely regulated to support membrane growth and organelle biogenesis during cell division, yet little is known about how this process is coordinated with other cell cycle events. Here, we show that de novo synthesis of sphingolipids during the S and G2 phases of the cell cycle is essential to increasing nuclear membranes. Indeed, the products of serine palmitoyltransferase (SPT), long-chain bases, localize to the nucleus and are integral components of nuclear membranes in yeast and human cells. Importantly, inhibition of SPT fails to induce cell cycle arrest, causing nuclear membrane collapse and loss of viability in yeast cells. In human cells, this causes abnormal nuclear morphology and genomic instability, evidenced by the increased incidence of nuclear blebs, micronuclei, anaphase bridges, and multipolar mitosis. These results indicate that dysregulated cell division under low sphingolipid availability can drive several disease-associated phenotypes, including aberrant nuclear morphologies and genomic instability.
    DOI:  https://doi.org/10.1083/jcb.202407209
  53. Proc Biol Sci. 2025 Jul;292(2050): 20250779
    The metabolic costs of meiotic drive.
    Sasha L Bradshaw, Enrique Rodríguez, Hanting Wang, Cyn Thea Yu, Cyril De Villiers De La Noue, Aadil Hafezjee, Andrew Pomiankowski, M Florencia Camus.
      Selfish genetic elements, such as meiotic drive genes, disrupt Mendel's law of equal segregation by biasing their own transmission, often at a detriment to the rest of the genome. Metabolic costs of the X-linked sex ratio (SR) meiotic drive were investigated in stalk-eyed flies (Teleopsis dalmanni). The experiments demonstrate that individuals with SR have reduced capacity for ATP synthesis. The disruption in mitochondrial function leads to compensation exhibited in increased basal metabolic rate and greater food consumption across a range of diets. The range of metabolic costs of drive was evident in males and females at a similar magnitude. The likely cause lies in the accumulation of deleterious mutations within the series of large inversions on the drive X chromosome, subject to low recombination and weak natural selection. In females, the drive chromosome had a dominant effect, with a single copy causing substantial metabolic compromise. There was little evidence of male-specific metabolic costs, nor evidence of greater effects of drive chromosomes on female metabolism. This suggests that direct metabolic costs from meiotic drive on spermatogenesis and from sexually antagonistic selection are relatively weak. Our results underscore the broad physiological impacts that selfish genetic elements have on host metabolism and fitness.
    Keywords:  chromosome inversion; meiotic drive; metabolism; mitochondria; respiration; selfish genetic element; sexual selection; stalk-eyed fly
    DOI:  https://doi.org/10.1098/rspb.2025.0779
  54. Mol Genet Metab. 2025 Jun 16. pii: S1096-7192(25)00170-2. [Epub ahead of print]145(4): 109179
    The mitochondrial disease biomarker GDF15 is dynamic, quantifiable in saliva, and correlates with disease severity.
    Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Jack Devine, Cynthia C Liu, Catherine Kelly, Mangesh Kurade, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Richard Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.
      Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109179
  55. Mol Cell. 2025 Jul 02. pii: S1097-2765(25)00543-X. [Epub ahead of print]
    Condensin II activation by M18BP1.
    Alessandro Borsellini, Duccio Conti, Erin E Cutts, Rebecca J Harris, Kai Walstein, Andrea Graziadei, Valentina Cecatiello, Tom F Aarts, Ren Xie, Abdelghani Mazouzi, Sushweta Sen, Claire Hoencamp, Richard Pleuger, Sabrina Ghetti, Lina Oberste-Lehn, Dongqing Pan, Tanja Bange, Judith H I Haarhuis, Anastassis Perrakis, Thijn R Brummelkamp, Benjamin D Rowland, Andrea Musacchio, Alessandro Vannini.
      Condensin I and II promote the drastic spatial rearrangement of the human genome upon mitotic entry. While condensin II is known to initiate this process in early mitosis, what triggers its activation and loading onto chromatin at this juncture remains unclear. Through genetic and proteomic approaches, we identify MIS18-binding protein 1 (M18BP1), a protein required to maintain centromere identity, as the elusive factor required for condensin II localization to chromatin. M18BP1 directly binds condensin II's CAP-G2 subunit. The condensin II antagonist MCPH1 also binds to CAP-G2 and outcompetes M18BP1 during interphase to maintain the genome in its uncondensed state. A switch from MCPH1 to M18BP1 at mitotic onset activates condensin II, thus promoting proper chromosome condensation. Regulation of this M18BP1-condensin interaction thus determines both the uncondensed state of the interphase genome and its compacted state in mitosis.
    Keywords:  AlphA Fold II; M18BP1; SMC complexes; centromeres; chromosome condensation; condensin II; crosslinking mass spectrometry; cryo-EM; haploid genetics; mitosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.014
  56. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  57. Nat Rev Mol Cell Biol. 2025 Jul 02.
    Regulation of inflammatory processes by caspases.
    Manuel Beltrán-Visiedo, Ruth Soler-Agesta, Kristopher A Sarosiek, Douglas R Green, Lorenzo Galluzzi.
      Historically, mammalian caspases (a group of cysteine proteases) have been catalogued into two main families based on major biological function: inflammatory caspases and apoptotic caspases. Accumulating evidence from preclinical models, however, argues against such a clearcut distinction, for two main reasons. First, at least in mammals, apoptotic caspases are generally dispensable for cells to succumb to apoptotic stimuli but instead regulate the kinetic and microenvironmental manifestations of the cellular demise in the context of a complex interplay with other cell death pathways. Second, most (if not all) mammalian caspases have evolved into positive or negative regulators of inflammatory processes, either directly or via their ability to control apoptotic and non-apoptotic cell death modalities. Here we discuss the molecular mechanisms through which mammalian caspases regulate inflammation, with emphasis on the ability of apoptotic caspases to suppress inflammatory responses in support of preserved organismal homeostasis.
    DOI:  https://doi.org/10.1038/s41580-025-00869-6
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