bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–01–19
forty-five papers selected by
Christian Frezza, Universität zu Köln
  1. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
  2. Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
  3. IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
  4. The systemic evolutionary theory of the origin of cancer (SETOC): an update.
  5. miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma.
  6. Metabolic Signaling in the Tumor Microenvironment.
  7. Mechanisms and rationales of SAM homeostasis.
  8. Reacting to reductive stress at the mitochondrial import gate.
  9. Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
  10. Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
  11. The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.
  12. Visualizing Cancer Heterogeneity at the Molecular and Cellular Levels: Lessons from Rosetta.
  13. TM6SF2 as new intestinal lipid player.
  14. A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.
  15. Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.
  16. Early prediction of healthy ageing and age-related diseases using blood protein biomarkers.
  17. Prolonged persistence of mutagenic DNA lesions in somatic cells.
  18. Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring.
  19. mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
  20. Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.
  21. Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells.
  22. Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
  23. Feeding the hippocampus … with specific nutrients.
  24. Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.
  25. Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas.
  26. Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
  27. Assays to Enhance Metabolic Phenotyping in the Kidney.
  28. Revealed: the fatty cells that are the 'bubble wrap' of the body.
  29. Epigenetic ageing clocks: statistical methods and emerging computational challenges.
  30. Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.
  31. Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.
  32. Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.
  33. Restimulation by macrophages exhausts T cells.
  34. Fumarate.
  35. Widening research horizons on metabolic dysfunction-associated steatotic liver disease and cancer.
  36. Simulating 500 million years of evolution with a language model.
  37. Somatic mutation as an explanation for epigenetic aging.
  38. Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
  39. Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
  40. Rusting away with age.
  41. Mutations in healthy breast tissue.
  42. Cancer Neuroscience of Brain Tumors: From Multicellular Networks to Neuroscience-Instructed Cancer Therapies.
  43. Label-free nanoscopy of cell metabolism by ultrasensitive reweighted visible stimulated Raman scattering.
  44. Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.
  45. No evidence for sex-differential transcriptomes driving genome-wide sex-differential natural selection.
  1. bioRxiv. 2025 Jan 02. pii: 2025.01.02.629617. [Epub ahead of print]
    In vivo itaconate tracing reveals degradation pathway and turnover kinetics.
    Hanna F Willenbockel, Alexander T Williams, Alfredo Lucas, Birte Dowerg, Pedro Cabrales, Christian M Metallo, Thekla Cordes.
      Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
    DOI:  https://doi.org/10.1101/2025.01.02.629617
  2. Nat Metab. 2025 Jan 15.
    Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
    Janine Tutas, Marianna Tolve, Ebru Özer-Yildiz, Lotte Ickert, Ines Klein, Quinn Silverman, Filip Liebsch, Frederik Dethloff, Patrick Giavalisco, Heike Endepols, Theodoros Georgomanolis, Bernd Neumaier, Alexander Drzezga, Guenter Schwarz, Bernard Thorens, Graziana Gatto, Christian Frezza, Natalia L Kononenko.
      Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
    DOI:  https://doi.org/10.1038/s42255-024-01196-4
  3. Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01550-X. [Epub ahead of print]44(1): 115199
    IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
    Seema Bachoo, Nancy Gudgeon, Rebecca Mann, Victoria Stavrou, Emma L Bishop, Audrey Kelly, Alejandro Huerta Uribe, Jordan Loeliger, Corina Frick, Oliver D K Maddocks, Paul Lavender, Christoph Hess, Sarah Dimeloe.
      Interleukin (IL)-7 promotes T cell expansion during lymphopenia. We studied the metabolic basis in CD4+ T cells, observing increased glucose usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Unlike other TCA metabolites, glucose-derived citrate does not accumulate upon IL-7 exposure, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility, notable at the loci of the amino acid-sensing Ragulator complex. Consistently, the expression of its subunit late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (LAMTOR5) is promoted by IL-7 in a glucose-dependent manner, and glucose availability determines amino acid-dependent mechanistic target of rapamycin (mTOR) activation, confirming integrated nutrient sensing. LAMTOR5 deletion impairs IL-7-mediated T cell expansion, establishing that glycolysis in the absence of Ragulator activation is insufficient to support this. Clinically, CD4+ T cells from stem cell transplant recipients demonstrate coordinated upregulation of glycolytic and TCA cycle enzymes, amino acid-sensing machinery, and mTOR targets, highlighting the potential to therapeutically target this pathway to fine-tune lymphopenia-induced T cell proliferation.
    Keywords:  IL-7; Immunology; Metabolism; T cell; T lymphocyte; mTOR; metabolism; nutrient sensing; proliferation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115199
  4. Mol Med. 2025 Jan 14. 31(1): 12
    The systemic evolutionary theory of the origin of cancer (SETOC): an update.
    Antonio Mazzocca, Giovanni Ferraro, Giovanni Misciagna.
      The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the 'endosymbiotic contract' between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, the TCA cycle, and oxidative phosphorylation (OxPhos). This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it.
    Keywords:  Archaea; Cancer theories; Endosymbiosis; Evolution; Mitochondria; Systems biology; Warburg effect
    DOI:  https://doi.org/10.1186/s10020-025-01069-w
  5. Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01522-5. [Epub ahead of print]44(1): 115171
    miR-449a/miR-340 reprogram cell identity and metabolism in fusion-negative rhabdomyosarcoma.
    Enrico Pozzo, Laura Yedigaryan, Nefele Giarratana, Chao-Chi Wang, Gabriel Miró Garrido, Ewoud Degreef, Vittoria Marini, Gianmarco Rinaldi, Bernard K van der Veer, Gabriele Sassi, Guy Eelen, Mélanie Planque, Alessandro Fanzani, Kian Peng Koh, Peter Carmeliet, Jason T Yustein, Sarah-Maria Fendt, Anne Uyttebroeck, Maurilio Sampaolesi.
      Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, arises in skeletal muscle and remains in an undifferentiated state due to transcriptional and post-transcriptional regulators. Among its subtypes, fusion-negative RMS (FN-RMS) accounts for the majority of diagnoses in the pediatric population. MicroRNAs (miRNAs) are non-coding RNAs that modulate cell identity via post-transcriptional regulation of messenger RNAs (mRNAs). In this study, we identify miRNAs impacting FN-RMS cell identity, revealing miR-449a and miR-340 as major regulators of the cell cycle and p53 signaling. Through miR-eCLIP technology, we demonstrate that miR-449a and miR-340 directly target transcripts involved in glycolysis and mitochondrial pyruvate transport, inhibiting the mitochondrial pyruvate carrier (MPC) complex. Pharmacological MPC inhibition induces a similar metabolic shift, reducing metastatic potential and leading to cell cycle exit. Overall, miR-449 and miR-340 orchestrate FN-RMS cell identity, positioning MPC inhibition as a strategy to shift FN-RMS cells toward a non-tumorigenic, quiescent state.
    Keywords:  CP: Cancer; UK-5099; cell identity; metabolism; miRNAs; mitochondrial pyruvate carrier; pediatric cancer; rhabdomyosarcoma
    DOI:  https://doi.org/10.1016/j.celrep.2024.115171
  6. Cancers (Basel). 2025 Jan 06. pii: 155. [Epub ahead of print]17(1):
    Metabolic Signaling in the Tumor Microenvironment.
    Ryan Clay, Kunyang Li, Lingtao Jin.
      Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.
    Keywords:  cancer metabolism; immune response; oncometabolite; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17010155
  7. Trends Biochem Sci. 2025 Jan 15. pii: S0968-0004(24)00281-0. [Epub ahead of print]
    Mechanisms and rationales of SAM homeostasis.
    Zheng Xing, Benjamin P Tu.
      S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms. This suggests that the need to maintain SAM homeostasis represents a significant evolutionary pressure across all kingdoms of life. Here, we review how SAM controls cellular functions at the molecular level and discuss strategies to maintain SAM homeostasis. We propose that SAM exerts a broad and underappreciated influence in cellular regulation that remains to be fully elucidated.
    Keywords:  S-adenosylmethionine (SAM); epigenetics; methionine; methyl-sink; methylation; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2024.12.009
  8. Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]
    Reacting to reductive stress at the mitochondrial import gate.
    Sylvie Callegari.
      A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.
    Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
  9. Nat Metab. 2025 Jan 16.
    Recommendations for mitochondria transfer and transplantation nomenclature and characterization.
    Jonathan R Brestoff, Keshav K Singh, Katia Aquilano, Lance B Becker, Michael V Berridge, Eric Boilard, Andrés Caicedo, Clair Crewe, José Antonio Enríquez, Jianqing Gao, Åsa B Gustafsson, Kazuhide Hayakawa, Maroun Khoury, Yun-Sil Lee, Daniele Lettieri-Barbato, Patricia Luz-Crawford, Heidi M McBride, James D McCully, Ritsuko Nakai, Jiri Neuzil, Martin Picard, Alexander G Rabchevsky, Anne-Marie Rodriguez, Shiladitya Sengupta, Alexander J Sercel, Toshio Suda, Michael A Teitell, Alain R Thierry, Rong Tian, Melanie Walker, Minghao Zheng.
      Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.
    DOI:  https://doi.org/10.1038/s42255-024-01200-x
  10. Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]
    Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
    Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.
       BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
    METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
    RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
    CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.
    Keywords:  Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence
    DOI:  https://doi.org/10.1093/neuonc/noaf008
  11. Nat Metab. 2025 Jan 10.
    The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.
    Shauni Loopmans, Katerina Rohlenova, Thomas van Brussel, Ingrid Stockmans, Karen Moermans, Nicolas Peredo, Peter Carmeliet, Diether Lambrechts, Steve Stegen, Geert Carmeliet.
      Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.
    DOI:  https://doi.org/10.1038/s42255-024-01187-5
  12. Cancer Discov. 2025 Jan 13. 15(1): 34-38
    Visualizing Cancer Heterogeneity at the Molecular and Cellular Levels: Lessons from Rosetta.
    Cancer Grand Challenges Rosetta Consortium
      Understanding tumor heterogeneity is a major challenge that was recognized as one of the first Cancer Grand Challenges, with a call to provide solutions to visualize tumor heterogeneity. The Rosetta team took on this challenge, exploiting advances in spatial-omics approaches centered around mass spectrometry imaging to map tumor heterogeneity at the cellular and molecular scales with different levels of resolution. See related article by Bressan et al., p. 16 See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0016
  13. Nat Metab. 2025 Jan 10.
    TM6SF2 as new intestinal lipid player.
    Herbert Tilg, Christoph Grander.
      
    DOI:  https://doi.org/10.1038/s42255-024-01156-y
  14. Proc Natl Acad Sci U S A. 2025 Jan 21. 122(3): e2412816122
    A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.
    Marco S Messina, Laura Torrente, Aidan T Pezacki, Hanna I Humpel, Erin L Li, Sophia G Miller, Odette Verdejo-Torres, Teresita Padilla-Benavides, Donita C Brady, David W Killilea, Alison N Killilea, Martina Ralle, Nathan P Ward, Jun Ohata, Gina M DeNicola, Christopher J Chang.
      Copper is an essential nutrient for sustaining vital cellular processes spanning respiration, metabolism, and proliferation. However, loss of copper homeostasis, particularly misregulation of loosely bound copper ions which are defined as the labile copper pool, occurs in major diseases such as cancer, where tumor growth and metastasis have a heightened requirement for this metal. To help decipher the role of copper in the etiology of cancer, we report a histochemical activity-based sensing approach that enables systematic, high-throughput profiling of labile copper status across many cell lines in parallel. Coppermycin-1 reacts selectively with Cu(I) to release puromycin, which is then incorporated into nascent peptides during protein translation, thus leaving a permanent and dose-dependent marker for labile copper that can be visualized with standard immunofluorescence assays. We showcase the utility of this platform for screening labile Cu(I) pools across the National Cancer Institute's 60 (NCI-60) human tumor cell line panel, identifying cell types with elevated basal levels of labile copper. Moreover, we use Coppermycin-1 to show that lung cancer cells with heightened activation of nuclear factor-erythroid 2-related factor 2 (NRF2) possess lower resting labile Cu(I) levels and, as a result, have reduced viability when treated with a copper chelator. This work establishes that methods for labile copper detection can be used to assess cuproplasia, an emerging form of copper-dependent cell growth and proliferation, providing a starting point for broader investigations into the roles of transition metal signaling in biology and medicine.
    Keywords:  activity-based sensing; antioxidant regulation; cancer metabolism; histochemical copper probe; transition metal signaling
    DOI:  https://doi.org/10.1073/pnas.2412816122
  15. Nat Genet. 2025 Jan;57(1): 165-179
    Loss of Kmt2c or Kmt2d primes urothelium for tumorigenesis and redistributes KMT2A-menin to bivalent promoters.
    Naitao Wang, Mohini R Pachai, Dan Li, Cindy J Lee, Sarah Warda, Makhzuna N Khudoynazarova, Woo Hyun Cho, Guojia Xie, Sagar R Shah, Li Yao, Cheng Qian, Elissa W P Wong, Juan Yan, Fanny V Tomas, Wenhuo Hu, Fengshen Kuo, Sizhi P Gao, Jiaqian Luo, Alison E Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar V Iyer, Jonathan E Rosenberg, David B Solit, Hikmat A Al-Ahmadie, Ping Chi, Yu Chen.
      Members of the KMT2C/D-KDM6A complex are recurrently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using genetically engineered mouse models, we demonstrate that Kmt2c/d knockout in the urothelium led to impaired differentiation, augmented responses to growth and inflammatory stimuli and sensitization to oncogenic transformation by carcinogen and oncogenes. Mechanistically, KMT2D localized to active enhancers and CpG-poor promoters that preferentially regulate the urothelial lineage program and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which leads to impaired differentiation. Kmt2c/d knockout further led to KMT2A-menin redistribution from KMT2D localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes. Therapeutically, Kmt2c/d knockout upregulated epidermal growth factor receptor signaling and conferred vulnerability to epidermal growth factor receptor inhibitors. Together, our data posit that functional loss of Kmt2c/d licenses a molecular 'field effect' priming histologically normal urothelium for oncogenic transformation and presents therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1038/s41588-024-02015-y
  16. Nat Metab. 2025 Jan 13.
    Early prediction of healthy ageing and age-related diseases using blood protein biomarkers.
      
    DOI:  https://doi.org/10.1038/s42255-024-01199-1
  17. Nature. 2025 Jan 15.
    Prolonged persistence of mutagenic DNA lesions in somatic cells.
    Michael Spencer Chapman, Emily Mitchell, Kenichi Yoshida, Nicholas Williams, Margarete A Fabre, Anna Maria Ranzoni, Philip S Robinson, Lori D Kregar, Matthias Wilk, Steffen Boettcher, Krishnaa Mahbubani, Kourosh Saeb Parsy, Kate H C Gowers, Sam M Janes, Stanley W K Ng, Matt Hoare, Anthony R Green, George S Vassiliou, Ana Cvejic, Markus G Manz, Elisa Laurenti, Iñigo Martincorena, Michael R Stratton, Jyoti Nangalia, Tim H H Coorens, Peter J Campbell.
      DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment1-3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5-12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS1913; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15-25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells.
    DOI:  https://doi.org/10.1038/s41586-024-08423-8
  18. Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00484-4. [Epub ahead of print]
    Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring.
    Na Yao, Kenichiro Kinouchi, Manami Katoh, Kousha Changizi Ashtiani, Sherif Abdelkarim, Hiroyuki Morimoto, Takuto Torimitsu, Takahide Kozuma, Akihide Iwahara, Shotaro Kosugi, Jin Komuro, Kyosuke Kato, Shun Tonomura, Toshifumi Nakamura, Arata Itoh, Shintaro Yamaguchi, Jun Yoshino, Junichiro Irie, Hisayuki Hashimoto, Shinsuke Yuasa, Akiko Satoh, Yohei Mikami, Shusaku Uchida, Takatoshi Ueki, Seitaro Nomura, Pierre Baldi, Kaori Hayashi, Hiroshi Itoh.
      Tissue-level oscillation is achieved by tissue-intrinsic clocks along with network-dependent signals originating from distal organs and organismal behavior. Yet, it remains unexplored whether maternal circadian rhythms during pregnancy influence fetal rhythms and impact long-term susceptibility to dietary challenges in offspring. Here, we demonstrate that circadian disruption during pregnancy decreased placental and neonatal weight yet retained transcriptional and structural maturation. Intriguingly, diet-induced obesity was exacerbated in parallel with arrhythmic feeding behavior, hypothalamic leptin resistance, and hepatic circadian reprogramming in offspring of chronodisrupted mothers. In utero circadian desynchrony altered the phase-relationship between the mother and fetus and impacted placental efficiency. Temporal feeding restriction in offspring failed to fully prevent obesity, whereas the circadian alignment of caloric restriction with the onset of the active phase virtually ameliorated the phenotype. Thus, maternal circadian rhythms during pregnancy confer adaptive properties to metabolic functions in offspring and provide insights into the developmental origins of health and disease.
    Keywords:  caloric restriction; circadian clock; circadian rhythm; developmental origins of health and disease; eating behavior; leptin; metabolism; obesity; pregnancy; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.002
  19. Cell Rep. 2025 Jan 13. pii: S2211-1247(24)01530-4. [Epub ahead of print]44(1): 115179
    mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
    Brittany Q Pham, Sang Ah Yi, Alban Ordureau, Heeseon An.
      One critical aspect of cell proliferation is increased nucleotide synthesis, including pyrimidines. Pyrimidines are synthesized through de novo and salvage pathways. Prior studies established that the mammalian target of rapamycin complex 1 (mTORC1) promotes pyrimidine synthesis by activating the de novo pathway for cell proliferation. However, the involvement of mTORC1 in regulating the salvage pathway remains unclear. Here, we report that mTORC1 controls the half-life of uridine cytidine kinase 2 (UCK2), the rate-limiting enzyme in the salvage pathway. Specifically, UCK2 is degraded via the CTLH-WDR26 E3 complex during mTORC1 inhibition, which is prevented when mTORC1 is active. We also find that UCK1, an isoform of UCK2, affects the turnover of UCK2 by influencing its cellular localization. Importantly, altered UCK2 levels through the mTORC1-CTLH E3 pathway affect pyrimidine salvage and the efficacy of pyrimidine analog prodrugs. Therefore, mTORC1-CTLH E3-mediated degradation of UCK2 adds another layer of complexity to mTORC1's role in regulating pyrimidine metabolism.
    Keywords:  CP: Metabolism; CP: Molecular biology; CTLH; UCK2; WDR26; YPEL5; degradomics; mTOR; mTORC1; pyrimidine; pyrimidine salvage; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2024.115179
  20. Res Sq. 2024 Dec 31. pii: rs.3.rs-5682984. [Epub ahead of print]
    Abnormal Redox Balance at Membrane Contact Sites Causes Axonopathy in Gdap1-related Charcot-marie-tooth Disease.
    Francesc Palau, Lara Cantarero, Mónica Roldán, María Rodríguez-Sanz, Angela Mathison, Yaiza Díaz-Osorio, Jordi Pijuan, Marcos Frías, Raul Urrutia, Janet Hoenicka.
      Pathogenic variants of GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited neuropathy characterized by axonal degeneration. GDAP1, an atypical glutathione S-transferase, localizes to the outer mitochondrial membrane (OMM), regulating this organelle's dynamics, transport, and membrane contact sites (MCSs). It has been proposed that GDAP1 functions as a cellular redox sensor. However, its precise contribution to redox homeostasis remains poorly understood, as does the possible redox regulation at mitochondrial MCSs. Given the relationship between the peroxisomal redox state and overall cellular redox balance, we investigated the role of GDAP1 in peroxisomal function and mitochondrial MCSs maintenance by using high-resolution microscopy, live cell imaging with pH-sensitive fluorescent probes, and transcriptomic and lipidomic analyses in the Gdap1-/- mice and patient-derived fibroblasts. We demonstrate that GDAP1 deficiency disrupts mitochondria-peroxisome MCSs and leads to peroxisomal abnormalities, which are reversible upon pharmacological activation of PPARγ or glutathione supplementation. These results identify GDAP1 as a new tether of mitochondria-peroxisome MCSs that maintain peroxisomal number and integrity. The supply of glutathione (GSH-MEE) or GDAP1 overexpression suffices to rescue these MCSs. Furthermore, GDAP1 may regulate the redox state within the microdomain of mitochondrial MCSs, as suggested by decreased pH at mitochondria-lysosome contacts in patient-derived fibroblasts, highlighting the relationship between GDAP1 and redox-sensitive targets. Finally, in vivo analysis of sciatic nerve tissue in Gdap1-/- mice revealed significant axonal structural abnormalities, including nodes of Ranvier disruption and defects in the distribution and morphology of mitochondria, lysosomes, and peroxisomes, emphasizing the importance of GDAP1 in sustaining axon integrity in the peripheral nervous system. Taken together, this study positions GDAP1 as a multifunctional protein that mediates mitochondrial interaction with cellular organelles of diverse functions, contributes to redox state sensing, and helps maintain axonal homeostasis. In addition, we identify PPAR as a novel therapeutic target, based on knowledge of the underlying pathogenetic mechanisms.
    DOI:  https://doi.org/10.21203/rs.3.rs-5682984/v1
  21. Nat Metab. 2025 Jan 14.
    Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells.
    Hooman Hefzi, Iván Martínez-Monge, Igor Marin de Mas, Nicholas Luke Cowie, Alejandro Gomez Toledo, Soo Min Noh, Karen Julie la Cour Karottki, Marianne Decker, Johnny Arnsdorf, Jose Manuel Camacho-Zaragoza, Stefan Kol, Sanne Schoffelen, Nuša Pristovšek, Anders Holmgaard Hansen, Antonio A Miguez, Sara Petersen Bjørn, Karen Kathrine Brøndum, Elham Maria Javidi, Kristian Lund Jensen, Laura Stangl, Emanuel Kreidl, Thomas Beuchert Kallehauge, Daniel Ley, Patrice Ménard, Helle Munck Petersen, Zulfiya Sukhova, Anton Bauer, Emilio Casanova, Niall Barron, Johan Malmström, Lars K Nielsen, Gyun Min Lee, Helene Faustrup Kildegaard, Bjørn G Voldborg, Nathan E Lewis.
      The Warburg effect, which describes the fermentation of glucose to lactate even in the presence of oxygen, is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production in cells for bioprocessing have failed as lactate dehydrogenase is essential for cell growth. Here, we effectively eliminate lactate production in Chinese hamster ovary and in the human embryonic kidney cell line HEK293 by simultaneous knockout of lactate dehydrogenases and pyruvate dehydrogenase kinases, thereby removing a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. These cells, which we refer to as Warburg-null cells, maintain wild-type growth rates while producing negligible lactate, show a compensatory increase in oxygen consumption, near total reliance on oxidative metabolism, and higher cell densities in fed-batch cell culture. Warburg-null cells remain amenable for production of diverse biotherapeutic proteins, reaching industrially relevant titres and maintaining product glycosylation. The ability to eliminate lactate production may be useful for biotherapeutic production and provides a tool for investigating a common metabolic phenomenon.
    DOI:  https://doi.org/10.1038/s42255-024-01193-7
  22. Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01557-2. [Epub ahead of print]44(1): 115206
    Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
    Jean-Ehrland Ricci.
      Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.
    Keywords:  CP: Cancer; CP: Metabolism; antitumor activity of immune cells; cancer; metabolism; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.115206
  23. Nat Metab. 2025 Jan 15.
    Feeding the hippocampus … with specific nutrients.
    Pierre Trifilieff, Guillaume Ferreira.
      
    DOI:  https://doi.org/10.1038/s42255-024-01180-y
  24. Nat Aging. 2025 Jan 10.
    Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence.
    Hao Yang, Tongyao Wang, Chenglang Qian, Huijing Wang, Dong Yu, Meifang Shi, Mengwei Fu, Xueguang Liu, Miaomiao Pan, Xingyu Rong, Zhenming Xiao, Xiejiu Chen, Anaguli Yeerken, Yonglin Wu, Yufan Zheng, Hui Yang, Ming Zhang, Tao Liu, Peng Qiao, Yifan Qu, Yong Lin, Yiqin Huang, Jianliang Jin, Nan Liu, Yumei Wen, Ning Sun, Chao Zhao.
      Gut microbiota plays a crucial role in the host health in the aging process. However, the mechanisms for how gut microbiota triggers cellular senescence and the consequent impact on human aging remain enigmatic. Here we show that phenylacetylglutamine (PAGln), a metabolite linked to gut microbiota, drives host cellular senescence. Our findings indicate that the gut microbiota alters with age, which leads to increased production of phenylacetic acid (PAA) and its downstream metabolite PAGln in older individuals. The PAGln-induced senescent phenotype was verified in both cellular models and mouse models. Further experiments revealed that PAGln induces mitochondrial dysfunction and DNA damage via adrenoreceptor (ADR)-AMP-activated protein kinase (AMPK) signaling. Blockade of ADRs as well as senolytics therapy impede PAGln-induced cellular senescence in vivo, implying potential anti-aging therapies. This combined evidence reveals that PAGln, a naturally occurring metabolite of human gut microbiota, mechanistically accelerates host cellular senescence.
    DOI:  https://doi.org/10.1038/s43587-024-00795-w
  25. bioRxiv. 2025 Jan 03. pii: 2025.01.02.631150. [Epub ahead of print]
    Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas.
    Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Simon P Robinson, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath.
      Oncogenes hyperactive lactate production, but the mechanisms by which lactate facilitates tumor growth are unclear. Here, we demonstrate that lactate is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U- 13 C]-glucose in DMGs. Lactate activates the nucleoside diphosphate kinase NME1 via lactylation and promotes the synthesis of nucleoside triphosphates essential for tumor proliferation. Importantly, we show that this mechanistic link between glycolysis and nucleotide biosynthesis provides a unique opportunity for deuterium metabolic imaging of DMGs. Spatially mapping 2 H-lactate production from [6,6- 2 H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard-of-care radiation and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations at the tissue level in preclinical DMG models in vivo at clinical field strength (3T). In essence, we have identified an H3K27M-lactate-NME1 axis that promotes DMG proliferation and facilitates non-invasive metabolic imaging of DMGs.
    STATEMENT OF SIGNIFICANCE: This study establishes a role for lactate in driving nucleotide biosynthesis in DMGs. Importantly, imaging lactate production from glucose using DMI provides a readout of tumor proliferation and early response to therapy in clinically relevant DMG models. Our studies lay the foundation for precision metabolic imaging of DMG patients.
    DOI:  https://doi.org/10.1101/2025.01.02.631150
  26. Sci Transl Med. 2025 Jan 15. 17(781): eadn8699
    Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
    TRR241 IBDome Consortium
      Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion-related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1-like protein in organoids derived from Opa1i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adn8699
  27. Am J Physiol Renal Physiol. 2025 Jan 17.
    Assays to Enhance Metabolic Phenotyping in the Kidney.
    Safaa Hammoud, Justin Kern, Sandip Mukherjee, Andrew Lutkewitte, Prabhleen Singh, Kate Newberry, Brian N Finck, Leslie S Gewin.
      The kidney is highly metabolically active, and injury induces changes in metabolism that can impact repair and fibrosis progression. Changes in expression of metabolism-related genes and proteins provide valuable data, but functional metabolic assays are critical to confirm changes in metabolic activity. Stable isotope metabolomics are the gold standard, but these involve considerable cost and specialized expertise. Both the Seahorse bioflux assays and substrate oxidation assays in tissues ex vivo are two relatively cost-effective assays for interrogating metabolism. Many institutions have access to Seahorse bioflux analyzers, which can easily and quickly generate data, but guidelines to enhance reproducibility are lacking. We investigate how variables (e.g. primary versus immortalized cells, time in culture) impact the data generated by Seahorse bioflux analyzers. In addition, we show the utility of 3H-palmitate, a new approach for assessing fatty acid oxidation in the kidney, in uninjured and injured kidney cortices. The 3H-palmitate substrate oxidation assays also demonstrate significant sex-dependent and strain-dependent differences in rates of fatty acid oxidation. These data should facilitate metabolic interrogation in the kidney field with enhanced reproducibility.
    Keywords:  fatty acid oxidation; kidney metabolism; mitochondrial respiration; proximal tubules
    DOI:  https://doi.org/10.1152/ajprenal.00232.2024
  28. Nature. 2025 Jan 09.
    Revealed: the fatty cells that are the 'bubble wrap' of the body.
    Max Kozlov.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00012-7
  29. Nat Rev Genet. 2025 Jan 13.
    Epigenetic ageing clocks: statistical methods and emerging computational challenges.
    Andrew E Teschendorff, Steve Horvath.
      Over the past decade, epigenetic clocks have emerged as powerful machine learning tools, not only to estimate chronological and biological age but also to assess the efficacy of anti-ageing, cellular rejuvenation and disease-preventive interventions. However, many computational and statistical challenges remain that limit our understanding, interpretation and application of epigenetic clocks. Here, we review these computational challenges, focusing on interpretation, cell-type heterogeneity and emerging single-cell methods, aiming to provide guidelines for the rigorous construction of interpretable epigenetic clocks at cell-type and single-cell resolution.
    DOI:  https://doi.org/10.1038/s41576-024-00807-w
  30. Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01534-1. [Epub ahead of print]44(1): 115183
    Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.
    Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay.
      AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize.
    Keywords:  AMPK; CD36; CP: Cancer; CP: Metabolism; ROS; breast cancer metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.115183
  31. Am J Physiol Endocrinol Metab. 2025 Jan 13.
    Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.
    Kyle D Dumont, Paulo R Jannig, Margareta Porsmyr-Palmertz, Jorge L Ruas.
      Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites of the kynurenine pathway of tryptophan degradation with opposing biological activities in the central nervous system. In the periphery, KYNA is known to positively affect metabolic health, whereas the effects of QUIN remain less explored. Interestingly, metabolic stressors, including exercise and obesity, differentially change the balance between circulating KYNA and QUIN. Here, we hypothesized that chronically elevated levels of circulating KYNA and reduced levels of QUIN would manifest as differences in whole-body energy metabolism. To test this, we used a mouse model lacking the enzyme kynurenine 3-monooxygenase (KMO), thus shunting kynurenine away from QUIN synthesis and towards KYNA production. KMO-deficient and wild-type littermate male and female mice were evaluated under chow and high-fat diets. Comprehensive kynurenine pathway metabolite profiling in plasma showed that the loss of KMO elicits robust changes in circulating levels of kynurenine metabolites. This included a 45-fold increase in kynurenine, a 26-fold increase in KYNA, and a 99% decrease in QUIN levels, depending on the diet. However, despite these changes, loss of KMO did not significantly impact whole-body energy metabolism or change the transcriptomic profile of subcutaneous adipose tissue on either diet. With KMO inhibitors being considered as therapeutic candidates for various disorders, this work shows that chronic systemic KMO inhibition does not have widespread metabolic effects. Our data also indicates that the beneficial effects of KYNA on metabolism may depend on its acute, intermittent elevation in circulation, akin to transient exercise-induced signals that mediate improved metabolic health.
    Keywords:  Adipose tissue; High-fat diet; KMO; Kynurenine monooxygenase; Metabolism; Transcriptomics; Tryptophan-kynurenine metabolites
    DOI:  https://doi.org/10.1152/ajpendo.00386.2024
  32. bioRxiv. 2025 Jan 02. pii: 2024.12.26.630414. [Epub ahead of print]
    Quantitative analyses of single mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplasticity.
    Mayank Saini, Swati Agarwala, Biratal Wagle, Brian Spurlock, Bharti Golchha, Danitra Parker, Kasturi Mitra.
      Quantitative understanding of mitochondrial heterogeneity is necessary for elucidating the precise role of these multifaceted organelles in tumor cell development. We demonstrate an early mechanistic role of mitochondria in initiating neoplasticity by performing quantitative analyses of structure-function of single mitochondrial components coupled with single cell transcriptomics. We demonstrate that the large Hyperfused-Mitochondrial-Networks (HMNs) of keratinocytes promptly get converted to the heterogenous Small-Mitochondrial-Networks (SMNs) as the stem cell enriching dose of the model carcinogen, TCDD, depolarizes mitochondria. This happens by physical reorganization of the HMN nodes and edges, which enriches redox tuned SMNs with distinct network complexity. This leads to establishment of transcriptomic interaction between the upregulated redox relevant mtDNA genes and the lineage specific stemness gene, KRT15, prior to cell cycle exit. The SMN enrichment and related transcriptomic connections are sustained in the neoplastic cell population. Consistently, carcinogenic dose incapable of causing pronounced neoplastic stem cell enrichment fails to establish specific enrichment of SMNs and its linked mtDNA-KRT15(stemness) transcriptomic interaction prior to cell cycle exit. The mtDNA-KRT15 modulation is confirmed in cSCC tumors, while highlighting patient heterogeneity. Therefore, we propose that early enrichment of redox-tuned SMNs primes neoplastic transformation by establishing mtDNA-stemness transcriptomic interaction prior to cell cycle exit towards specifying quiescent neoplastic stem cells. Our data implies that redox-tuned SMNs, created by mitochondrial fission, would be sustained by tuning the balance of mitochondrial fission-fusion during neoplastic transformation. The proposed early role of mitochondria in cancer etiology is potentially relevant for designing precision strategies for cancer prevention and therapy.
    Significance Statement: The challenges of understanding the complex role of the multifaceted and heterogenous cellular organelles, mitochondria, can be potentially overcome with their quantitative analyses. We use a combinatorial approach of quantitative analyses of single-mitochondrial-components and scRNA-seq to elucidate a mechanism of mitochondrial priming of cancer initiation by a model carcinogen. We propose that conversion of large Hyperfused-Mitochondrial-Networks (HMNs) to Small-Mitochondrial-Networks (SMNs) primes non-transformed keratinocytes towards their neoplastic transformation. Mechanistically, the SMNs, enriched by modulation of the physical nodes and edges of mitochondrial networks, tunes mitochondrial redox balance to establish transcriptomic interactions towards specifying a state of stemness. Further probing of our fundamental findings in the light of cancer heterogeneity may facilitate refinement of the various proposed mitochondria based targeted cancer therapies.
    DOI:  https://doi.org/10.1101/2024.12.26.630414
  33. Immunity. 2025 Jan 14. pii: S1074-7613(24)00574-0. [Epub ahead of print]58(1): 12-14
    Restimulation by macrophages exhausts T cells.
    Fernando Fernández-García, Barbara B Maier.
      Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. In this issue of Immunity, Waibl Polania et al. examine the microenvironmental signals regulating terminal T cell exhaustion and find that antigen presentation by tumor-associated macrophages, not tumor cells, drives terminal T cell exhaustion in glioblastoma.
    DOI:  https://doi.org/10.1016/j.immuni.2024.12.010
  34. Trends Endocrinol Metab. 2025 Jan 15. pii: S1043-2760(24)00332-1. [Epub ahead of print]
    Fumarate.
    Désirée Schatton, Christian Frezza.
      
    DOI:  https://doi.org/10.1016/j.tem.2024.12.010
  35. Trends Endocrinol Metab. 2025 Jan 09. pii: S1043-2760(24)00331-X. [Epub ahead of print]
    Widening research horizons on metabolic dysfunction-associated steatotic liver disease and cancer.
    Amedeo Lonardo, Norbert Stefan, Alessandro Mantovani.
      Liver fibrosis and biological sex variably modulate the risks of hepatocellular carcinoma (HCC) and extrahepatic cancers (EHCs) arising in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we highlight how these variables may have implications in the setting of chemoprevention and precision medicine approaches in MASLD and guide additional research.
    DOI:  https://doi.org/10.1016/j.tem.2024.12.009
  36. Science. 2025 Jan 16. eads0018
    Simulating 500 million years of evolution with a language model.
    Thomas Hayes, Roshan Rao, Halil Akin, Nicholas J Sofroniew, Deniz Oktay, Zeming Lin, Robert Verkuil, Vincent Q Tran, Jonathan Deaton, Marius Wiggert, Rohil Badkundri, Irhum Shafkat, Jun Gong, Alexander Derry, Raul S Molina, Neil Thomas, Yousuf A Khan, Chetan Mishra, Carolyn Kim, Liam J Bartie, Matthew Nemeth, Patrick D Hsu, Tom Sercu, Salvatore Candido, Alexander Rives.
      More than three billion years of evolution have produced an image of biology encoded into the space of natural proteins. Here we show that language models trained at scale on evolutionary data can generate functional proteins that are far away from known proteins. We present ESM3, a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. ESM3 can follow complex prompts combining its modalities and is highly responsive to alignment to improve its fidelity. We have prompted ESM3 to generate fluorescent proteins. Among the generations that we synthesized, we found a bright fluorescent protein at a far distance (58% sequence identity) from known fluorescent proteins, which we estimate is equivalent to simulating five hundred million years of evolution.
    DOI:  https://doi.org/10.1126/science.ads0018
  37. Nat Aging. 2025 Jan 13.
    Somatic mutation as an explanation for epigenetic aging.
    Zane Koch, Adam Li, Daniel S Evans, Steven Cummings, Trey Ideker.
      DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
    DOI:  https://doi.org/10.1038/s43587-024-00794-x
  38. Cell Metab. 2025 Jan 10. pii: S1550-4131(24)00482-0. [Epub ahead of print]
    Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
    Shihao Zhang, Zenghui Cui, Danni Zhang, Deyu Zhang, Ke Jin, Zemeng Li, Bo Li, Boyi Cong, Juan Liu, Lei Wang, Mingyue Wen, Xuetao Cao.
      Bacterial infection reprograms cellular metabolism and epigenetic status, but how the metabolic-epigenetic crosstalk empowers host antibacterial defense remains unclear. Here, we report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a sensor for metabolite adenine to launch an antimicrobial innate response through increasing Il1b transcription. Myeloid cell-specific Hnrnpa2b1-cKO mice are more susceptible to bacterial infection, while interleukin 1 beta (IL-1β) supplementation rescues the phenotype. Through a large-scale metabolites-hnRNPA2B1 interaction screen, we reveal that adenine directly binds and activates hnRNPA2B1 to mediate innate antibacterial response. Mechanistically, adenine directly recruits hnRNPA2B1 to Il1b enhancers, and hnRNPA2B1 increases Il1b enhancer chromatin accessibility through binding and recruiting nucleolin and fat mass and obesity-associated protein (FTO) to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation. Furthermore, bacterial infection elevates nuclear adenine at the early stage of infection, and in vivo adenine administration protects mice from death upon bacterial infection through the hnRNPA2B1-IL-1β circuit. Our findings offer new insights into metabolic-epigenetic crosstalk relevant to antibacterial innate immunity and indicate potential approaches for treating bacterial infections.
    Keywords:  DNA N(6)-methyladenosine; adenine; antibacterial immunity; hnRNPA2B1; interleukin 1; nucleolin
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.014
  39. J Physiol. 2025 Jan 14.
    Adenine nucleotide translocator and ATP synthase cooperate in mediating the mitochondrial permeability transition.
    Ludovica Tommasin, Andrea Carrer, Federica Boscolo Nata, Elena Frigo, Federico Fogolari, Giovanna Lippe, Michela Carraro, Paolo Bernardi.
      The permeability transition (PT) is a permeability increase of the mitochondrial inner membrane causing mitochondrial swelling in response to matrix Ca2+. The PT is mediated by regulated channel(s), the PT pore(s) (PTP), which can be generated by at least two components, adenine nucleotide translocator (ANT) and ATP synthase. Whether these provide independent permeation pathways remains to be established. Here, we assessed the contribution of ANT to the PT based on the effects of the selective ANT inhibitors atractylate (ATR) and bongkrekate (BKA), which trigger and inhibit channel formation by ANT, respectively. BKA partially inhibited Ca2+-dependent PT and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT to the PT emerged at pH 6.5 (a condition that inhibits ATP synthase channel opening) in the presence of ATR, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Unexpectedly, ANT-dependent PT at pH 6.5 could also be stimulated by benzodiazepine-423 [a selective ligand of the oligomycin sensitivity conferral protein (OSCP) subunit of ATP synthase], suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. In keeping with docking simulations, ANT could be co-immunoprecipitated with ATP synthase subunits c and g, and oligomycin (which binds adjacent c subunits) decreased the association of ANT with subunit c. These results reveal a close cooperation between ANT and ATP synthase in the PT and open new perspectives in the study of this process. KEY POINTS: We have assessed the relative role of adenine nucleotide translocator (ANT) and ATP synthase in generating the mitochondrial permeability transition (PT). At pH 7.4, bongkrekate had little effect on Ca2+-dependent PT, and did not prevent the inducing effect of phenylarsine oxide, which was still present in mouse embryonic fibroblasts deleted for all ANT isoforms. The contribution of ANT emerged at pH 6.5 (which inhibits ATP synthase channel opening) in the presence of atractylate, which triggered mitochondrial swelling and elicited currents in patch-clamped mitoplasts. Benzodiazepine-423, a selective ligand of the oligomycin sensitivity conferral protein subunit of ATP synthase, stimulated ANT-dependent PT at pH 6.5, suggesting that the ANT channel is regulated by the peripheral stalk of ATP synthase. ANT could be co-immunoprecipitated with ATP synthase subunits c and g; oligomycin, which binds adjacent c subunits, decreased the association with subunit c, in keeping with docking simulations.
    Keywords:  ATP synthase; adenine nucleotide translocator; calcium; mitochondria; permeability transition
    DOI:  https://doi.org/10.1113/JP287147
  40. Nat Rev Cancer. 2025 Jan 14.
    Rusting away with age.
    Gabrielle Brewer.
      
    DOI:  https://doi.org/10.1038/s41568-025-00790-2
  41. Nat Genet. 2025 Jan;57(1): 2
    Mutations in healthy breast tissue.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-024-02060-7
  42. Cancer Discov. 2025 Jan 13. 15(1): 39-51
    Cancer Neuroscience of Brain Tumors: From Multicellular Networks to Neuroscience-Instructed Cancer Therapies.
    Varun Venkataramani, Yvonne Yang, Sebastian Ille, Bogdana Suchorska, Sonja Loges, Heike Tost, Felix Sahm, Stefan M Pfister, Andreas Trumpp, Sandro M Krieg, Thomas Kuner, Wolfgang Wick, Frank Winkler.
      Deepening our understanding of neuro-cancer interactions can innovate brain tumor treatment. This mini review unfolds the most relevant and recent insights into the neural mechanisms contributing to brain tumor initiation, progression, and resistance, including synaptic connections between neurons and cancer cells, paracrine neuro-cancer signaling, and cancer cells' intrinsic neural properties. We explain the basic and clinical-translational relevance of these findings, identify unresolved questions and particularly interesting future research avenues, such as central nervous system neuro-immunooncology, and discuss the potential transferability to extracranial cancers. Lastly, we conceptualize ways toward clinical trials and develop a roadmap toward neuroscience-instructed brain tumor therapies. Significance: Neural influences on brain tumors drive their growth and invasion. Herein, we develop a roadmap to use these fundamentally new insights into brain tumor biology for improved outcomes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0194
  43. Nat Methods. 2025 Jan 16.
    Label-free nanoscopy of cell metabolism by ultrasensitive reweighted visible stimulated Raman scattering.
    Haonan Lin, Scott Seitz, Yuying Tan, Jean-Baptiste Lugagne, Le Wang, Guangrui Ding, Hongjian He, Tyler J Rauwolf, Mary J Dunlop, John H Connor, John A Porco, Lei Tian, Ji-Xin Cheng.
      Super-resolution imaging of cell metabolism is hindered by the incompatibility of small metabolites with fluorescent dyes and the limited resolution of imaging mass spectrometry. We present ultrasensitive reweighted visible stimulated Raman scattering (URV-SRS), a label-free vibrational imaging technique for multiplexed nanoscopy of intracellular metabolites. We developed a visible SRS microscope with extensive pulse chirping to improve the detection limit to ~4,000 molecules and introduced a self-supervised multi-agent denoiser to suppress non-independent noise in SRS by over 7.2 dB, resulting in a 50-fold sensitivity enhancement over near-infrared SRS. Leveraging the enhanced sensitivity, we employed Fourier reweighting to amplify sub-100-nm spatial frequencies that were previously overwhelmed by noise. Validated by Fourier ring correlation, we achieved a lateral resolution of 86 nm in cell imaging. We visualized the reprogramming of metabolic nanostructures associated with virus replication in host cells and subcellular fatty acid synthesis in engineered bacteria, demonstrating its capability towards nanoscopic spatial metabolomics.
    DOI:  https://doi.org/10.1038/s41592-024-02575-1
  44. bioRxiv. 2024 Dec 12. pii: 2024.12.10.627730. [Epub ahead of print]
    Spatially resolved rewiring of mitochondria-lipid droplet interactions in hepatic lipid homeostasis.
    Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      Hepatic lipid accumulation, or Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a significant risk factor for liver cancer. Despite the rising incidence of MASLD, the underlying mechanisms of steatosis and lipotoxicity remain poorly understood. Interestingly, lipid accumulation also occurs during fasting, driven by the mobilization of adipose tissue-derived fatty acids into the liver. However, how hepatocytes adapt to increased lipid flux during nutrient deprivation and what occurs differently in MASLD is not known. To investigate the differences in lipid handling in response to nutrient deficiency and excess, we developed a novel single-cell tissue imaging (scPhenomics) technique coupled with spatial proteomics. Our investigation revealed extensive remodeling of lipid droplet (LD) and mitochondrial topology in response to dietary conditions. Notably, fasted mice exhibited extensive mitochondria-LD interactions, which were rarely observed in Western Diet (WD)-fed mice. Spatial proteomics showed an increase in PLIN5 expression, a known mediator of LD-mitochondria interaction, in response to fasting. To examine the functional role of mitochondria-LD interaction on lipid handling, we overexpressed PLIN5 variants. We found that the phosphorylation state of PLIN5 impacts its capacity to form mitochondria-LD contact sites. PLIN5 S155A promoted extensive organelle interactions, triglyceride (TG) synthesis, and LD expansion in mice fed a control diet. Conversely, PLIN5 S155E expressing cells had fewer LDs and contact sites and contained less TG. Wild-type (WT) PLIN5 overexpression in WD-fed mice reduced steatosis and improved redox state despite continued WD consumption. These findings highlight the importance of organelle interactions in lipid metabolism, revealing a critical mechanism by which hepatocytes maintain homeostasis during metabolic stress. Our study underscores the potential utility of targeting mitochondria-LD interactions for therapeutic intervention.
    DOI:  https://doi.org/10.1101/2024.12.10.627730
  45. Am J Hum Genet. 2025 Jan 07. pii: S0002-9297(24)00458-0. [Epub ahead of print]
    No evidence for sex-differential transcriptomes driving genome-wide sex-differential natural selection.
    Matthew J Ming, Changde Cheng, Mark Kirkpatrick, Arbel Harpak.
      Sex differences in human transcriptomes have been argued to drive sex-differential selection (SDS). Here, we show that previous evidence supporting this hypothesis has been largely unfounded. We develop a method to test for a genome-wide relationship between sex differences in expression and selection on expression-influencing alleles (expression quantitative trait loci [eQTLs]). We apply it across 34 human tissues and find no evidence for a general relationship. We offer possible explanations for the lack of evidence, including that it is due in part to eQTL ascertainment bias toward sites under weak selection. We conclude that the drivers of ongoing SDS in humans remain to be identified.
    Keywords:  gene expression; inference of selection; population genetics; sex-differential selection
    DOI:  https://doi.org/10.1016/j.ajhg.2024.12.016
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒19 at 6:30.