bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–03–09
71 papers selected by
Christian Frezza, Universität zu Köln
  1. Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
  2. Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
  3. Regulation of mammalian cellular metabolism by endogenous cyanide production.
  4. Metabolic alterations in HSCs during aging and leukemogenesis.
  5. Clonal dynamics and somatic evolution of haematopoiesis in mouse.
  6. Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
  7. Evolutionary fingerprints of epithelial-to-mesenchymal transition.
  8. Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
  9. p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
  10. Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
  11. Pulling back the mitochondria's iron curtain.
  12. Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
  13. Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
  14. Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
  15. PLK1 inhibition delays mitotic entry revealing changes to the phosphoproteome of mammalian cells early in division.
  16. Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.
  17. ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.
  18. The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster.
  19. Dodging mitochondrial mislocalization.
  20. HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.
  21. Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells.
  22. Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
  23. ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
  24. Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
  25. Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.
  26. An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.
  27. Autophagy-dependent versus autophagy-independent ferroptosis.
  28. De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.
  29. Gases define redox signalling: NO, H2S, O2 … and cyanide.
  30. iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.
  31. The complex interplay between aging and cancer.
  32. Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.
  33. Discovery of metabolites prevails amid in-source fragmentation.
  34. Metabolic engineering to facilitate anti-tumor immunity.
  35. Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
  36. Vacuoles provide the source membrane for TORC1-containing signaling endosomes.
  37. Geometrically balanced model of cell growth.
  38. ASPiring metabolic-immunotherapy by ASParaginase.
  39. Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy.
  40. Chimeric origins and dynamic evolution of central carbon metabolism in eukaryotes.
  41. Immunomodulatory role of the stem cell circadian clock in muscle repair.
  42. Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma.
  43. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.
  44. G protein-coupled oestrogen receptor regulates branched-chain amino acid metabolism through c-Jun N-terminal kinase.
  45. The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity.
  46. Famsin and fasting adaptation: A glucagon connection.
  47. We cannot ignore the cancer risks of wildfires.
  48. PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
  49. Disruption of mitochondrial DNA integrity in cardiomyocyte injury upon ischemia/reperfusion.
  50. Regulation of gene expression through protein-metabolite interactions.
  51. Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
  52. MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.
  53. Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.
  54. Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
  55. "Shunt-ing" down obesity with novel endogenous metabolites.
  56. Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
  57. Checkpoint kinases regulate the circadian clock after DNA damage by influencing chromatin dynamics.
  58. State-dependent motion of a genetically encoded fluorescent biosensor.
  59. Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1.
  60. Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
  61. Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.
  62. AMPK phosphosite profiling by label-free mass spectrometry reveals a multitude of mTORC1-regulated substrates.
  63. Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
  64. Adenosine deaminase and deoxyadenosine regulate intracellular immune response in C. elegans.
  65. Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.
  66. Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?
  67. PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression.
  68. -----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
  69. Novel roles of ammonia in physiology and cancer.
  70. The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes.
  71. scMitoMut for calling mitochondrial lineage-related mutations in single cells.
  1. bioRxiv. 2025 Feb 19. pii: 2025.02.18.638948. [Epub ahead of print]
    Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
    Madeleine L Hart, Kristian Davidsen, Serwah Danquah, Eric Zheng, David Sokolov, Lucas B Sullivan.
      Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    Keywords:  SDH; aspartate; biosensor; cancer; metabolism; metabolomics; proliferation; pyrimidines
    DOI:  https://doi.org/10.1101/2025.02.18.638948
  2. Nat Commun. 2025 Mar 06. 16(1): 2250
    Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
    Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.
      Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
    DOI:  https://doi.org/10.1038/s41467-025-57286-8
  3. Nat Metab. 2025 Mar 03.
    Regulation of mammalian cellular metabolism by endogenous cyanide production.
    Karim Zuhra, Maria Petrosino, Lucia Janickova, Jovan Petric, Kelly Ascenção, Thibaut Vignane, Moustafa Khalaf, Thilo M Philipp, Stella Ravani, Abhishek Anand, Vanessa Martins, Sidneia Santos, Serkan Erdemir, Sait Malkondu, Barbara Sitek, Taha Kelestemur, Anna Kieronska-Rudek, Tomas Majtan, Luis Filgueira, Darko Maric, Stefan Chlopicki, David Hoogewijs, György Haskó, Andreas Papapetropoulos, Brian A Logue, Gerry R Boss, Milos R Filipovic, Csaba Szabo.
      Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.
    DOI:  https://doi.org/10.1038/s42255-025-01225-w
  4. Physiology (Bethesda). 2025 Feb 28.
    Metabolic alterations in HSCs during aging and leukemogenesis.
    Yi-Hsuan Chiang, Stephan Emmrich, Nicola Vannini.
      Aging is a multifaceted process associated with a functional decline in cellular function over time, affecting all lifeforms. During the aging process, metabolism, a fundamental hallmark of life (1), is profoundly altered. In the context of hematopoiesis, the proper function of hematopoietic stem cells - at the apex of the blood system - is tightly linked to their energy metabolism, which in turn shapes hematopoietic output. Here, we review the latest developments in our understanding of the metabolic states and changes in aged hematopoietic stem cells, molecular players and pathways involved in aged hematopoietic stem cell metabolism, the consequences of perturbed metabolism on clonal hematopoiesis and leukemogenesis, and pharmacologic/ genetic strategies to reverse or rejuvenate altered metabolic phenotypes.
    Keywords:  aging; clonal hematopoiesis; hematopoietic stem cell; leukemogenesis; metabolism
    DOI:  https://doi.org/10.1152/physiol.00054.2024
  5. Nature. 2025 Mar 05.
    Clonal dynamics and somatic evolution of haematopoiesis in mouse.
    Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia.
      Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.
    DOI:  https://doi.org/10.1038/s41586-025-08625-8
  6. Sci Adv. 2025 Mar 07. 11(10): eadr0690
    Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
    Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adr0690
  7. Nature. 2025 Mar 05.
    Evolutionary fingerprints of epithelial-to-mesenchymal transition.
    Luigi Perelli, Li Zhang, Sarah Mangiameli, Francesca Giannese, Krishnan K Mahadevan, Fuduan Peng, Francesca Citron, Hania Khan, Courtney Le, Enrico Gurreri, Federica Carbone, Andrew J C Russell, Melinda Soeung, Truong Nguyen Anh Lam, Sebastian Lundgren, Sujay Marisetty, Cihui Zhu, Desiree Catania, Alaa M T Mohamed, Ningping Feng, Jithesh Jose Augustine, Alessandro Sgambato, Giampaolo Tortora, Giulio F Draetta, Giovanni Tonon, Andrew Futreal, Virginia Giuliani, Alessandro Carugo, Andrea Viale, Michael P Kim, Timothy P Heffernan, Linghua Wang, Raghu Kalluri, Davide Cittaro, Fei Chen, Giannicola Genovese.
      Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.
    DOI:  https://doi.org/10.1038/s41586-025-08671-2
  8. Cell. 2025 Feb 27. pii: S0092-8674(25)00145-X. [Epub ahead of print]
    Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
    Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M Asara, Ke Zhang, Lewis C Cantley, Jean J Zhao.
      Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
    Keywords:  STAT1; immune response; protein modification; vitamin C; vitcylation
    DOI:  https://doi.org/10.1016/j.cell.2025.01.043
  9. Nat Commun. 2025 Mar 05. 16(1): 2229
    p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Shreeya Patel, Xue Lei, Adarsh Rajesh, Marcos G Teneche, Aaron P Havas, Armin Gandhi, Carolina Cano Macip, Jun Lyu, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Michael A LaPorta, Tianhui Liu, Nirmalya Dasgupta, Sha Li, Andrew Davis, Anatoly Korotkov, Erik Hultenius, Zichen Gao, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Andrei Seluanov, Vera Gorbunova, Susan M Kaech, Xiao Tian, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Here we report a mechanism directly linking genomic instability and inflammation in senescent cells through a mitochondria-regulated molecular circuit involving p53 and cytoplasmic chromatin fragments (CCF) that are enriched for DNA damage signaling marker γH2A.X. We show that p53 suppresses CCF accumulation and its downstream inflammatory phenotype. p53 activation suppresses CCF formation linked to enhanced DNA repair and genome integrity. Activation of p53 in aged mice by pharmacological inhibition of MDM2 reverses transcriptomic signatures of aging and age-associated accumulation of monocytes and macrophages in liver. Mitochondrial ablation in senescent cells suppresses CCF formation and activates p53 in an ATM-dependent manner, suggesting that mitochondria-dependent formation of γH2A.X + CCF dampens nuclear DNA damage signaling and p53 activity. These data provide evidence for a mitochondria-regulated p53 signaling circuit in senescent cells that controls DNA repair, genome integrity, and senescence- and age-associated inflammation, with relevance to therapeutic targeting of age-associated disease.
    DOI:  https://doi.org/10.1038/s41467-025-57229-3
  10. Nature. 2025 Mar 05.
    Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
    Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.
      The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
    DOI:  https://doi.org/10.1038/s41586-025-08667-y
  11. NPJ Metab Health Dis. 2025 ;3(1): 6
    Pulling back the mitochondria's iron curtain.
    Shani Ben Zichri-David, Liraz Shkuri, Tslil Ast.
      Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.
    Keywords:  Biochemistry; Cell biology; Metabolic pathways
    DOI:  https://doi.org/10.1038/s44324-024-00045-y
  12. J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):
    Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
    Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.
      Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.
    DOI:  https://doi.org/10.1083/jcb.202407110
  13. Nat Metab. 2025 Mar 06.
    Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.
    Trine S Nicolaisen, Aslak E Lyster, Kim A Sjøberg, Daniel T Haas, Christian T Voldstedlund, Anne-Marie Lundsgaard, Jakob K Jensen, Ea M Madsen, Casper K Nielsen, Mads Bloch-Ibenfeldt, Nicolai J Wewer Albrechtsen, Adam J Rose, Natalie Krahmer, Christoffer Clemmensen, Erik A Richter, Andreas M Fritzen, Bente Kiens.
      Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
    DOI:  https://doi.org/10.1038/s42255-025-01236-7
  14. Nat Commun. 2025 Feb 28. 16(1): 2053
    Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Josef P Clark, Timothy W Rhoads, Tiaira J Porter, Kevin W Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.
    DOI:  https://doi.org/10.1038/s41467-025-57363-y
  15. EMBO J. 2025 Mar 03.
    PLK1 inhibition delays mitotic entry revealing changes to the phosphoproteome of mammalian cells early in division.
    Monica Gobran, Antonio Z Politi, Luisa Welp, Jasmin Jakobi, Henning Urlaub, Peter Lenart.
      Polo-like kinase 1 (PLK1) is a conserved regulator of cell division. During mitotic prophase, PLK1 contributes to the activation of the cyclin-dependent kinase 1 (CDK1). However, the exact functions of PLK1 in prophase remain incompletely understood. Here, we show that PLK1 inhibition in synchronous G2 cell populations of multiple mammalian cell lines delays or prevents mitotic entry with high variability between individual cells. Using a mathematical model, we recapitulate this phenomenon and provide an explanation for the observed phenotypic variability. We show that PLK1-inhibited cells are delayed in a prophase-like state with low CDK1 activity that increases slowly and gradually over hours. These cells display progressively condensing chromosomes, increased microtubule dynamics, and reorganization of the actin cortex, while the nuclear envelope remains intact. We characterize this state further by phosphoproteomics, revealing phosphorylation of regulators of chromatin organization and the cytoskeleton consistent with the cellular phenotypes. Together, our results indicate that PLK1 inhibition stabilizes cells in a prophase-like state with low CDK1 activity displaying a specific set of early mitotic phosphorylation events.
    Keywords:  Cell Cycle; Mitosis; Mitotic Entry; Phosphoproteomics; Polo-like Kinase 1
    DOI:  https://doi.org/10.1038/s44318-025-00400-9
  16. Nature. 2025 Mar 05.
    Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity.
    Jie Yang, Yumi Yamashita-Kanemaru, Benjamin I Morris, Annalisa Contursi, Daniel Trajkovski, Jingru Xu, Ilinca Patrascan, Jayme Benson, Alexander C Evans, Alberto G Conti, Aws Al-Deka, Layla Dahmani, Adnan Avdic-Belltheus, Baojie Zhang, Hanneke Okkenhaug, Sarah K Whiteside, Charlotte J Imianowski, Alexander J Wesolowski, Louise V Webb, Simone Puccio, Stefania Tacconelli, Annalisa Bruno, Sara Di Berardino, Alessandra De Michele, Heidi C E Welch, I-Shing Yu, Shu-Wha Lin, Suman Mitra, Enrico Lugli, Louise van der Weyden, Klaus Okkenhaug, Kourosh Saeb-Parsy, Paola Patrignani, David J Adams, Rahul Roychoudhuri.
      Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-025-08626-7
  17. Nat Cell Biol. 2025 Mar 03.
    ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion.
    Yuran Duan, Zhiqiang Hu, Peng Han, Bo Lei, Shuo Wang, Zheng Wang, Yueru Hou, Yanni Lin, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Shenghan Lou, Laishou Yang, Xueli Bai, Shengzhong Duan, Peng Zhan, Tong Liu, Zhimin Lu, Daqian Xu.
      Highly aggressive tumours have evolved to restrain the cGAS-STING pathway for immune evasion, and the mechanisms underlying this hijacking remain unknown. Here we demonstrate that hypoxia induces robust STING activation in normal mammary epithelial cells but not in breast cancer cells. Mechanistically, adenylosuccinate lyase (ADSL), a key metabolic enzyme in de novo purine synthesis, is highly expressed in breast cancer tissues and is phosphorylated at T350 by hypoxia-activated IKKβ. Phosphorylated ADSL interacts with STING at the endoplasmic reticulum, where ADSL-produced fumarate binds to STING, leading to the inhibition of cGAMP binding to STING, STING activation and subsequent IRF3-dependent cytokine gene expression. Disrupting the ADSL-STING association promotes STING activation and blunts tumour growth. Notably, a combination treatment with ADSL endoplasmic reticulum translocation-blocking peptide and anti-PD-1 antibody induces an additive inhibitory effect on tumour growth accompanying a substantially increased immune response. Notably, ADSL T350 phosphorylation levels are inversely correlated with levels of STING activation and predicate poor prognosis in patients with breast cancer. These findings highlight a pivotal role of the metabolite fumarate in inhibiting STING activation and uncover new strategies to improve immune-checkpoint therapy by targeting ADSL-moonlighting function-mediated STING inhibition.
    DOI:  https://doi.org/10.1038/s41556-025-01627-8
  18. bioRxiv. 2025 Feb 21. pii: 2025.02.20.639223. [Epub ahead of print]
    The alternative oxidase reconfigures the larval mitochondrial electron transport system to accelerate growth and development in Drosophila melanogaster.
    Geovana S Garcia, Murilo F Othonicar, Antonio Thiago P Campos, Eric A Kilbourn, Kenia C Bicego, Johannes Lerchner, Jason M Tennessen, Marcos T Oliveira.
      The alternative oxidase (AOX) is naturally present in the mitochondrial electron transfer system (ETS) of many organisms but absent in vertebrates and most insects. AOX oxidizes coenzyme Q and reduces O 2 in H 2 O, partially replacing the ETS cytochrome c segment and alleviating the oxidative stress caused by ETS overload. As successfully demonstrated in animal models, AOX shows potential in mitigating mitochondrial diseases. However, its non-proton-pumping nature may uncouple mitochondria, leading to excessive heat generation and interference with normal metabolism and physiology. Here we show that AOX from the tunicate Ciona intestinalis accelerates development of Drosophila melanogaster , elevating larval biomass accumulation (primarily due to increased fat), mobility and food intake, without increasing body heat production. AOX intensifies Leak respiration and lowers oxidative phosphorylation efficiency through functional interactions with the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH). This is associated with increased complex I (CI)-driven respiration and supercomplex formation, higher cellular NAD+/NADH ratios, and an enhanced flux through the central carbon metabolism. Chemical uncouplers and rotenone confirm the roles of mitochondrial uncoupling and CI in the development of AOX-expressing larvae. Thus, AOX appears to be promoting increased growth by reinforcing the larval proliferative metabolic program via an intricate mechanism that reconfigures the larval ETS.
    DOI:  https://doi.org/10.1101/2025.02.20.639223
  19. Nat Rev Mol Cell Biol. 2025 Mar 06.
    Dodging mitochondrial mislocalization.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00840-5
  20. Cell. 2025 Feb 25. pii: S0092-8674(25)00156-4. [Epub ahead of print]
    HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy.
    Qinqin Jiang, David A Braun, Karl R Clauser, Vijyendra Ramesh, Nitin H Shirole, Joseph E Duke-Cohan, Nancy Nabilsi, Nicholas J Kramer, Cleo Forman, Isabelle E Lippincott, Susan Klaeger, Kshiti M Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, Yijia Jiang, Rong Li, Sudeepa Syamala, Suzanna Rachimi, Eva K Verzani, Jonathan D Stevens, William J Lane, Sabrina Y Camp, Kevin Meli, Melissa B Pappalardi, Zachary T Herbert, Xintao Qiu, Paloma Cejas, Henry W Long, Sachet A Shukla, Eliezer M Van Allen, Toni K Choueiri, L Stirling Churchman, Jennifer G Abelin, Cagan Gurer, Gavin MacBeath, Richard W Childs, Steven A Carr, Derin B Keskin, Catherine J Wu, William G Kaelin.
      Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
    Keywords:  ERV; HIF; cancer vaccine; ccRCC; immunopeptidomic; immunotherapy; kidney cancer; neoantigen
    DOI:  https://doi.org/10.1016/j.cell.2025.01.046
  21. Arch Biochem Biophys. 2025 Mar 01. pii: S0003-9861(25)00080-3. [Epub ahead of print] 110367
    Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells.
    Yuqi Wang, Hao Wu, Xun Hu.
       BACKGROUND: The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.
    RESULTS: In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2%, 24.0%, and 5.7%, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6%), conversion from serine (45.1%), and other sources (9.4%). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7%) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3%) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100%), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation substantially mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.
    CONCLUSIONS: By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.
    Keywords:  Serine; cancer cell; glycine; isotope tracing; metabolic rates
    DOI:  https://doi.org/10.1016/j.abb.2025.110367
  22. EMBO J. 2025 Feb 28.
    Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
    Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji.
      Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.
    Keywords:  Bioenergetics; Pyrimidine Nucleotides; SLC25; Thermogenesis; Uncoupling Protein
    DOI:  https://doi.org/10.1038/s44318-025-00395-3
  23. Nat Commun. 2025 Feb 28. 16(1): 2071
    ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
    Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li, Pingyu Liu.
      Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-57334-3
  24. Mech Ageing Dev. 2025 Feb 27. pii: S0047-6374(25)00020-X. [Epub ahead of print] 112044
    Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
    Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, Olivier R Baris.
      Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.
    Keywords:  Aging; Cardiovascular diseases; Inflammation; Mitochondria; Mitochondrial dynamics; Senescence; mtDNA
    DOI:  https://doi.org/10.1016/j.mad.2025.112044
  25. Elife. 2025 Mar 06. pii: RP97649. [Epub ahead of print]13
    Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.
    Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Ella M M A Martin, Alena Sipka, Paul Young, David T Humphreys, Sally L Dunwoodie.
      Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NAD de novo during early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.
    Keywords:  NAD; birth defects; congenital malformation; developmental biology; embryogenesis; metabolism; mouse; yolk sac
    DOI:  https://doi.org/10.7554/eLife.97649
  26. Life Sci Alliance. 2025 May;pii: e202403014. [Epub ahead of print]8(5):
    An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.
    Mónica Román-Trufero, Istvan T Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-García, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M Michel, Eric O Aboagye, Mariia Yuneva, Glenn R Masson, Vahid Shahrezaei, Holger W Auner.
      The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.
    DOI:  https://doi.org/10.26508/lsa.202403014
  27. Trends Cell Biol. 2025 Mar 05. pii: S0962-8924(25)00005-4. [Epub ahead of print]
    Autophagy-dependent versus autophagy-independent ferroptosis.
    Ye Zhu, Motoki Fujimaki, David C Rubinsztein.
      Ferroptosis is an iron-dependent cell death pathway that, until recently, has been considered to be dependent on autophagy. However, recent studies have reported conflicting results, raising the question about which cell contexts determine the roles of autophagy in ferroptosis. This opinion article addresses this question by summarizing the contexts and/or diseases in which autophagy is a driver or suppressor of ferroptosis. The execution of ferroptosis depends on levels of (labile) iron, unsaturated (phospho)lipids and free radicals. We propose that the cell context in which these three factors and/or their upstream pathways are differentially regulated dictates whether autophagy positively or negatively regulates ferroptosis.
    Keywords:  autophagy; ferroptosis; iron; lysosome; polyunsaturated phospholipid; tissue-specificity
    DOI:  https://doi.org/10.1016/j.tcb.2025.01.005
  28. Cancer Res. 2025 Mar 03.
    De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.
    Manon Teisseire, Umakant Sahu, Julien Parola, Meng-Chen Tsai, Valérie Vial, Jérôme Durivault, Renaud Grépin, Yann Cormerais, Clément Molina, Arthur Gouraud, Gilles Pagès, Issam Ben-Sahra, Sandy Giuliano.
      Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the mechanistic link between sunitinib treatment and elevated serine production. The increased serine biosynthesis supported nucleotide synthesis and sustained cell proliferation, migration, and invasion following sunitinib treatment. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhanced the sensitivity of resistant cells to sunitinib. Beyond RCC, similar activation of serine synthesis following sunitinib treatment occurred in a variety of other cancer types, suggesting a shared adaptive response to sunitinib therapy. Together, this study identifies the de novo serine synthesis pathway as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1393
  29. Nat Metab. 2025 Mar 03.
    Gases define redox signalling: NO, H2S, O2 … and cyanide.
    Zachary W Grimmett, Joseph C Schindler, Jonathan S Stamler.
      
    DOI:  https://doi.org/10.1038/s42255-025-01229-6
  30. Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00146-9. [Epub ahead of print]44(3): 115375
    iMetAct: An integrated systematic inference of metabolic activity for dissecting tumor metabolic preference and tumor-immune microenvironment.
    Binxian Wang, Chao Huang, Xuan Liu, Zhenni Liu, Yilei Zhang, Wei Zhao, Qiuran Xu, Ping-Chih Ho, Zhengtao Xiao.
      Metabolic enzymes play a central role in cancer metabolic reprogramming, and their dysregulation creates vulnerabilities that can be exploited for therapy. However, accurately measuring metabolic enzyme activity in a high-throughput manner remains challenging due to the complex, multi-layered regulatory mechanisms involved. Here, we present iMetAct, a framework that integrates metabolic-transcription networks with an information propagation strategy to infer enzyme activity from gene expression data. iMetAct outperforms expression-based methods in predicting metabolite conversion rates by accounting for the effects of post-translational modifications. With iMetAct, we identify clinically significant subtypes of hepatocellular carcinoma with distinct metabolic preferences driven by dysregulated enzymes and metabolic regulators acting at both the transcriptional and non-transcriptional levels. Moreover, applying iMetAct to single-cell RNA sequencing data allows for the exploration of cancer cell metabolism and its interplay with immune regulation in the tumor microenvironment. An accompanying online platform further facilitates tumor metabolic analysis, patient stratification, and immune microenvironment characterization.
    Keywords:  CP: Cancer; CP: Metabolism; hepatocellular carcinoma; information propagation; metabolic enzyme activity; tumor stratification; tumor-immune microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115375
  31. Nat Aging. 2025 Mar 04.
    The complex interplay between aging and cancer.
    Lucrezia A Trastus, Fabrizio d'Adda di Fagagna.
      Cancer is an age-related disease, but the interplay between cancer and aging is complex and their shared molecular drivers are deeply intertwined. This Review provides an overview of how different biological pathways affect cancer and aging, leveraging evidence mainly derived from animal studies. We discuss how genome maintenance and accumulation of DNA mutations affect tumorigenesis and tissue homeostasis during aging. We describe how age-related telomere dysfunction and cellular senescence intricately modulate tumor development through mechanisms involving genomic instability and inflammation. We examine how an aged immune system and chronic inflammation shape tumor immunosurveillance, fueling DNA damage and cellular senescence. Finally, as animal models are important to untangling the relative contributions of these aging-modulated pathways to cancer progression and to test interventions, we discuss some of the limitations of physiological and accelerated aging models, aiming to improve experimental designs and enhance translation.
    DOI:  https://doi.org/10.1038/s43587-025-00827-z
  32. J Inherit Metab Dis. 2025 Mar;48(2): e70018
    Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.
    Melissa A King, Katherine C Heger, Marija Drikic, Ayush Mandwal, Aneal Khan, David S Sinasac, Keir Pittman, Edward L Huttlin, Steven C Greenway, Ian A Lewis.
      The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.
    Keywords:  3‐methylglutaconic aciduria; DCMA; dilated cardiomyopathy; glutamine; metabolism
    DOI:  https://doi.org/10.1002/jimd.70018
  33. Nat Metab. 2025 Feb 28.
    Discovery of metabolites prevails amid in-source fragmentation.
    Yasin El Abiead, Adriano Rutz, Simone Zuffa, Bashar Amer, Shipei Xing, Corinna Brungs, Robin Schmid, Mario S P Correia, Andres Mauricio Caraballo-Rodriguez, Amir Zarrinpar, Helena Mannochio-Russo, Michael Witting, Ipsita Mohanty, Tomáš Pluskal, Wout Bittremieux, Rob Knight, Andrew D Patterson, Justin J J van der Hooft, Sebastian Böcker, Warwick B Dunn, Roger G Linington, David S Wishart, Jean-Luc Wolfender, Oliver Fiehn, Nicola Zamboni, Pieter C Dorrestein.
      
    DOI:  https://doi.org/10.1038/s42255-025-01239-4
  34. Cancer Cell. 2025 Feb 21. pii: S1535-6108(25)00056-X. [Epub ahead of print]
    Metabolic engineering to facilitate anti-tumor immunity.
    Tanya Schild, Patrick Wallisch, Yixuan Zhao, Ya-Ting Wang, Lyric Haughton, Rachel Chirayil, Kaitlyn Pierpont, Kevin Chen, Sara Nunes-Violante, Justin Cross, Elisa de Stanchina, Craig B Thompson, David A Scheinberg, Justin S A Perry, Kayvan R Keshari.
      Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.
    Keywords:  CAR-T; fructose; macrophages; metabolic engineering; slc2a5; t cell
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.004
  35. Elife. 2025 Mar 04. pii: RP100570. [Epub ahead of print]13
    Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
    Rui Vasco Simoes, Rafael Neto Henriques, Jonas L Olesen, Beatriz M Cardoso, Francisca F Fernandes, Mariana A V Monteiro, Sune N Jespersen, Tânia Carvalho, Noam Shemesh.
      Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.
    Keywords:  cancer biology; deuterium metabolic imaging; glioblastoma; glycolysis; kinetic modeling; mitochondrial metabolism; mouse
    DOI:  https://doi.org/10.7554/eLife.100570
  36. J Cell Biol. 2025 May 05. pii: e202407021. [Epub ahead of print]224(5):
    Vacuoles provide the source membrane for TORC1-containing signaling endosomes.
    Kenji Muneshige, Riko Hatakeyama.
      Organelle biogenesis is fundamental to eukaryotic cell biology. Yeast signaling endosomes were recently identified as a signaling platform for the evolutionarily conserved Target of Rapamycin Complex 1 (TORC1) kinase complex. Despite the importance of signaling endosomes for TORC1-mediated control of cellular metabolism, how this organelle is generated has been a mystery. Here, we developed a system to induce synchronized de novo formation of signaling endosomes, enabling real-time monitoring of their biogenesis. Using this system, we identify vacuoles as a membrane source for newly formed signaling endosomes. Membrane supply from vacuoles is mediated by the CROP membrane-cutting complex, consisting of Atg18 PROPPIN and retromer subunits. The formation of signaling endosomes requires TORC1 activity, suggestive of a tightly regulated process. This study unveiled the first mechanistic principles and molecular participants of signaling endosome biogenesis.
    DOI:  https://doi.org/10.1083/jcb.202407021
  37. J Theor Biol. 2025 Mar 01. pii: S0022-5193(25)00051-7. [Epub ahead of print]604 112085
    Geometrically balanced model of cell growth.
    Alexei Vazquez, Tomáš Gedeon.
      The proteome balance constraint in metabolic flux balance analysis asserts that the proteome is constructed by ribosomes, which themselves contain many proteins. This leads to a fundamental question of optimal allocation of limited proteome among different pools of enzymes, which include ribosomes themselves. However, recent work points to additional constraints imposed by the cell geometry. In this paper we deduce the proteogeometric constraintπ¯A=πA+θπL/πP, where πA, πP and πL are the proteomic fractions allocated to the cell surface area, protein synthesis and cell membrane phospholipids synthesis and π¯A and θ are constants imposed by geometry of the cell. We illustrate the relevance of this constraint using a reduced model of cell metabolism, illuminating the interplay between cell metabolism and cell geometry.
    Keywords:  Cell geometry; Metabolism; Molecular crowding; Natural selection; Proteomic fractions
    DOI:  https://doi.org/10.1016/j.jtbi.2025.112085
  38. Nat Metab. 2025 Mar 05.
    ASPiring metabolic-immunotherapy by ASParaginase.
    Rushil Shah, Ruoning Wang.
      
    DOI:  https://doi.org/10.1038/s42255-025-01241-w
  39. Cell Rep. 2025 Mar 01. pii: S2211-1247(25)00159-7. [Epub ahead of print]44(3): 115388
    Inflammatory cytokines mediate the induction of and awakening from metastatic dormancy.
    Paulo Pereira, Joshua Panier, Marc Nater, Michael Herbst, Anna Laura Calvanese, Hakan Köksal, Héctor Castañón, Virginia Cecconi, Paulino Tallón de Lara, Steve Pascolo, Maries van den Broek.
      Metastases arise from disseminated cancer cells (DCCs) that detach from the primary tumor and seed distant organs. There, quiescent DCCs can survive for an extended time, a state referred to as metastatic dormancy. The mechanisms governing the induction, maintenance, and awakening from metastatic dormancy are unclear. We show that the differentiation of dormancy-inducing CD8+ T cells requires CD4+ T cell help and that interferon (IFN)γ directly induces dormancy in DCCs. The maintenance of metastatic dormancy, however, is independent of T cells. Instead, awakening from dormancy requires an inflammatory signal, and we identified CD4+ T cell-derived interleukin (IL)-17A as an essential wake-up signal for dormant DCCs in the lungs. Thus, the induction of and awakening from metastatic dormancy require an external stimulus, while the maintenance of dormancy does not rely on continuous surveillance by lymphocytes.
    Keywords:  CP: Cancer; CP: Immunology; IFNγ; IL-17A; breast cancer; metastatic dormancy
    DOI:  https://doi.org/10.1016/j.celrep.2025.115388
  40. Nat Ecol Evol. 2025 Mar 03.
    Chimeric origins and dynamic evolution of central carbon metabolism in eukaryotes.
    Carlos Santana-Molina, Tom A Williams, Berend Snel, Anja Spang.
      The origin of eukaryotes was a key event in the history of life. Current leading hypotheses propose that a symbiosis between an asgardarchaeal host cell and an alphaproteobacterial endosymbiont represented a crucial step in eukaryotic origin and that metabolic cross-feeding between the partners provided the basis for their subsequent evolutionary integration. A major unanswered question is whether the metabolism of modern eukaryotes bears any vestige of this ancestral syntrophy. Here we systematically analyse the evolutionary origins of the eukaryotic gene repertoires mediating central carbon metabolism. Our phylogenetic and sequence analyses reveal that this gene repertoire is chimeric, with ancestral contributions from Asgardarchaeota and Alphaproteobacteria operating predominantly in glycolysis and the tricarboxylic acid cycle, respectively. Our analyses also reveal the extent to which this ancestral metabolic interplay has been remodelled via gene loss, transfer and subcellular retargeting in the >2 billion years since the origin of eukaryotic cells, and we identify genetic contributions from other prokaryotic sources in addition to the asgardarchaeal host and alphaproteobacterial endosymbiont. Our work demonstrates that, in contrast to previous assumptions, modern eukaryotic metabolism preserves information about the nature of the original asgardarchaeal-alphaproteobacterial interactions and supports syntrophy scenarios for the origin of the eukaryotic cell.
    DOI:  https://doi.org/10.1038/s41559-025-02648-0
  41. Sci Adv. 2025 Mar 07. 11(10): eadq8538
    Immunomodulatory role of the stem cell circadian clock in muscle repair.
    Pei Zhu, Eric M Pfrender, Adam W T Steffeck, Colleen R Reczek, Yalu Zhou, Abhishek Vijay Thakkar, Neha R Gupta, Ariana Kupai, Amber Willbanks, Richard L Lieber, Ishan Roy, Navdeep S Chandel, Clara B Peek.
      Circadian rhythms orchestrate physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day (TOD). This study identifies an interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We reveal that the SC clock triggers TOD-dependent inflammatory gene transcription after injury, particularly genes related to neutrophil activity and chemotaxis. These responses are driven by cytosolic regeneration of the signaling metabolite nicotinamide adenine dinucleotide (oxidized form) (NAD+), as enhancing cytosolic NAD+ regeneration in SCs is sufficient to induce inflammatory responses that influence muscle regeneration. Mononuclear single-cell sequencing of the regenerating muscle niche further implicates the cytokine CCL2 in mediating SC-neutrophil cross-talk in a TOD-dependent manner. Our findings highlight the intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.
    DOI:  https://doi.org/10.1126/sciadv.adq8538
  42. Cell Metab. 2025 Feb 28. pii: S1550-4131(25)00021-X. [Epub ahead of print]
    Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma.
    Klaudia Borbényi-Galambos, Katalin Erdélyi, Tamás Ditrói, Eszter Petra Jurányi, Noémi Szántó, Réka Szatmári, Ágnes Czikora, Edward E Schmidt, Dorottya Garai, Mihály Cserepes, Gabriella Liszkay, Erika Tóth, József Tóvári, Péter Nagy.
      BRAF V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRAF V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.
    Keywords:  BRAF V600E targeted therapy resistance; cystathionine γ-lyase; cysteine metabolism; fluxomics of metabolic reprogramming; hydrogen sulfide; melanoma; persister cells; persulfide; redox regulation; transsulfuration
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.021
  43. Sci Adv. 2025 Mar 07. 11(10): eads4957
    Citrulline regulates macrophage metabolism and inflammation to counter aging in mice.
    Zhangdan Xie, Moubin Lin, Beizi Xing, Hongmiao Wang, Haosong Zhang, Zimu Cai, Xinyu Mei, Zheng-Jiang Zhu.
      Metabolic dysregulation and altered metabolite concentrations are widely recognized as key characteristics of aging. Comprehensive exploration of endogenous metabolites that drive aging remains insufficient. Here, we conducted an untargeted metabolomics analysis of aging mice, revealing citrulline as a consistently down-regulated metabolite associated with aging. Systematic investigations demonstrated that citrulline exhibited antiaging effects by reducing cellular senescence, protecting against DNA damage, preventing cell cycle arrest, modulating macrophage metabolism, and mitigating inflammaging. Long-term citrulline supplementation in aged mice yielded beneficial effects and ameliorated age-associated phenotypes. We further elucidated that citrulline acts as an endogenous metabolite antagonist to inflammation, suppressing proinflammatory responses in macrophages. Mechanistically, citrulline served as a potential inhibitor of mammalian target of rapamycin (mTOR) activation in macrophage and regulated the mTOR-hypoxia-inducible factor 1α-glycolysis signaling pathway to counter inflammation and aging. These findings underscore the significance of citrulline deficiency as a driver of aging, highlighting citrulline supplementation as a promising therapeutic intervention to counteract aging-related changes.
    DOI:  https://doi.org/10.1126/sciadv.ads4957
  44. FEBS Lett. 2025 Mar 06.
    G protein-coupled oestrogen receptor regulates branched-chain amino acid metabolism through c-Jun N-terminal kinase.
    Anshu Gupta, Prasad Govind Shinde, Sachin Jorvekar, Akash Suresh Humane, Mythri Chandrasekaran, Roshan M Borkar, Sudhagar Selvaraju.
      Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling and energy balance, and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite the importance of BCAA in human health, our understanding of their metabolic regulation is limited. Here, we present evidence that G protein-coupled oestrogen receptor (GPER) activation inhibits the key BCAA metabolic regulatory enzyme branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in leucine, isoleucine and valine accumulation in cells. Interestingly, GPER did not alter the levels of the kinase BCKDK and the phosphatase PPM1K, which regulate BCKDH activity, but activated MAPK signalling. Using gene silencing, we identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling.
    Keywords:  G protein‐coupled oestrogen receptor; branched‐chain amino acids; branched‐chain α‐keto acid dehydrogenase complex; branched‐chain α‐keto acid dehydrogenase kinase; c‐Jun N‐terminal kinase
    DOI:  https://doi.org/10.1002/1873-3468.70030
  45. bioRxiv. 2025 Feb 17. pii: 2025.02.17.638704. [Epub ahead of print]
    The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity.
    Yifei Zhou, Fasih M Ahsan, Alexander A Soukas.
      As the only gateway governing nucleocytoplasmic transport, the nuclear pore complex (NPC) maintains fundamental cellular processes and deteriorates with age. However, the study of age-related roles of single NPC components remains challenging owing to the complexity of NPC composition. Here we demonstrate that the master energy sensor, AMPK, post-translationally regulates the abundance of the nucleoporin NPP-16/NUP50 in response to nutrient availability and energetic stress. In turn, NPP-16/NUP50 promotes transcriptomic activation of lipid catabolism to extend the lifespan of Caenorhabditis elegans independently of its role in nuclear transport. Rather, the intrinsically disordered region (IDR) of NPP-16/NUP50, through direct interaction with the transcriptional machinery, transactivates the promoters of catabolic genes. Remarkably, elevated NPP-16/NUP50 levels are sufficient to promote longevity and metabolic stress defenses. AMPK-NUP50 signaling is conserved to human, indicating that bridging energy sensing to metabolic adaptation is an ancient role of this signaling axis.
    DOI:  https://doi.org/10.1101/2025.02.17.638704
  46. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00058-0. [Epub ahead of print]37(3): 561-563
    Famsin and fasting adaptation: A glucagon connection.
    Siming Li, Ziyi Meng, Jiandie D Lin.
      Starvation triggers an organismal adaptive response that is orchestrated by endocrine factors. In this issue of Cell Metabolism, Long et al.1 uncover a famsin-glucagon axis that relays gut-derived hormonal cues to systemic glucose homeostasis during fasting.
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.030
  47. Nat Rev Cancer. 2025 Mar 05.
    We cannot ignore the cancer risks of wildfires.
    Scott Weichenthal.
      
    DOI:  https://doi.org/10.1038/s41568-025-00804-z
  48. Cell Death Dis. 2025 Mar 01. 16(1): 145
    PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
    Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.
      Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.
    DOI:  https://doi.org/10.1038/s41419-025-07463-w
  49. Genes Dis. 2025 May;12(3): 101282
    Disruption of mitochondrial DNA integrity in cardiomyocyte injury upon ischemia/reperfusion.
    Shengnan Hu, Xueying Tang, Fangrui Zhu, Chen Liang, Sa Wang, Hongjie Wang, Peifeng Li, Yuzhen Li.
      Mitochondria serve as the energy provider and enable life activities, and they are the only organelles containing extra-chromosomal DNA. Each mitochondrion contains multiple copies of its genome, which is usually referred to as mitochondrial DNA (mtDNA). mtDNA encodes necessary electron transport chain complex subunits, as well as the essential RNAs for their translation within the organelle. Therefore, the precondition for intact mitochondrial function and cardiomyocyte survival is the integrity of mtDNA. Accumulating evidence suggests that the disruption of mtDNA integrity is involved in ischemia/reperfusion-induced mitochondrial dysfunction and cardiomyocyte injury. Here, we review the current opinions about the pathways of mtDNA integrity maintenance and discuss the role of mtDNA integrity in cardiomyocyte injury reacting to ischemia/reperfusion. We also discuss the mechanisms by which mtDNA mediates ischemia/reperfusion-induced cardiomyocyte injury, together with therapeutic strategies by targeting mtDNA.
    Keywords:  Cardiomyocyte; Ischemia/reperfusion; Package; Repair; Replication; Transcription; mtDNA
    DOI:  https://doi.org/10.1016/j.gendis.2024.101282
  50. NPJ Metab Health Dis. 2025 ;3(1): 7
    Regulation of gene expression through protein-metabolite interactions.
    Maximilian Hornisch, Ilaria Piazza.
      Organisms have to adapt to changes in their environment. Cellular adaptation requires sensing, signalling and ultimately the activation of cellular programs. Metabolites are environmental signals that are sensed by proteins, such as metabolic enzymes, protein kinases and nuclear receptors. Recent studies have discovered novel metabolite sensors that function as gene regulatory proteins such as chromatin associated factors or RNA binding proteins. Due to their function in regulating gene expression, metabolite-induced allosteric control of these proteins facilitates a crosstalk between metabolism and gene expression. Here we discuss the direct control of gene regulatory processes by metabolites and recent progresses that expand our abilities to systematically characterize metabolite-protein interaction networks. Obtaining a profound map of such networks is of great interest for aiding metabolic disease treatment and drug target identification.
    Keywords:  Biochemistry; Chemical biology; Systems biology
    DOI:  https://doi.org/10.1038/s44324-024-00047-w
  51. Cytometry A. 2025 Mar 07.
    Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
    Nicole Vaughn.
      Landmark studies at the turn of the century revealed metabolic reprogramming as a driving force for lymphocyte differentiation and function. In addition to metabolic changes, differentiating lymphocytes must remodel their epigenetic landscape to properly rewire their gene expression. Recent discoveries have shown that metabolic shifts can shape the fate of lymphocytes by altering their epigenetic state, bringing together these two areas of inquiry. The ongoing evolution of high-dimensional cytometry has enabled increasingly comprehensive analyses of metabolic and epigenetic landscapes in lymphocytes that transcend the technical limitations of the past. Here, we review recent insights into the interplay between metabolism and epigenetics in lymphocytes and how its dysregulation can lead to immunological dysfunction and disease. We also discuss the latest technical advances in cytometry that have enabled these discoveries and that we anticipate will advance future work in this area.
    DOI:  https://doi.org/10.1002/cyto.a.24919
  52. Cell Metab. 2025 Feb 26. pii: S1550-4131(25)00018-X. [Epub ahead of print]
    MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.
    Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.
      Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.
    Keywords:  ACKR3; MIF; adipose remodeling; adipose stem and progenitor cells; cancer cachexia
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.018
  53. bioRxiv. 2025 Feb 17. pii: 2025.02.12.637975. [Epub ahead of print]
    Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.
    Oliver J Newsom, Lucas B Sullivan.
      Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.
    DOI:  https://doi.org/10.1101/2025.02.12.637975
  54. Immunol Lett. 2025 Mar 06. pii: S0165-2478(25)00024-0. [Epub ahead of print]274 106992
    Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
    Valentina Artusa, Lara De Luca, Mario Clerici, Daria Trabattoni.
      Mitochondria are more than mere energy generators; they are multifaceted organelles that integrate metabolic, signalling, and immune functions, making them indispensable players in maintaining cellular and systemic health. Mitochondrial transfer has recently garnered attention due to its potential role in several physiological and pathological processes. This process involves multiple mechanisms by which mitochondria, along with mitochondrial DNA and other components, are exchanged between cells. In this review, we examine the critical roles of mitochondrial transfer in health and disease, focusing on its impact on immune cell function, the resolution of inflammation, tissue repair, and regeneration. Additionally, we explore its implications in viral infections and cancer progression. We also provide insights into emerging therapeutic applications, emphasizing its potential to address unmet clinical needs.
    Keywords:  Cancer; Immunity; Inflammation; Mitochondrial transfer; Mitotherapy
    DOI:  https://doi.org/10.1016/j.imlet.2025.106992
  55. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00063-4. [Epub ahead of print]37(3): 564-565
    "Shunt-ing" down obesity with novel endogenous metabolites.
    Victor J Pai, Alan Saghatelian.
      Obesity is a growing public health issue that has recently been transformed through the advent of new medicines. However, our understanding of the pathways and mechanisms that regulate energy balance in mammals is still developing. Recent discoveries on this front include an exciting new finding that there exists a novel class of metabolites in humans and mice that can regulate obesity in rodents.
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.005
  56. bioRxiv. 2025 Feb 20. pii: 2025.02.19.639160. [Epub ahead of print]
    Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. How mitochondrial damage is sensed by the PINK1-Parkin pathway, however, remains uncertain. Here, using a Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Consistently, the MMP but not the presequence translocase-associated motor (PAM) import motor provided the essential driving force for endogenous PINK1 import through the inner membrane translocase TIM23. In the absence of TIM23, PINK1 arrested in the translocase of the outer membrane (TOM) during import. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Our results identify separation of PINK1 from TOM by the MMP, as the key damage-sensing switch in the PINK1-Parkin mitophagy pathway.
    Highlights: MFN2-Halo is a quantitative single-cell reporter of PINK1-Parkin activation.Diverse forms of mitochondrial damage, identified in whole-genome screens, activate the PINK1-Parkin pathway by disrupting the mitochondrial membrane potential (MMP).The primary driving force for endogenous PINK1 import through the TIM23 translocase is the MMP with the PAM import motor playing a supporting role.Loss of TIM23 is sufficient to stabilize PINK1 in the TOM complex and activate Parkin.
    DOI:  https://doi.org/10.1101/2025.02.19.639160
  57. Nucleic Acids Res. 2025 Feb 27. pii: gkaf162. [Epub ahead of print]53(5):
    Checkpoint kinases regulate the circadian clock after DNA damage by influencing chromatin dynamics.
    Yulin Yang, Zeyu Duan, Xiao-Lan Liu, Zhanbiao Li, Zhenghao Shen, Shimin Gong, Qiaojia Lu, Yue Hu, Linhao Song, Zeyu Wang, Xuemei Cao, Yunkun Dang, Linqi Wang, Qun He, Xiao Liu.
      The interplay between circadian clocks, the cell cycle, and DNA repair has been extensively documented, yet the epigenetic control of circadian clocks by DNA damage responses remains relatively unexplored. Here, we showed that checkpoint kinases CHK1/2 regulate chromatin structure during DNA damage in Neurospora crassa to maintain robust circadian rhythms. Under DNA damage stress, deletion of chk1/2 disrupted the rhythmic transcription of the clock gene frq by suppressing the rhythmic binding of the transcription activator White Collar complex (WCC) at the frq promoter, as the chromatin structure remained condensed. Mechanistically, CHK1/2 interacted with WC-2 and were recruited by WCC to bind at the frq promoter to phosphorylate H3T11, promoting H3 acetylation, especially H3K56 acetylation, to counteract the histone variant H2A.Z deposition, thereby establishing a suitable chromatin state to maintain robust circadian rhythms despite DNA damage. Additionally, a genome-wide correlation was discovered between H3T11 phosphorylation and H3K56 acetylation, showing a specific function at the frq promoter that is dependent on CHK1/2. Furthermore, transcriptome analysis revealed that CHK1/2 are responsible for robust rhythmic transcription of metabolic and DNA repair genes during DNA damage. These findings highlight the essential role of checkpoint kinases in maintaining robust circadian rhythms under DNA damage stress.
    DOI:  https://doi.org/10.1093/nar/gkaf162
  58. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2426324122
    State-dependent motion of a genetically encoded fluorescent biosensor.
    Paul C Rosen, Samantha M Horwitz, Daniel J Brooks, Erica Kim, Joseph A Ambarian, Lidia Waidmann, Katherine M Davis, Gary Yellen.
      Genetically encoded biosensors can measure biochemical properties such as small-molecule concentrations with single-cell resolution, even in vivo. Despite their utility, these sensors are "black boxes": Very little is known about the structures of their low- and high-fluorescence states or what features are required to transition between them. We used LiLac, a lactate biosensor with a quantitative fluorescence-lifetime readout, as a model system to address these questions. X-ray crystal structures and engineered high-affinity metal bridges demonstrate that LiLac exhibits a large interdomain twist motion that pulls the fluorescent protein away from a "sealed," high-lifetime state in the absence of lactate to a "cracked," low-lifetime state in its presence. Understanding the structures and dynamics of LiLac will help to think about and engineer other fluorescent biosensors.
    Keywords:  genetically encoded fluorescent biosensor; metabolite biosensor; protein conformational change
    DOI:  https://doi.org/10.1073/pnas.2426324122
  59. Nat Commun. 2025 Mar 05. 16(1): 2158
    Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1.
    Preeti Kumari, Lauren M Sullivan, Zhaozhi Li, E Parker Conquest, Elizabeth Cornforth, Rojashree Jayakumar, Ningyan Hu, J Alexander Sizemore, Brigham B McKee, Robert R Kitchen, Paloma González-Pérez, Constance Linville, Karla Castro, Hilda Gutierrez, Soleil Samaan, Elise L Townsend, Basil T Darras, Seward B Rutkove, Susan T Iannaccone, Paula R Clemens, Araya Puwanant, Sudeshna Das, Thurman M Wheeler.
      Chronic kidney disease (CKD) and the genetic disorder myotonic dystrophy type 1 (DM1) each are associated with progressive muscle wasting, whole-body insulin resistance, and impaired systemic metabolism. However, CKD is undocumented in DM1 and the molecular pathogenesis driving DM1 is unknown to involve the kidney. Here we use urinary extracellular vesicles (EVs), RNA sequencing, droplet digital PCR, and predictive modeling to identify downregulation of metabolism transcripts Phosphoenolpyruvate carboxykinase-1, 4-Hydroxyphenylpyruvate dioxygenase, Dihydropyrimidinase, Glutathione S-transferase alpha-1, Aminoacylase-1, and Electron transfer flavoprotein B in DM1. Expression of these genes localizes to the kidney, especially the proximal tubule, and correlates with muscle strength and function. In DM1 autopsy kidney tissue, characteristic ribonuclear inclusions are evident throughout the nephron. We show that urinary organic acids and acylglycines are elevated in DM1, and correspond to enzyme deficits of downregulated genes. Our study identifies a previously unrecognized site of DM1 molecular pathogenesis and highlights the potential of urinary EVs as biomarkers of renal and metabolic disturbance in these individuals.
    DOI:  https://doi.org/10.1038/s41467-025-56479-5
  60. bioRxiv. 2025 Feb 22. pii: 2025.02.20.639242. [Epub ahead of print]
    Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
    Athena L Munden, Dominique S Lui, Daniel P Higgins, Matthew J Fanelli, Thien-Kim Ngyuen, Katherine M Edwards, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.
      S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans , which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.
    DOI:  https://doi.org/10.1101/2025.02.20.639242
  61. Sci Immunol. 2025 Mar 07. 10(105): eado1710
    Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.
    Benjamin Klein, Mack B Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C Berthier, Svenja Henning, Lam C Tsoi, Shannon N Loftus, Kelsey E McNeely, Christine M Goudsmit, Amanda M Victory, Craig Dobry, Grace A Hile, Feiyang Ma, Jessica L Turnier, Johann E Gudjonsson, Mary X O'Riordan, J Michelle Kahlenberg.
      Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.
    DOI:  https://doi.org/10.1126/sciimmunol.ado1710
  62. NPJ Metab Health Dis. 2025 ;3(1): 8
    AMPK phosphosite profiling by label-free mass spectrometry reveals a multitude of mTORC1-regulated substrates.
    William J Smiles, Ashley J Ovens, Dingyi Yu, Naomi X Y Ling, Andrea C Poblete Goycoolea, Kaitlin R Morrison, Emmanuel O Murphy, Astrid Glaser, Sophie F Monks O'Byrne, Scott Taylor, Alistair M Chalk, Carl R Walkley, Luke M McAloon, John W Scott, Bruce E Kemp, Ashfaqul Hoque, Christopher G Langendorf, Janni Petersen, Sandra Galic, Jonathan S Oakhill.
      The nutrient-sensitive protein kinases AMPK and mTORC1 form a fundamental negative feedback loop that governs cell growth and proliferation. mTORC1 phosphorylates α2-S345 in the AMPK αβγ heterotrimer to suppress its activity and promote cell proliferation under nutrient stress conditions. Whether AMPK contains other functional mTORC1 substrates is unknown. Using mass spectrometry, we generated precise stoichiometry profiles of phosphorylation sites across all twelve AMPK complexes expressed in proliferating human cells and identified seven sites displaying sensitivity to pharmacological mTORC1 inhibition. These included the abundantly phosphorylated residues β1-S182 and β2-S184, which were confirmed as mTORC1 substrates on purified AMPK, and four residues in the unique γ2 N-terminal extension. β-S182/184 phosphorylation was elevated in α1-containing complexes relative to α2, an effect attributed to the α-subunit serine/threonine-rich loop. Mutation of β1-S182 to non-phosphorylatable Ala had no effect on basal and ligand-stimulated AMPK activity; however, β2-S184A mutation increased nuclear AMPK activity, enhanced cell proliferation under nutrient stress and altered expression of genes implicated in glucose metabolism and Akt signalling. Our results indicate that mTORC1 directly or indirectly phosphorylates multiple AMPK residues that may contribute to metabolic rewiring in cancerous cells.
    Keywords:  Biochemistry; Biological techniques; Cancer
    DOI:  https://doi.org/10.1038/s44324-025-00052-7
  63. Nat Metab. 2025 Mar 05.
    Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
    Hsuan-Chia Chang, Chung-Ying Tsai, Cheng-Lung Hsu, Tzong-Shyuan Tai, Mei-Ling Cheng, Yu-Ming Chuang, Hsiang-Yu Tang, Kun-Ju Lin, Jia-Jin Chen, Szu-Han Chang, Yi-Ching Ko, Yu-Wen Chi, Hsuan Liu, Bertrand Chin-Ming Tan, Chia-Rui Shen, Chih-Wei Yang, Ping-Chih Ho, Huang-Yu Yang.
      Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8+T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01245-6
  64. iScience. 2025 Mar 21. 28(3): 111950
    Adenosine deaminase and deoxyadenosine regulate intracellular immune response in C. elegans.
    Nicole D Wernet, Eillen Tecle, Mario Bardan Sarmiento, Cheng-Ju Kuo, Crystal B Chhan, Ian Baick, Lakshmi E Batachari, Latisha Franklin, Alice Herneisen, Gira Bhabha, Damian C Ekiert, Wendy Hanna-Rose, Emily R Troemel.
      Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are enzymes in the purine salvage pathway, which recycles purines to meet cellular demands. Mutations of these enzymes in humans cause inflammatory and immunodeficiency syndromes, but the mechanisms are not well understood. Prior work in the nematode Caenorhabditis elegans demonstrated that loss of PNP ortholog PNP-1 induced an immune response called the intracellular pathogen response (IPR). Here, we show that loss of the enzyme upstream of PNP-1 called ADAH-1 (ADA homolog) also induces the IPR and promotes resistance against intracellular pathogens. Unlike PNP-1, ADAH-1 is essential for organismal development. Importantly, we find that supplementation of deoxyadenosine, a substrate for ADA, induces the IPR and promotes resistance to intracellular pathogens in C. elegans, a finding we extend to human cells. Thus, mutations in ADA and PNP induce innate immunity through increased deoxyadenosine, a phenomenon that is conserved from C. elegans to humans.
    Keywords:  cell biology; functional aspects of cell biology; immunity
    DOI:  https://doi.org/10.1016/j.isci.2025.111950
  65. Commun Biol. 2025 Mar 07. 8(1): 384
    Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.
    Hongxi Zhang, Nuo Ji, Shuxin Su, Meng Zhao, Huiyu Du, Lakesh Kumar Sahoo, Yi Wu, Yaoyu Feng, Nishith Gupta, Lihua Xiao, Ningbo Xia.
      Toxoplasma gondii, an intracellular pathogenic protist with a remarkable ability to infect a wide range of host cells, displays an equally exceptional design of its carbon metabolism. There are, however, critical gaps in our understanding of the metabolic network in T. gondii. We characterized the mito-nuclear metabolism and organelle coupling during its acute infection (lytic cycle). The major enzymes of the TCA cycle, i.e., citrate synthase (CS1), succinyl-CoA synthase alpha subunit (SCSα), succinate dehydrogenase (SDHA) and FAD malate dehydrogenase (MDH-FAD) located in the parasite mitochondrion support its asexual reproduction but are not needed for its survival. The SCSα and SDHA mutants are nearly avirulent in a mouse model, and they can protect the host against a lethal challenge infection. Genetic deletion of MDH-FAD dysregulated glucose-derived carbon flux, leading to a collapse of the mitochondrial membrane potential. The parasite also harbors a cytosolic isoform of MDH and a nuclear malic enzyme (ME) contributing to malate oxidation; however, only the latter is essential for the lytic cycle. Expression of ME in the nucleus is crucial for the parasite development. Besides, conditional knockdown of ME impairs the histone acetylation and disrupts the expression of several genes in tachyzoites. Our work discloses novel network design features of T. gondii and highlights the therapeutic and vaccination potential of the parasite metabolism.
    DOI:  https://doi.org/10.1038/s42003-025-07823-4
  66. J Lipid Res. 2025 Feb 26. pii: S0022-2275(25)00025-2. [Epub ahead of print] 100765
    Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function?
    Graeme I Lancaster, Andrew J Murphy.
      Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids (PLs). Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of PLs containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Such changes may impact the pathogenesis of diseases where ferroptosis is involved.
    DOI:  https://doi.org/10.1016/j.jlr.2025.100765
  67. Oncogene. 2025 Mar 01.
    PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression.
    Zhi Li, Yidi Guan, Jie Gao, Lan Zhu, Zimei Zeng, Qianyu Jing, Quan Wan, Qi Fan, Xinxin Ren, Haiping Pei, Dexiang Zhang, Yefei Rong, Zhuoxian Rong, Junju He, Yuefang Zhang, Nan Li, Pan Chen, Lunquan Sun, Bin Xu, Yingjie Nie, Yuezhen Deng.
      Tumor cells display profound changes in the metabolism of branched-chain amino acids (BCAA). However, how these changes are regulated to facilitate tumorigenesis is not yet completely understood. Here, we identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a BCAA-responsive protein through extensive screening using stable isotope labeling with amino acids in cell culture (SILAC). PPDPF is upregulated in cholangiocarcinoma to enhance the malignant phenotype of cholangiocarcinoma cells by activating the mTORC1 signaling pathway. Metabolic flux analysis and mechanistic studies revealed that PPDPF prevented the interaction between MCCA and MCCB, thus inhibiting leucine catabolism and activating mTORC1 signaling. Moreover, upon amino acid starvation, ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) and OTU deubiquitinase 4 (OTUD4) cooperatively regulated the stability of the PPDPF protein by modulating its ubiquitination. Additionally, monocytes/macrophage-derived IL-10 increased the BCAA content in cholangiocarcinoma cells and stabilized the PPDPF protein, even under amino acid starvation conditions. Knockout of PPDPF or restriction of leucine intake significantly inhibits the progression of cholangiocarcinoma in a mouse model. Collectively, we discovered a novel role for PPDPF in promoting the progression of cholangiocarcinoma by activating mTORC1 signaling through the inhibition of leucine catabolism. The present study suggests that targeting PPDPF or decreasing dietary leucine intake may provide a new strategy to improve the treatment efficacy of cholangiocarcinoma.
    DOI:  https://doi.org/10.1038/s41388-025-03320-4
  68. Clin Cancer Res. 2025 Mar 07.
    -----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.
    Eugenio Morelli, Caroline Fidalgo Ribeiro, Silvia D Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C Anderson, Giorgio Inghirami, Nikhil C Munshi, Massimo Loda.
       PURPOSE: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.
    EXPERIMENTAL DESIGN: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms.
    RESULTS: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
    CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2000
  69. J Mol Cell Biol. 2025 Mar 06. pii: mjaf007. [Epub ahead of print]
    Novel roles of ammonia in physiology and cancer.
    Guantong Chen, Chenxi Wang, Shuo Huang, Shibo Yang, Qiyuan Su, Yige Wang, Weiwei Dai.
      Ammonia, traditionally recognized as a toxic nitrogen waste product, has recently emerged as a significant player in diverse physiological processes and implicated in cancer biology. This review article provides an overview of the multifaceted impact of ammonia on cellular signaling pathways, energy metabolism, and tumor microenvironment dynamics, in particular its novel roles in neurotransmission, metabolic homeostasis, cancer cell proliferation, and immune modulation. Notably, ammonia accumulates within the tumor microenvironment, promoting non-essential amino acid synthesis, stimulating mTORC1 activation, promoting lipid synthesis, and impairing various immune cell functions, thereby promoting tumor progression. Furthermore, the potential dual role of ammonia as tumorigenic factor and cancer therapeutic target are discussed, shedding light on its complex regulatory mechanisms and clinical implications. This timely review aims to deepen our understanding of the emerging physiological and pathological roles of ammonia, offering valuable insights into its significance as a potential target for diagnostic and therapeutic interventions in cancer and beyond.
    Keywords:  ammonia; glutamine synthetase; mTOR; tumour microenvironment; urea cycle
    DOI:  https://doi.org/10.1093/jmcb/mjaf007
  70. Nat Genet. 2025 Mar 04.
    The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes.
    Alex Tokolyi, Elodie Persyn, Artika P Nath, Katie L Burnham, Jonathan Marten, Thomas Vanderstichele, Manuel Tardaguila, David Stacey, Ben Farr, Vivek Iyer, Xilin Jiang, Samuel A Lambert, Guillaume Noell, Michael A Quail, Diana Rajan, Scott C Ritchie, Benjamin B Sun, Scott A J Thurston, Yu Xu, Christopher D Whelan, Heiko Runz, Slavé Petrovski, Daniel J Gaffney, David J Roberts, Emanuele Di Angelantonio, James E Peters, Nicole Soranzo, John Danesh, Adam S Butterworth, Michael Inouye, Emma E Davenport, Dirk S Paul.
      The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans ( https://IntervalRNA.org.uk ).
    DOI:  https://doi.org/10.1038/s41588-025-02096-3
  71. Brief Bioinform. 2024 Nov 22. pii: bbaf072. [Epub ahead of print]26(1):
    scMitoMut for calling mitochondrial lineage-related mutations in single cells.
    Wenjie Sun, Daphne van Ginneken, Leïla Perié.
      Tracing cell lineages has become a valuable tool for studying biological processes. Among the available tools for human data, mitochondrial DNA (mtDNA) has a high potential due to its ability to be used in conjunction with single-cell chromatin accessibility data, giving access to the cell phenotype. Nonetheless, the existing mutation calling tools are ill-equipped to deal with the polyploid nature of the mtDNA and lack a robust statistical framework. Here we introduce scMitoMut, an innovative R package that leverages statistical methodologies to accurately identify mitochondrial lineage-related mutations at the single-cell level. scMitoMut assigns a mutation quality q-value based on beta-binomial distribution to each mutation at each locus within individual cells, ensuring higher sensitivity and precision of lineage-related mutation calling in comparison to current methodologies. We tested scMitoMut using single-cell DNA sequencing, single-cell transposase-accessible chromatin (scATAC) sequencing, and 10× Genomics single-cell multiome datasets. Using a single-cell DNA sequencing dataset from a mixed population of cell lines, scMitoMut demonstrated superior sensitivity in identifying a small proportion of cancer cell line compared to existing methods. In a human colorectal cancer scATAC dataset, scMitoMut identified more mutations than state-of-the-art methods. Applied to 10× Genomics multiome datasets, scMitoMut effectively measured the lineage distance in cells from blood or brain tissues. Thus, the scMitoMut is a freely available, and well-engineered toolkit (https://www.bioconductor.org/packages/devel/bioc/html/scMitoMut.html) for mtDNA mutation calling with high memory and computational efficiency. Consequently, it will significantly advance the application of single-cell sequencing, facilitating the precise delineation of mitochondrial mutations for lineage-tracing purposes in development, tumour, and stem cell biology.
    Keywords:  lineage tracing; mitochondrial mutation; single-cell sequencing
    DOI:  https://doi.org/10.1093/bib/bbaf072
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