bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–01–12
48 papers selected by
Christian Frezza, Universität zu Köln
  1. The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
  2. SLC7A5 is required for cancer cell growth under arginine-limited conditions.
  3. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  4. Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.
  5. Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
  6. α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
  7. Precursor occupancy controls mitochondrial import channel via proteolysis.
  8. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
  9. Tryptophan metabolite atlas uncovers organ, age, and sex-specific variations.
  10. Cellular and organismal function of choline metabolism.
  11. Advancing de novo lipogenesis: Genetic and metabolic insights.
  12. Hydrogen sulfide mediates the interaction between C. elegans and Actinobacteria from its natural microbial environment.
  13. KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
  14. Inferring metabolic objectives and trade-offs in single cells during embryogenesis.
  15. The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
  16. NAC regulates metabolism and cell fate in intestinal stem cells.
  17. Career pathways, part 16.
  18. Host metabolism balances microbial regulation of bile acid signalling.
  19. Mechanisms of metabolism-coupled protein modifications.
  20. Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.
  21. The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism.
  22. Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
  23. De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.
  24. Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer.
  25. The integrated stress response drives MET oncogene overexpression in cancers.
  26. Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
  27. Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.
  28. Making sense of gene expression control by flux sensing.
  29. MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
  30. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  31. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
  32. Fructose takes a detour to feed cancer.
  33. MDM2 functions as a timer reporting the length of mitosis.
  34. Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs.
  35. The hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair.
  36. Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
  37. Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.
  38. S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism.
  39. Low-avidity T cells drive endogenous tumor immunity in mice and humans.
  40. How a small but mighty protein protects a life-sustaining enzyme.
  41. Divergent roles for propionate and butyrate in colorectal cancer epigenetics.
  42. Complex rearrangements fuel ER+ and HER2+ breast tumours.
  43. Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.
  44. Systemic metabolic crosstalk as driver of cancer cachexia.
  45. Formation of I2+III2 supercomplex rescues respiratory chain defects.
  46. Conserved patterns of transcriptional dysregulation, heterogeneity, and cell states in clear cell kidney cancer.
  47. Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
  48. Multi-dimensional analyses identify genes of high priority for pancreatic cancer research.
  1. Nat Metab. 2025 Jan 06.
    The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
    Julius Palme, Ang Li, Michael Springer.
      Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of Saccharomyces cerevisiae, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p-GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation.
    DOI:  https://doi.org/10.1038/s42255-024-01181-x
  2. Cell Rep. 2025 Jan 03. pii: S2211-1247(24)01481-5. [Epub ahead of print]44(1): 115130
    SLC7A5 is required for cancer cell growth under arginine-limited conditions.
    Kyle N Dunlap, Austin Bender, Alexis Bowles, Alex J Bott, Joshua Tay, Allie H Grossmann, Jared Rutter, Gregory S Ducker.
      Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.
    Keywords:  CP: Cancer; CP: Metabolism; CRISPR screening; SLC7A5; amino acid transport; arginine; cancer metabolism; citrulline
    DOI:  https://doi.org/10.1016/j.celrep.2024.115130
  3. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  4. Nat Cell Biol. 2025 Jan 06.
    Metabolic rewiring in skin epidermis drives tolerance to oncogenic mutations.
    Anupama Hemalatha, Zongyu Li, David G Gonzalez, Catherine Matte-Martone, Karen Tai, Elizabeth Lathrop, Daniel Gil, Smirthy Ganesan, Lauren E Gonzalez, Melissa Skala, Rachel J Perry, Valentina Greco.
      Skin epithelial stem cells correct aberrancies induced by oncogenic mutations. Oncogenes invoke different strategies of epithelial tolerance; while wild-type cells outcompete β-catenin-gain-of-function (βcatGOF) cells, HrasG12V cells outcompete wild-type cells. Here we ask how metabolic states change as wild-type stem cells interface with mutant cells and drive different cell-competition outcomes. By tracking the endogenous redox ratio (NAD(P)H/FAD) with single-cell resolution in the same mouse over time, we discover that βcatGOF and HrasG12V mutations, when interfaced with wild-type epidermal stem cells, lead to a rapid drop in redox ratios, indicating more oxidized cellular redox. However, the resultant redox differential persists through time in βcatGOF, whereas it is flattened rapidly in the HrasG12Vmodel. Using 13C liquid chromatography-tandem mass spectrometry, we find that the βcatGOF and HrasG12V mutant epidermis increase the fractional contribution of glucose through the oxidative tricarboxylic acid cycle. Treatment with metformin, a modifier of cytosolic redox, inhibits downstream mutant phenotypes and reverses cell-competition outcomes of both mutant models.
    DOI:  https://doi.org/10.1038/s41556-024-01574-w
  5. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6
    Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
    Sijie Tan, Nora Kory.
      Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.006
  6. Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]
    α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
    Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.
      Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
    DOI:  https://doi.org/10.1182/blood.2024025245
  7. Nat Cell Biol. 2025 Jan 08.
    Precursor occupancy controls mitochondrial import channel via proteolysis.
      
    DOI:  https://doi.org/10.1038/s41556-024-01575-9
  8. Science. 2025 Jan 10. 387(6730): 192-201
    Bile acid synthesis impedes tumor-specific T cell responses during liver cancer.
    Siva Karthik Varanasi, Dan Chen, Yingluo Liu, Melissa A Johnson, Cayla M Miller, Souradipta Ganguly, Kathryn Lande, Michael A LaPorta, Filipe Araujo Hoffmann, Thomas H Mann, Marcos G Teneche, Eduardo Casillas, Kailash C Mangalhara, Varsha Mathew, Ming Sun, Isaac J Jensen, Yagmur Farsakoglu, Timothy Chen, Bianca Parisi, Shaunak Deota, Aaron Havas, Jin Lee, H Kay Chung, Andrea Schietinger, Satchidananda Panda, April E Williams, Donna L Farber, Debanjan Dhar, Peter D Adams, Gen-Sheng Feng, Gerald S Shadel, Mark S Sundrud, Susan M Kaech.
      The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
    DOI:  https://doi.org/10.1126/science.adl4100
  9. bioRxiv. 2024 Dec 23. pii: 2024.12.23.630041. [Epub ahead of print]
    Tryptophan metabolite atlas uncovers organ, age, and sex-specific variations.
    Lizbeth Perez-Castro, Afshan F Nawas, Jessica A Kilgore, Roy Garcia, M Carmen Lafita-Navarro, Paul H Acosta, Pedro A S Nogueira, Noelle S Williams, Maralice Conacci-Sorrell.
      Although tryptophan (Trp) is the largest and most structurally complex amino acid, it is the least abundant in the proteome. Its distinct indole ring and high carbon content enable it to generate various biologically active metabolites such as serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in diseases ranging from depression to cancer. Investigating Trp and its metabolites in healthy tissues offers pathways to target disease-associated disruptions selectively, while preserving essential functions. In this study, we comprehensively mapped Trp metabolites across the Kyn, serotonin, and I3P pathways, as well as the microbiome-derived metabolite tryptamine, in C57BL/6 mice. Our comprehensive analysis covered 12 peripheral organs, the central nervous system, and serum in both male and female mice at three life stages: young (3 weeks), adult (54 weeks), and aged (74 weeks). We found significant tissue-, sex-, and age-specific variations in Trp metabolism, with notably higher levels of the oncometabolites I3P and Kyn in aging males. These findings emphasize the value of organ-specific analysis of Trp metabolism for understanding its role in disease progression and identifying targeted therapeutic opportunities.
    AUTHOR SUMMARY: Trp metabolism has primarily been studied in cell lines, often leading to generalized assumptions about its role in health and disease. However, how Trp and its metabolites are allocated across tissues, sexes, and life stages has remained poorly understood. This gap is critical, as Trp is the largest amino acid, minimally used for protein synthesis, and largely metabolized in the liver, yet its distribution and metabolism in other tissues are unknown. Misconceptions, such as the idea that all cancers universally increase Kyn production, have contributed to therapeutic failures, highlighting the need for rigorous, tissue-specific studies. Our study systematically quantifies Trp metabolites across organs and tissues in vivo, revealing significant organ-, sex-, and age-specific variations. These findings provide a foundational resource for understanding Trp metabolism in normal physiology and disease, with potential applications in cancer, neurodegeneration, and other metabolic disorders.
    DOI:  https://doi.org/10.1101/2024.12.23.630041
  10. Nat Metab. 2025 Jan 08.
    Cellular and organismal function of choline metabolism.
    Timothy C Kenny, Samantha Scharenberg, Monther Abu-Remaileh, Kıvanç Birsoy.
      Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.
    DOI:  https://doi.org/10.1038/s42255-024-01203-8
  11. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00483-2. [Epub ahead of print]37(1): 3-4
    Advancing de novo lipogenesis: Genetic and metabolic insights.
    Sean M Hartig, Mark A Herman.
      De novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.001
  12. Cell Rep. 2025 Jan 08. pii: S2211-1247(24)01521-3. [Epub ahead of print]44(1): 115170
    Hydrogen sulfide mediates the interaction between C. elegans and Actinobacteria from its natural microbial environment.
    Om Patange, Peter Breen, Giulia Arsuffi, Gary Ruvkun.
      Caenorhabditis elegans proliferates poorly in the presence of abundant Actinobacteria from its natural ecology, but it is unknown why. Here, we show how perturbed levels of hydrogen sulfide modulate the growth rate of both C. elegans and Actinobacteria. From a forward genetic selection, we find C. elegans mutants with faster growth on an Actinobacteria Microbacterium species and mutant alleles of conserved cystathionine gamma-lyase (cth-2/CTH) that improve growth rate. Conversely, null alleles of cth-2 cause developmental arrest of animals grown on Actinobacteria, but not on Proteobacteria, which can be rescued by exogenous H2S. We also find mutations in a leucine-rich-repeat gene that regulates cysteine and H2S production, lrr-2/LRRC58. We place lrr-2 in the animal sulfur metabolism pathway by demonstrating its role in post-translationally regulating levels of cysteine dioxygenase (cdo-1/CDO1). Exogenously supplied H2S inhibits the growth of Actinobacteria but not Proteobacteria. Thus, we conclude that the C. elegans-Actinobacteria interaction is mediated by H2S.
    Keywords:  Actinobacteria; C. elegans; CP: Developmental biology; CP: Metabolism; H(2)S; cdo-1/CDO1; cth-2/CTH; ecology; lrr-2/LRRC58
    DOI:  https://doi.org/10.1016/j.celrep.2024.115170
  13. Nat Commun. 2025 Jan 08. 16(1): 480
    KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
    Samah W Awwad, Colm Doyle, Josie Coulthard, Aldo S Bader, Nadia Gueorguieva, Simon Lam, Vipul Gupta, Rimma Belotserkovskaya, Tuan-Anh Tran, Shankar Balasubramanian, Stephen P Jackson.
      ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.
    DOI:  https://doi.org/10.1038/s41467-024-55637-5
  14. Cell Syst. 2024 Dec 31. pii: S2405-4712(24)00370-3. [Epub ahead of print] 101164
    Inferring metabolic objectives and trade-offs in single cells during embryogenesis.
    Da-Wei Lin, Ling Zhang, Jin Zhang, Sriram Chandrasekaran.
      While proliferating cells optimize their metabolism to produce biomass, the metabolic objectives of cells that perform non-proliferative tasks are unclear. The opposing requirements for optimizing each objective result in a trade-off that forces single cells to prioritize their metabolic needs and optimally allocate limited resources. Here, we present single-cell optimization objective and trade-off inference (SCOOTI), which infers metabolic objectives and trade-offs in biological systems by integrating bulk and single-cell omics data, using metabolic modeling and machine learning. We validated SCOOTI by identifying essential genes from CRISPR-Cas9 screens in embryonic stem cells, and by inferring the metabolic objectives of quiescent cells, during different cell-cycle phases. Applying this to embryonic cell states, we observed a decrease in metabolic entropy upon development. We further uncovered a trade-off between glutathione and biosynthetic precursors in one-cell zygote, two-cell embryo, and blastocyst cells, potentially representing a trade-off between pluripotency and proliferation. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  genome-scale metabolic modeling; machine learning; metabolic networks; metabolomics; proteomics; stem cells; transcriptomics
    DOI:  https://doi.org/10.1016/j.cels.2024.12.005
  15. Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01505-5. [Epub ahead of print]44(1): 115154
    The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
    Jaromir Novak, Zuzana Nahacka, Gabriela L Oliveira, Petra Brisudova, Maria Dubisova, Sarka Dvorakova, Sona Miklovicova, Marketa Dalecka, Verena Puttrich, Lenka Grycova, Silvia Magalhaes-Novais, Catarina Mendes Correia, Jennifer Levoux, Ludek Stepanek, Jan Prochazka, David Svec, David Pajuelo Reguera, Guillermo Lopez-Domenech, Renata Zobalova, Radek Sedlacek, Mikkel G Terp, Payam A Gammage, Zdenek Lansky, Josef Kittler, Paulo J Oliveira, Henrik J Ditzel, Michael V Berridge, Anne-Marie Rodriguez, Stepana Boukalova, Jakub Rohlena, Jiri Neuzil.
      Recent research has shown that mtDNA-deficient cancer cells (ρ0 cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1KO) mice markedly delayed tumor formation after grafting ρ0 cancer cells. Miro1KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ0 cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs.
    Keywords:  CP: Cancer; CP: Cell biology; Miro1; RHOT1; cancer; horizontal transfer of mitochondria; melanoma; mitochondria; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.celrep.2024.115154
  16. Sci Adv. 2025 Jan 10. 11(2): eadn9750
    NAC regulates metabolism and cell fate in intestinal stem cells.
    Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.
      Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
    DOI:  https://doi.org/10.1126/sciadv.adn9750
  17. Nat Metab. 2025 Jan 07.
    Career pathways, part 16.
    Cholsoon Jang, Min-Dian Li.
      
    DOI:  https://doi.org/10.1038/s42255-024-01192-8
  18. Nature. 2025 Jan 08.
    Host metabolism balances microbial regulation of bile acid signalling.
    JRI Live Cell Bank
      Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2-4, immune responses5-7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08379-9
  19. Nat Chem Biol. 2025 Jan 07.
    Mechanisms of metabolism-coupled protein modifications.
    Bingsen Zhang, Frank C Schroeder.
      Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of 'modification of a modification', as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41589-024-01805-z
  20. Nat Metab. 2025 Jan 09.
    Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.
    Michael Nshanian, Joshua J Gruber, Benjamin S Geller, Faye Chleilat, Samuel M Lancaster, Shannon M White, Ludmila Alexandrova, Jeannie M Camarillo, Neil L Kelleher, Yingming Zhao, Michael P Snyder.
      The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation and ion transport. We propose a mechanism involving direct modification of specific genomic regions by SCFAs resulting in increased chromatin accessibility and, in the case of butyrate, opposing effects on the proliferation of normal versus CRC cells.
    DOI:  https://doi.org/10.1038/s42255-024-01191-9
  21. PLoS Biol. 2025 Jan;23(1): e3002996
    The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism.
    Steffen N Lindner, Markus Ralser.
      The structure of the early metabolic network is unknown. Here, we report that when considered together, pentose utilization pathways form all life-essential precursors. We speculate that the chemistry preserved in pentose metabolism could therefore have been a central structural element in early metabolism.
    DOI:  https://doi.org/10.1371/journal.pbio.3002996
  22. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2403862122
    Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
    Noa Furth, Niv Cohen, Avishay Spitzer, Tomer-Meir Salame, Bareket Dassa, Tevie Mehlman, Alexander Brandis, Arieh Moussaieff, Dinorah Friedmann-Morvinski, Maria G Castro, Jerome Fortin, Mario L Suvà, Itay Tirosh, Ayelet Erez, Guy Ron, Efrat Shema.
      Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.
    Keywords:  CyTOF; chromatin; epigenetics; mutant-IDH1; oncometabolite
    DOI:  https://doi.org/10.1073/pnas.2403862122
  23. Redox Biol. 2024 Dec 31. pii: S2213-2317(24)00458-0. [Epub ahead of print]80 103480
    De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.
    Beatriz Puente-Cobacho, Cintia Esteo, Patricia Altea-Manzano, Jose Luis Garcia-Perez, José L Quiles, Pedro Sanchez-Rovira, María D Martín-Salvago, Lucía Molina-Jiménez, Rafael J Luque, Sarah-Maria Fendt, Laura Vera-Ramirez.
      Dormant disseminated tumor cells (DTCs) remain viable for years to decades before establishing a clinically overt metastatic lesion. DTCs are known to be highly resilient and able to overcome the multiple biological hurdles imposed along the metastatic cascade. However, the specific metabolic adaptations of dormant DTCs remain to be elucidated. Here, we reveal that dormant DTCs upregulate de novo lipogenesis and favor the activation and incorporation of monounsaturated fatty acids (MUFAs) to their cellular membranes through the activation of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3). Pharmacologic inhibition of de novo lipogenesis or genetic knockdown of ACSL3 results in lipid peroxidation and non-apoptotic cell death through ferroptosis. Clinically, ACSL3 was found to be overexpressed in quiescent DTCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Our work provides new insights into the molecular mechanisms enabling the survival of dormant DTCs and supports the use of de novo lipogenesis inhibitors to prevent breast cancer metastasis.
    Keywords:  Breast cancer; Ferroptosis; Lipid metabolism; Lipid peroxidation; Metastasis; Monounsaturated fatty acids activation; Tumor cell dormancy
    DOI:  https://doi.org/10.1016/j.redox.2024.103480
  24. Cell Rep. 2025 Jan 03. pii: S2211-1247(24)01479-7. [Epub ahead of print]44(1): 115128
    Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer.
    Ge Li, Zhenke Wen, Sidong Xiong.
      CD8+ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8+ T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8+ Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC.
    Keywords:  CP: Cancer; CP: Immunology; NSCLC; T cell exhaustion; amino acid transport; β-TrCP
    DOI:  https://doi.org/10.1016/j.celrep.2024.115128
  25. EMBO J. 2025 Jan 07.
    The integrated stress response drives MET oncogene overexpression in cancers.
    Marina Cerqua, Marco Foiani, Carla Boccaccio, Paolo M Comoglio, Dogus M Altintas.
      Cancer cells rely on invasive growth to survive in a hostile microenvironment; this growth is characterised by interconnected processes such as epithelial-to-mesenchymal transition and migration. A master regulator of these events is the MET oncogene, which is overexpressed in the majority of cancers; however, since mutations in the MET oncogene are seen only rarely in cancers and are relatively infrequent, the mechanisms that cause this widespread MET overexpression remain obscure. Here, we show that the 5' untranslated region (5'UTR) of MET mRNA harbours two functional stress-responsive elements, conferring translational regulation by the integrated stress response (ISR), regulated by phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) at serine 52. ISR activation by serum starvation, leucine deprivation, hypoxia, irradiation, thapsigargin or gemcitabine is followed by MET protein overexpression. We mechanistically link MET translation to the ISR by (i) mutation of the two uORFs within the MET 5'UTR, (ii) CRISPR/Cas9-mediated mutation of eIF2α (S52A), or (iii) the application of ISR pathway inhibitors. All of these interventions reduce stress-induced MET overexpression. Finally, we show that blocking stress-induced MET translation blunts MET-dependent invasive growth. These findings indicate that upregulation of the MET oncogene is a functional requirement linking integrated stress response to cancer progression.
    Keywords:  Integrated Stress Response; Invasive Growth; MET Oncogene
    DOI:  https://doi.org/10.1038/s44318-024-00338-4
  26. Cancer Res. 2025 Jan 09.
    Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
    Steven Tau, Mary D Chamberlin, Huijuan Yang, Jonathan D Marotti, Patricia C Muskus, Alyssa M Roberts, Melissa M Carmichael, Lauren Cressey, Christo Philip C Dragnev, Eugene Demidenko, Riley A Hampsch, Shannon M Soucy, Fred W Kolling, Kimberley S Samkoe, James V Alvarez, Arminja N Kettenbach, Todd W Miller.
      Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1204
  27. Antioxidants (Basel). 2024 Dec 19. pii: 1563. [Epub ahead of print]13(12):
    Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.
    Milagros Junco, Clara Ventura, Florencia Ximena Santiago Valtierra, Eduardo Nestor Maldonado.
      Cancer metabolism is sustained both by enhanced aerobic glycolysis, characteristic of the Warburg phenotype, and oxidative metabolism. Cell survival and proliferation depends on a dynamic equilibrium between mitochondrial function and glycolysis, which is heterogeneous between tumors and even within the same tumor. During oxidative phosphorylation, electrons from NADH and FADH2 originated in the tricarboxylic acid cycle flow through complexes of the electron transport chain. Single electron leaks at specific complexes of the electron transport chain generate reactive oxygen species (ROS). ROS are a concentration-dependent double-edged sword that plays multifaceted roles in cancer metabolism. ROS serve either as signaling molecules favoring cellular homeostasis and proliferation or damage DNA, protein and lipids, causing cell death. Several aspects of ROS biology still remain unsolved. Among the unknowns are the actual levels at which ROS become cytotoxic and if toxicity depends on specific ROS species or if it is caused by a cumulative effect of all of them. In this review, we describe mechanisms of mitochondrial ROS production, detoxification, ROS-induced cytotoxicity, and the use of antioxidants in cancer treatment. We also provide updated information about critical questions on the biology of ROS on cancer metabolism and discuss dogmas that lack adequate experimental demonstration. Overall, this review brings a comprehensive perspective of ROS as drivers of cancer progression, inducers of cell death, and the potential use of antioxidants as anticancer therapy.
    Keywords:  ROS; VDAC; antioxidants; cancer; lipid peroxidation; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/antiox13121563
  28. Nat Metab. 2025 Jan 06.
    Making sense of gene expression control by flux sensing.
    Bas Teusink, Robert Planqué, Frank J Bruggeman.
      
    DOI:  https://doi.org/10.1038/s42255-024-01182-w
  29. Bioinform Adv. 2025 ;5(1): vbae172
    MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
    Stephen Chapman, Theo Brunet, Arnaud Mourier, Bianca H Habermann.
       Motivation: Mitochondria are essential for cellular metabolism and are inherently flexible to allow correct function in a wide range of tissues. Consequently, dysregulated mitochondrial metabolism affects different tissues in different ways leading to challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is useful in studying tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism in research, no mouse specific mitochondrial metabolic model is currently available.
    Results: Building upon the similarity between human and mouse mitochondrial metabolism, we present mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is able to model mouse and human mitochondrial metabolism. To demonstrate this, using an adapted E-Flux algorithm, we integrated proteomic data from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue, as well as transcriptomic data from in vitro differentiated human brown adipocytes and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research in cardiac disease and diabetes in both mouse and human contexts.
    Availability and implementation: The MitoMammal Jupyter Notebook is available at: https://gitlab.com/habermann_lab/mitomammal.
    DOI:  https://doi.org/10.1093/bioadv/vbae172
  30. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
  31. Nat Commun. 2025 Jan 09. 16(1): 541
    CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
    Dorian V Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving, Lluis Fajas.
      The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
    DOI:  https://doi.org/10.1038/s41467-024-55605-z
  32. Nat Rev Cancer. 2025 Jan 08.
    Fructose takes a detour to feed cancer.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-024-00789-1
  33. Nat Cell Biol. 2025 Jan 09.
    MDM2 functions as a timer reporting the length of mitosis.
    Luke J Fulcher, Tomoaki Sobajima, Caleb Batley, Ian Gibbs-Seymour, Francis A Barr.
      Delays in mitosis trigger p53-dependent arrest in G1 of the next cell cycle, thus preventing repeated cycles of chromosome instability and aneuploidy. Here we show that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises due to the attenuation of protein synthesis in mitosis. Because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration, the amount of MDM2 gradually falls during mitosis but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilizing p53. Subsequent p53-dependent p21 accumulation then channels G1 cells into a sustained cell-cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.
    DOI:  https://doi.org/10.1038/s41556-024-01592-8
  34. Cell Rep. 2025 Jan 04. pii: S2211-1247(24)01504-3. [Epub ahead of print]44(1): 115153
    Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs.
    Kitra Cates, Luorongxin Yuan, Yan Yang, Andrew S Yoo.
      Neurogenic microRNAs 9/9∗ and 124 (miR-9/9∗-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9∗-124 fate erasure logic extends to the neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9∗-124 induces neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell-type-specific and pan-somatic gene network erasure induced by miR-9/9∗-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53), whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9∗-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9∗-124, and shows a neurogenic role for p53 inhibition in the miR-9/9∗-124 signaling cascade.
    Keywords:  CP: Molecular biology; CP: Stem cell research; cell fate; direct conversion; fate erasure; microRNA; neuronal reprogramming; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115153
  35. Nat Metab. 2025 Jan 07.
    The hepatic clock synergizes with HIF-1α to regulate nucleotide availability during liver damage repair.
    Linyuan Peng, Siliang Xiang, Tianzhi Wang, Mei Yang, Yajun Duan, Xiaoyu Ma, Su Li, Cong Yu, Xin Zhang, Haiyang Hu, Zuojun Liu, Jie Sun, Chunmeng Sun, Chen Wang, Baohua Liu, Zhongyuan Wang, Minxian Qian.
      Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy.
    DOI:  https://doi.org/10.1038/s42255-024-01184-8
  36. J Cell Biol. 2025 Mar 03. pii: e202404084. [Epub ahead of print]224(3):
    Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
    Agustian Surya, Blythe Marie Bolton, Reed Rothe, Raquel Mejia-Trujillo, Amanda Leonita, Qiuxia Zhao, Alia Arya, Yue Liu, Rekha Rangan, Yasash Gorusu, Pamela Nguyen, Can Cenik, Elif Sarinay Cenik.
      The interplay between ribosomal protein (RP) composition and mitochondrial function is essential for energy homeostasis. Balanced RP production optimizes protein synthesis while minimizing energy costs, but its impact on mitochondrial functionality remains unclear. Here, we investigated haploinsufficiency for RP genes (rps-10, rpl-5, rpl-33, and rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Significant mitochondrial morphological differences, upregulation of glutathione transferases, and SKN-1-dependent oxidative stress resistance were observed across mutants. Loss of a Datasingle rps-10 copy reduced mitochondrial activity, energy levels, and oxygen consumption, mirrored by similar reductions in mitochondrial activity and energy levels in lymphoblast cells with 50% lower RPS10 transcripts. Both systems exhibited altered translation efficiency (TE) of mitochondrial electron transport chain components, suggesting a conserved mechanism to adjust mitochondrial protein synthesis under ribosomal stress. Finally, mitochondrial membrane and cytosolic RPs showed significant RNA and TE covariation in lymphoblastoid cells, highlighting the interplay between protein synthesis machinery and mitochondrial energy production.
    DOI:  https://doi.org/10.1083/jcb.202404084
  37. Cancer Discov. 2025 Jan 08.
    Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.
    Ángel Fernández-Sanromán, Annika Fendler, Benjy J Y Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T C Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J S Furness, Kate Young, David Nicol, Sarah Maria Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic.
      While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0499
  38. Nat Commun. 2025 Jan 08. 16(1): 509
    S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism.
    Min Yang, Weiwei Cui, Xiaoting Lv, Gaozhong Xiong, Caiyu Sun, Haocheng Xuan, Wei Ma, Xiuling Cui, Yeping Cheng, Lihui Han, Bo Chu.
      Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. However, emerging evidence indicates that hepatocellular carcinoma (HCC) cells are generally resistant to ferroptosis and the underlying molecular mechanism is poorly understood. Here, our study confirms that S100 calcium binding protein P (S100P), which is significantly up-regulated in ferroptosis-resistant HCC cells, efficiently inhibits ferroptosis. Mechanistically, S100P facilitates lysosomal degradation of acetyl-CoA carboxylase alpha (ACC1), which is indispensable for de novo biosynthesis of lipids. Loss of S100P elevates the expression of ACC1 and promotes ferroptotic sensitivity of HCC cells. S100P-mediated ACC1 degradation relies on RAB5C, which directs ACC1 to lysosome via P62-dependent selective autophagy. Knockdown of RAB5C or P62 abrogates S100P-induced lysosomal degradation of ACC1 and restores resistance of HCC cells to ferroptosis. Our work reveals an alternative anti-ferroptosis pathway and suggests S100P as a promising druggable target for ferroptosis-related therapy of HCC.
    DOI:  https://doi.org/10.1038/s41467-024-55785-8
  39. Nat Immunol. 2025 Jan 09.
    Low-avidity T cells drive endogenous tumor immunity in mice and humans.
    Summit Singhaviranon, Joseph P Dempsey, Adam T Hagymasi, Ion I Mandoiu, Pramod K Srivastava.
      T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor-peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an 'avidity score', which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies.
    DOI:  https://doi.org/10.1038/s41590-024-02044-z
  40. Nature. 2025 Jan 08.
    How a small but mighty protein protects a life-sustaining enzyme.
    Amy C Rosenzweig.
      
    Keywords:  Biochemistry; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-04108-4
  41. Nat Metab. 2025 Jan 09.
    Divergent roles for propionate and butyrate in colorectal cancer epigenetics.
    Yuen Jian Cheong, Sophie Trefely.
      
    DOI:  https://doi.org/10.1038/s42255-024-01186-6
  42. Nature. 2025 Jan 08.
    Complex rearrangements fuel ER+ and HER2+ breast tumours.
    Kathleen E Houlahan, Lise Mangiante, Cristina Sotomayor-Vivas, Alvina Adimoelja, Seongyeol Park, Aziz Khan, Sophia J Pribus, Zhicheng Ma, Jennifer L Caswell-Jin, Christina Curtis.
      Breast cancer is a highly heterogeneous disease whose prognosis and treatment as defined by the expression of three receptors-oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2; encoded by ERBB2)-is insufficient to capture the full spectrum of clinical outcomes and therapeutic vulnerabilities. Previously, we demonstrated that transcriptional and genomic profiles define eleven integrative subtypes with distinct clinical outcomes, including four ER+ subtypes with increased risk of relapse decades after diagnosis1,2. Here, to determine whether these subtypes reflect distinct evolutionary histories, interactions with the immune system and pathway dependencies, we established a meta-cohort of 1,828 breast tumours spanning pre-invasive, primary invasive and metastatic disease with whole-genome and transcriptome sequencing. We demonstrate that breast tumours fall along a continuum constrained by three genomic archetypes. The ER+ high-risk integrative subgroup is characterized by complex focal amplifications, similar to HER2+ tumours, including cyclic extrachromosomal DNA amplifications induced by ER through R-loop formation and APOBEC3B-editing, which arise in pre-invasive lesions. By contrast, triple-negative tumours exhibit genome-wide instability and tandem duplications and are enriched for homologous repair deficiency-like signatures, whereas ER+ typical-risk tumours are largely genomically stable. These genomic archetypes, which replicate in an independent cohort of 2,659 primary tumours, are established early during tumorigenesis, sculpt the tumour microenvironment and are conserved in metastatic disease. These complex structural alterations contribute to replication stress and immune evasion, and persist throughout tumour evolution, unveiling potential vulnerabilities.
    DOI:  https://doi.org/10.1038/s41586-024-08377-x
  43. bioRxiv. 2024 Dec 27. pii: 2024.12.27.630525. [Epub ahead of print]
    Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.
    Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner.
      Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and drug candidates for both lean MASLD and support of urea cycle function in CD.
    DOI:  https://doi.org/10.1101/2024.12.27.630525
  44. Trends Endocrinol Metab. 2025 Jan 04. pii: S1043-2760(24)00327-8. [Epub ahead of print]
    Systemic metabolic crosstalk as driver of cancer cachexia.
    Elisabeth Wyart, Giovanna Carrà, Elia Angelino, Fabio Penna, Paolo E Porporato.
      Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.
    Keywords:  cachexia; cross-talk; metabolism; muscle wasting
    DOI:  https://doi.org/10.1016/j.tem.2024.12.005
  45. Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]
    Formation of I2+III2 supercomplex rescues respiratory chain defects.
    Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.
      Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.
    Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
  46. Cell Rep. 2025 Jan 08. pii: S2211-1247(24)01520-1. [Epub ahead of print]44(1): 115169
    Conserved patterns of transcriptional dysregulation, heterogeneity, and cell states in clear cell kidney cancer.
    Olivia Lombardi, Ran Li, Faiz Jabbar, Hannah Evans, Silvia Halim, Joanna D C C Lima, Lisa Browning, Helen M Byrne, Hani Choudhry, Peter J Ratcliffe, David R Mole.
      Clear cell kidney cancers are characterized both by conserved oncogenic driver events and by marked intratumor genetic and phenotypic heterogeneity, which help drive tumor progression, metastasis, and resistance to therapy. How these are reflected in transcriptional programs within the cancer and stromal cell components remains an important question with the potential to drive novel therapeutic approaches to treating cancer. To better understand these programs, we perform single-cell transcriptomics on 75 multi-regional biopsies from kidney tumors and normal kidney. We identify conserved patterns of transcriptional dysregulation and their upstream regulators within the tumor and associated vasculature. We describe recurrent subclonal transcriptional consequences of Chr14q loss linked to metastatic potential. We identify prognostically significant conserved patterns of intratumor transcriptional heterogeneity. These reflect co-existing cell states found in both cancer cells and normal kidney cells, indicating that rather than arising from genetic heterogeneity they are a consequence of lineage plasticity.
    Keywords:  CP: Cancer; CP: Genomics; HIF; VHL; aneuploidy; ccRCC; evolution; heterogeneity; hypoxia; plasticity; single-cell; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115169
  47. Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01523-7. [Epub ahead of print]44(1): 115172
    Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
    Juliana Escher Toller-Kawahisa, Paula Ramos Viacava, Eva Margareta Palsson-McDermott, Daniele Carvalho Nascimento, Mariana Patricia Cervantes-Silva, Shane Myles O'Carroll, Alessia Zotta, Luis Eduardo Alves Damasceno, Gabriel Azevedo Públio, Pedro Forti, João Paulo Mesquita Luiz, Bruno Marcel Silva de Melo, Timna Varela Martins, Vitor Marcel Faça, Annie Curtis, Thiago Mattar Cunha, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.
      Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.
    Keywords:  CP: Immunology; CP: Metabolism; IL-10; PKM2; adenosine; macrophage; mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115172
  48. JCI Insight. 2025 Jan 07. pii: e174264. [Epub ahead of print]
    Multi-dimensional analyses identify genes of high priority for pancreatic cancer research.
    Zeribe C Nwosu, Heather Giza, Maya Nassif, Verodia Charlestin, Rosa E Menjivar, Daeho Kim, Samantha B Kemp, Peter Sajjakulnukit, Anthony Andren, Li Zhang, William Km Lai, Ian Loveless, Nina G Steele, Jiantao Hu, Biao Hu, Shaomeng Wang, Marina Pasca di Magliano, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDAC) is a drug resistant and lethal cancer. Identification of the genes that consistently show altered expression across patients' cohorts can expose effective therapeutic targets and strategies. To identify such genes, we separately analyzed five human PDAC microarray datasets. We defined genes as 'consistent' if upregulated or downregulated in ≥ 4 datasets (adjusted P<0.05). The genes were subsequently queried in additional datasets, including single-cell RNA-sequencing data, and we analyzed their pathway enrichment, tissue-specificity, essentiality for cell viability, association with cancer features e.g., tumor subtype, proliferation, metastasis and poor survival outcome. We identified 2,010 consistently upregulated and 1,928 downregulated genes of which >50%, to our knowledge, were uncharacterized in PDAC. These genes spanned multiple processes, including cell cycle, immunity, transport, metabolism, signaling and transcriptional/epigenetic regulation - cell cycle and glycolysis being the most altered. Several upregulated genes correlated with cancer features, and their suppression impaired PDAC cell viability in prior CRISPR/Cas9 and RNA interference screens. Further, the upregulated genes predicted sensitivity to bromodomain and extraterminal (epigenetic) protein inhibition, which, in combination with gemcitabine, disrupted amino acid metabolism and in vivo tumor growth. Our results highlight genes for further studies in the quest for PDAC mechanisms, therapeutic targets and biomarkers.
    Keywords:  Cancer; Gastroenterology; Glucose metabolism; Molecular genetics; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.174264
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒12 at 6:39.