bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–10–27
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Glutamine sensing licenses cholesterol synthesis.
  2. Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.
  3. Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.
  4. Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
  5. Mitochondrial fatty acid oxidation drives senescence.
  6. A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
  7. Sulfur metabolism under stress: Oxidized glutathione inhibits methionine biosynthesis by destabilizing the enzyme cystathionine γ-synthase.
  8. Glycolysis: A multifaceted metabolic pathway and signalling hub.
  9. Cyclophilin D plays a critical role in the survival of senescent cells.
  10. Osteopontin is a therapeutic target that drives breast cancer recurrence.
  11. iTraNet: a web-based platform for integrated trans-omics network visualization and analysis.
  12. Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
  13. Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
  14. PRC2-EZH1 contributes to circadian gene expression by orchestrating chromatin states and RNA polymerase II complex stability.
  15. When Do Tumours Develop? Neoplastic Processes Across Different Timescales: Age, Season and Round the Circadian Clock.
  16. SRSF2 safeguards efficient transcription of DNA damage and repair genes.
  17. O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer.
  18. Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
  19. Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis.
  20. Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.
  21. One-shot 13C15N-metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux.
  22. Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
  23. P-stalk ribosomes act as master regulators of cytokine-mediated processes.
  24. Using human disease mutations to understand de novo DNA methyltransferase function.
  25. USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.
  26. A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint.
  27. Transgelin 2 guards T cell lipid metabolism and antitumour function.
  28. Allometric scaling of somatic mutation and epimutation rates in trees.
  29. METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
  30. ERMCS Ca2+ transmission fuels cell division.
  31. The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
  32. Convergent inducers and effectors of T cell paralysis in the tumour microenvironment.
  33. Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
  34. Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
  35. Generation of Murine Cancer Cell Lines.
  36. Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues.
  37. Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
  38. Differential stiffness between brain vasculature and parenchyma promotes metastatic infiltration through vessel co-option.
  39. Single-cell chemoproteomics identifies metastatic activity signatures in breast cancer.
  40. Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer.
  41. Hierarchy or Heterarchy of Mammalian Circadian Timekeepers?
  42. Crosstalk between the circatidal and circadian clocks mediates behavioral adaptation to tidal patterns.
  43. Mitochondrial DNA damage, repair, and replacement in cancer.
  44. Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.
  45. Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function.
  46. Nuclear release of eIF1 restricts start-codon selection during mitosis.
  47. The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
  1. EMBO J. 2024 Oct 21.
    Glutamine sensing licenses cholesterol synthesis.
    Bruna Martins Garcia, Philipp Melchinger, Tania Medeiros, Sebastian Hendrix, Kavan Prabhu, Mauro Corrado, Jenina Kingma, Andrej Gorbatenko, Soni Deshwal, Matteo Veronese, Luca Scorrano, Erika Pearce, Patrick Giavalisco, Noam Zelcer, Lena Pernas.
      The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.
    Keywords:  Cholesterol; HMGCR; MFN2; Nutrient Sensing; SREBP2
    DOI:  https://doi.org/10.1038/s44318-024-00269-0
  2. Cell Chem Biol. 2024 Oct 14. pii: S2451-9456(24)00404-5. [Epub ahead of print]
    Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.
    Kelly H Sokol, Cameron J Lee, Thomas J Rogers, Althea Waldhart, Abigail E Ellis, Sahithi Madireddy, Samuel R Daniels, Rachel Rae J House, Xinyu Ye, Mary Olesnavich, Amy Johnson, Benjamin R Furness, Ryan D Sheldon, Evan C Lien.
      Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.
    Keywords:  cancer; ferroptosis; lipid metabolism; phospholipids; polyunsaturated fatty acids; triglycerides
    DOI:  https://doi.org/10.1016/j.chembiol.2024.09.008
  3. EMBO Mol Med. 2024 Oct 21.
    Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis.
    Tobias Ackermann, Engy Shokry, Ruhi Deshmukh, Jayanthi Anand, Laura C A Galbraith, Louise Mitchell, Giovanny Rodriguez-Blanco, Victor H Villar, Britt Amber Sterken, Colin Nixon, Sara Zanivan, Karen Blyth, David Sumpton, Saverio Tardito.
      The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.
    Keywords:  Breast Cancer; Ferroptosis; Lipid Metabolism; Metastasis; Selenium Metabolism
    DOI:  https://doi.org/10.1038/s44321-024-00142-x
  4. Nat Cell Biol. 2024 Oct 21.
    Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.
    Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont.
      Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission. Strikingly, mitochondrial fission is also a general mechanotransduction mechanism. Indeed, we found that DRP1- and MIEF1/2-dependent fission is required and sufficient to regulate three transcription factors of broad relevance-YAP/TAZ, SREBP1/2 and NRF2-to control cell proliferation, lipogenesis, antioxidant metabolism, chemotherapy resistance and adipocyte differentiation in response to mechanical cues. This extends to the mouse liver, where DRP1 regulates hepatocyte proliferation and identity-hallmark YAP-dependent phenotypes. We propose that mitochondria fulfil a unifying signalling function by which the mechanical tissue microenvironment coordinates complementary cell functions.
    DOI:  https://doi.org/10.1038/s41556-024-01527-3
  5. Sci Adv. 2024 Oct 25. 10(43): eado5887
    Mitochondrial fatty acid oxidation drives senescence.
    Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.
      Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
    DOI:  https://doi.org/10.1126/sciadv.ado5887
  6. Cell. 2024 Oct 19. pii: S0092-8674(24)00903-6. [Epub ahead of print]
    A two-front nutrient supply environment fuels small intestinal physiology through differential regulation of nutrient absorption and host defense.
    Jian Zhang, Ruonan Tian, Jia Liu, Jie Yuan, Siwen Zhang, Zhexu Chi, Weiwei Yu, Qianzhou Yu, Zhen Wang, Sheng Chen, Mobai Li, Dehang Yang, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Rongbin Zhou, Xue Zhang, Wanlu Liu, Di Wang.
      The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment.
    Keywords:  adaptation; breakfast skipping; in vivo metabolite tracing; metabolic heterogeneity; multi-omics; the small intestine; two-front nutrient supply; zonated function of enterocyte
    DOI:  https://doi.org/10.1016/j.cell.2024.08.012
  7. J Integr Plant Biol. 2024 Oct 23.
    Sulfur metabolism under stress: Oxidized glutathione inhibits methionine biosynthesis by destabilizing the enzyme cystathionine γ-synthase.
    Yael Hacham, Alex Kaplan, Elad Cohen, Maayan Gal, Rachel Amir.
      Cysteine is the precursor for the biosynthesis of glutathione, a key stress-protective metabolite, and methionine, which is imperative for cell growth and protein synthesis. The exact mechanism that governs the routing of cysteine toward glutathione or methionine during stresses remains unclear. Our study reveals that under oxidative stress, methionine and glutathione compete for cysteine and that the increased oxidized glutathione (GSSG) levels under stress hinder methionine biosynthesis. Moreover, we find that inhibition occurs as GSSG binds to and accelerates the degradation of cystathionine γ-synthase, a key enzyme in the methionine synthesis pathway. Consequently, this leads to a reduction in the flux toward methionine-derived metabolites and redirects cysteine utilization toward glutathione, thereby enhancing plant protection. Our study suggests a novel regulatory feedback loop involving glutathione, methionine, and cysteine, shedding light on the plant stress response and the adaptive rerouting of cysteine. These findings offer new insights into the intricate balance of growth and protection in plants and its impact on their nutritional value due to low methionine levels under stress.
    Keywords:  cystathionine γ‐synthase (CGS); cysteine; glutathione; metabolic competition; methionine; oxidative stress; sulfur metabolism; tobacco
    DOI:  https://doi.org/10.1111/jipb.13799
  8. J Biol Chem. 2024 Oct 21. pii: S0021-9258(24)02408-6. [Epub ahead of print] 107906
    Glycolysis: A multifaceted metabolic pathway and signalling hub.
    Sarah J Kierans, Cormac T Taylor.
      Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilised by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g. hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signalling hub, producing several metabolic intermediates which serve roles in both signalling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype and fate, and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signalling molecules in eukaryotic cells, emphasising the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107906
  9. EMBO J. 2024 Oct 24.
    Cyclophilin D plays a critical role in the survival of senescent cells.
    Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.
      Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
    Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering
    DOI:  https://doi.org/10.1038/s44318-024-00259-2
  10. Nat Commun. 2024 Oct 24. 15(1): 9174
    Osteopontin is a therapeutic target that drives breast cancer recurrence.
    Yu Gu, Tarek Taifour, Tung Bui, Dongmei Zuo, Alain Pacis, Alexandre Poirier, Sherif Attalla, Anne-Marie Fortier, Virginie Sanguin-Gendreau, Tien-Chi Pan, Vasilios Papavasiliou, Nancy U Lin, Melissa E Hughes, Kalie Smith, Morag Park, Michel L Tremblay, Lewis A Chodosh, Rinath Jeselsohn, William J Muller.
      Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin's multiaxial role in breast cancer progression and recurrence.
    DOI:  https://doi.org/10.1038/s41467-024-53023-9
  11. Bioinform Adv. 2024 ;4(1): vbae141
    iTraNet: a web-based platform for integrated trans-omics network visualization and analysis.
    Hikaru Sugimoto, Keigo Morita, Dongzi Li, Yunfan Bai, Matthias Mattanovich, Shinya Kuroda.
       Motivation: Visualization and analysis of biological networks play crucial roles in understanding living systems. Biological networks include diverse types, from gene regulatory networks and protein-protein interactions to metabolic networks. Metabolic networks include substrates, products, and enzymes, which are regulated by allosteric mechanisms and gene expression. However, the analysis of these diverse omics types is challenging due to the diversity of databases and the complexity of network analysis.
    Results: We developed iTraNet, a web application that visualizes and analyses trans-omics networks involving four types of networks: gene regulatory networks, protein-protein interactions, metabolic networks, and metabolite exchange networks. Using iTraNet, we found that in wild-type mice, hub molecules within the network tended to respond to glucose administration, whereas in ob/ob mice, this tendency disappeared. With its ability to facilitate network analysis, we anticipate that iTraNet will help researchers gain insights into living systems.
    Availability and implementation: iTraNet is available at https://itranet.streamlit.app/.
    DOI:  https://doi.org/10.1093/bioadv/vbae141
  12. J Vis Exp. 2024 Oct 04.
    Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
    Terri A Pietka, Rita T Brookheart.
      Mitochondrial function, a cornerstone of cellular energy production, is critical for maintaining metabolic homeostasis. Its dysfunction in skeletal muscle is linked to prevalent metabolic disorders (e.g., diabetes and obesity), muscular dystrophies, and sarcopenia. While there are many techniques to evaluate mitochondrial content and morphology, the hallmark method to assess mitochondrial function is the measurement of mitochondrial oxidative phosphorylation (OXPHOS) by respirometry. Quantification of mitochondrial OXPHOS provides insight into the efficiency of mitochondrial oxidative energy production and cellular bioenergetics. A high-resolution respirometer provides highly sensitive, robust measurements of mitochondrial OXPHOS in permeabilized muscle fibers by measuring real-time changes in mitochondrial oxygen consumption rate. The use of permeabilized muscle fibers, as opposed to isolated mitochondria, preserves mitochondrial networks, maintains mitochondrial membrane integrity, and ultimately allows for more physiologically relevant measurements. This system also allows for the measurement of fuel preference and metabolic flexibility - dynamic aspects of muscle energy metabolism. Here, we provide a comprehensive guide for mitochondrial OXPHOS measurements in human and mouse skeletal muscle fibers using a high-resolution respirometer. Skeletal muscle groups are composed of different fiber types that vary in their mitochondrial fuel preference and bioenergetics. Using a high-resolution respirometer, we describe methods for evaluating both aerobic glycolytic and fatty acid substrates to assess fuel preference and metabolic flexibility in a fiber-type-dependent manner. The protocol is versatile and applicable to both human and rodent muscle fibers. The goal is to enhance the reproducibility and accuracy of mitochondrial function assessments, which will improve our understanding of an organelle important to muscle health.
    DOI:  https://doi.org/10.3791/66834
  13. Nat Commun. 2024 Oct 24. 15(1): 9181
    Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
    Leighton H Daigh, Debarya Saha, David L Rosenthal, Katherine R Ferrick, Tobias Meyer.
      DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
    DOI:  https://doi.org/10.1038/s41467-024-52820-6
  14. EMBO J. 2024 Oct 21.
    PRC2-EZH1 contributes to circadian gene expression by orchestrating chromatin states and RNA polymerase II complex stability.
    Peng Liu, Seba Nadeef, Maged F Serag, Andreu Paytuví-Gallart, Maram Abadi, Francesco Della Valle, Santiago Radío, Xènia Roda, Jaïr Dilmé Capó, Sabir Adroub, Nadine Hosny El Said, Bodor Fallatah, Mirko Celii, Gian Marco Messa, Mengge Wang, Mo Li, Paola Tognini, Lorena Aguilar-Arnal, Satoshi Habuchi, Selma Masri, Paolo Sassone-Corsi, Valerio Orlando.
      Circadian rhythmicity of gene expression is a conserved feature of cell physiology. This involves fine-tuning between transcriptional and post-transcriptional mechanisms and strongly depends on the metabolic state of the cell. Together these processes guarantee an adaptive plasticity of tissue-specific genetic programs. However, it is unclear how the epigenome and RNA Pol II rhythmicity are integrated. Here we show that the PcG protein EZH1 has a gateway bridging function in postmitotic skeletal muscle cells. On the one hand, the circadian clock master regulator BMAL1 directly controls oscillatory behavior and periodic assembly of core components of the PRC2-EZH1 complex. On the other hand, EZH1 is essential for circadian gene expression at alternate Zeitgeber times, through stabilization of RNA Polymerase II preinitiation complexes, thereby controlling nascent transcription. Collectively, our data show that PRC2-EZH1 regulates circadian transcription both negatively and positively by modulating chromatin states and basal transcription complex stability.
    Keywords:  Circadian Rhythm; EZH1; H3K27me3; Transcription
    DOI:  https://doi.org/10.1038/s44318-024-00267-2
  15. Evol Appl. 2024 Oct;17(10): e70024
    When Do Tumours Develop? Neoplastic Processes Across Different Timescales: Age, Season and Round the Circadian Clock.
    Margaux Bieuville, Antoine M Dujon, Nynke Raven, Beata Ujvari, Pascal Pujol, Zahra Eslami-S, Catherine Alix Panabières, Jean-Pascal Capp, Frédéric Thomas.
      While it is recognised that most, if not all, multicellular organisms harbour neoplastic processes within their bodies, the timing of when these undesirable cell proliferations are most likely to occur and progress throughout the organism's lifetime remains only partially documented. Due to the different mechanisms implicated in tumourigenesis, it is highly unlikely that this probability remains constant at all times and stages of life. In this article, we summarise what is known about this variation, considering the roles of age, season and circadian rhythm. While most studies requiring that level of detail be done on humans, we also review available evidence in other animal species. For each of these timescales, we identify mechanisms or biological functions shaping the variation. When possible, we show that evolutionary processes likely played a role, either directly to regulate the cancer risk or indirectly through trade-offs. We find that neoplastic risk varies with age in a more complex way than predicted by early epidemiological models: rather than resulting from mutations alone, tumour development is dictated by tissue- and age-specific processes. Similarly, the seasonal cycle can be associated with risk variation in some species with life-history events such as sexual competition or mating being timed according to the season. Lastly, we show that the circadian cycle influences tumourigenesis in physiological, pathological and therapeutic contexts. We also highlight two biological functions at the core of these variations across our three timescales: immunity and metabolism. Finally, we show that our understanding of the entanglement between tumourigenic processes and biological cycles is constrained by the limited number of species for which we have extensive data. Improving our knowledge of the periods of vulnerability to the onset and/or progression of (malignant) tumours is a key issue that deserves further investigation, as it is key to successful cancer prevention strategies.
    Keywords:  age; circadian rhythm; evolution; neoplasia risk; season; senescence
    DOI:  https://doi.org/10.1111/eva.70024
  16. Cell Rep. 2024 Oct 23. pii: S2211-1247(24)01220-8. [Epub ahead of print]43(11): 114869
    SRSF2 safeguards efficient transcription of DNA damage and repair genes.
    Rebecca E Wagner, Leonie Arnetzl, Thiago Britto-Borges, Anke Heit-Mondrzyk, Ali Bakr, Etienne Sollier, Nikoletta A Gkatza, Jasper Panten, Sylvain Delaunay, Daniela Sohn, Peter Schmezer, Duncan T Odom, Karin Müller-Decker, Christoph Plass, Christoph Dieterich, Pavlo Lutsik, Susanne Bornelöv, Michaela Frye.
      The serine-/arginine-rich splicing factor 2 (SRSF2) plays pivotal roles in pre-mRNA processing and gene transcription. Recurrent mutations, particularly a proline-to-histidine substitution at position 95 (P95H), are common in neoplastic diseases. Here, we assess SRSF2's diverse functions in squamous cell carcinoma. We show that SRSF2 deletion or homozygous P95H mutation both cause extensive DNA damage leading to cell-cycle arrest. Mechanistically, SRSF2 regulates efficient bi-directional transcription of DNA replication and repair genes, independent from its function in splicing. Further, SRSF2 haploinsufficiency induces DNA damage without halting the cell cycle. Exposing mouse skin to tumor-promoting carcinogens enhances the clonal expansion of heterozygous Srsf2 P95H epidermal cells but unexpectedly inhibits tumor formation. To survive carcinogen treatment, Srsf2 P95H+/- cells undergo substantial transcriptional rewiring and restore bi-directional gene expression. Thus, our study underscores SRSF2's importance in regulating transcription to orchestrate the cell cycle and the DNA damage response.
    Keywords:  CP: Cancer; CP: Molecular biology; DNA damage; DNA repair; DNA replication; Transcription; bi-directional promoters; epithelia; skin
    DOI:  https://doi.org/10.1016/j.celrep.2024.114869
  17. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2408354121
    O-GlcNAcylation of enolase 1 serves as a dual regulator of aerobic glycolysis and immune evasion in colorectal cancer.
    Qiang Zhu, Jingchao Li, Haofan Sun, Zhiya Fan, Jiating Hu, Siyuan Chai, Bingyi Lin, Liming Wu, Weijie Qin, Yong Wang, Linda C Hsieh-Wilson, Wen Yi.
      Aerobic glycolysis and immune evasion are two key hallmarks of cancer. However, how these two features are mechanistically linked to promote tumor growth is not well understood. Here, we show that the glycolytic enzyme enolase-1 (ENO1) is dynamically modified with an O-linked β-N-acetylglucosamine (O-GlcNAcylation), and simultaneously regulates aerobic glycolysis and immune evasion via differential glycosylation. Glycosylation of threonine 19 (T19) on ENO1 promotes its glycolytic activity via the formation of active dimers. On the other hand, glycosylation of serine 249 (S249) on ENO1 inhibits its interaction with PD-L1, decreases association of PD-L1 with the E3 ligase STUB1, resulting in stabilization of PD-L1. Consequently, blockade of T19 glycosylation on ENO1 inhibits glycolysis, and decreases cell proliferation and tumor growth. Blockade of S249 glycosylation on ENO1 reduces PD-L1 expression and enhances T cell-mediated immunity against tumor cells. Notably, elimination of glycosylation at both sites synergizes with PD-L1 monoclonal antibody therapy to promote antitumor immune response. Clinically, ENO1 glycosylation levels are up-regulated and show a positive correlation with PD-L1 levels in human colorectal cancers. Thus, our findings provide a mechanistic understanding of how O-GlcNAcylation bridges aerobic glycolysis and immune evasion to promote tumor growth, suggesting effective therapeutic opportunities.
    Keywords:  O-GlcNAcylation; cancer; enolase; glycolysis; immune evasion
    DOI:  https://doi.org/10.1073/pnas.2408354121
  18. Cell Stem Cell. 2024 Oct 18. pii: S1934-5909(24)00329-1. [Epub ahead of print]
    Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
    Yawen Li, Yalin He, Qi Zheng, Jiazhu Zhang, Xinwen Pan, Xi Zhang, Huairui Yuan, Guangchuan Wang, Xin Liu, Xiaolong Zhou, Xueliang Zhu, Tao Ren, Pengfei Sui.
      Basal cells (BCs) are the progenitor cells responsible for tracheal epithelium integrity. Here, we demonstrate that mitochondrial pyruvate carriers (MPCs) act as metabolic checkpoints that are essential for BC fate decision. Inhibition of MPCs enables long-term expansion of BCs from both mice and humans. Genetic inactivation of Mpc2 in mice leads to BC hyperplasia and reduced ciliated cells during homeostasis, as well as delayed epithelial regeneration and accumulation of intermediate cells following injury. Mechanistically, MPC2 links glycolysis to ATP citrate lyase (ACLY)-dependent cytosolic acetyl-coenzyme A (CoA) generation, which is required for the epigenetic control of differentiation-related gene transcription. Modulating this metabolic-epigenetic axis partially rescues Yes-associated protein (YAP)-dysfunction-induced changes in BCs. Importantly, exogenous citrate promotes the differentiation of BCs from chronic obstructive lung disease (COPD) patients. Thus, beyond demonstrating the role of pyruvate metabolism in BC fate decision, our study suggests that targeting pyruvate-citrate metabolism may serve as a potential strategy to rectify abnormal BC behavior in lung diseases.
    Keywords:  airway; cell fate decision; injury repair; lung basal progenitor cell; lung epithelium homeostasis; lung progenitor cell metabolism; mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1016/j.stem.2024.09.015
  19. Nat Cancer. 2024 Oct 22.
    Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis.
    Leona A Nease, Kellsey P Church, Ines Delclaux, Shino Murakami, Maider Astorkia, Marwa Zerhouni, Graciela Cascio, Riley O Hughes, Kelsey N Aguirre, Paul Zumbo, Lukas E Dow, Samie Jaffrey, Doron Betel, Elena Piskounova.
      Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process and is dependent on two tRNASec isodecoders differing by a single 2'-O-ribose methylation called Um34. Here we characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and show decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.
    DOI:  https://doi.org/10.1038/s43018-024-00844-8
  20. Biochim Biophys Acta Mol Cell Res. 2024 Oct 20. pii: S0167-4889(24)00205-2. [Epub ahead of print]1872(1): 119862
    Mitoception, or transfer of normal cell mitochondria to cancer cells, reverses remodeling of store-operated Ca2+ entry in tumor cells.
    Verónica Feijóo, Sendoa Tajada, Alejandra Méndez-Mena, Lucía Núñez, Carlos Villalobos.
      Most cancer cells show the Warburg effect, the rewiring of aerobic metabolism to glycolysis due to defective mitochondrial ATP synthesis. As a consequence, tumor cells display enhanced mitochondrial potential (∆Ψ), the driving force for mitochondrial Ca2+ uptake. Mitochondria control the Ca2+-dependent inactivation of store-operated channels (SOCs), leading to enhanced and sustained store-operated Ca2+ entry (SOCE) involved in cancer hallmarks. We asked here whether the transfer of mitochondria (mitoception) from normal cells to tumor cells may reverse SOCE remodeling in cancer cells. For this end, we labeled mitochondria in normal NCM460 human colonic cells, isolated them and transferred them to tumor HT29 cells. We tested the viability and efficiency of mitoception using flow cytometry and confocal microscopy, as well as calcium imaging to investigate the effects of mitoception on SOCE. Our results show that mitoception of tumor HT29 cells with normal mitochondria restores a low ∆Ψ and SOCE. Conversely, self-mitoception of tumor HT29 cells with tumor cell mitochondria increases further ∆Ψ and SOCE, thus excluding the possibility that effects of mitoception are due to increased mitochondrial mass. Strikingly, mitoception of normal NCM460 cells with tumor cell mitochondria has no effects on either ∆Ψ or SOCE. These results are consistent with the previous proposal that transformed mitochondria may modulate SOC channels involved in SOCE. Further research is warranted to test whether mitoception of cancer cells with normal mitochondria may reverse Ca2+ remodeling associated to cancer.
    Keywords:  Colon cancer; Mitoception; Mitochondria; Store-operated Ca(2+) entry
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119862
  21. Mol Syst Biol. 2023 Jan 27. 19(3): MSB202211099
    One-shot 13C15N-metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux.
    Khushboo Borah Slater, Martin Beyß, Ye Xu, Jim Barber, Catia Costa, Jane Newcombe, Axel Theorell, Melanie J Bailey, Dany J V Beste, Johnjoe McFadden, Katharina Nöh.
      Metabolic flux is the final output of cellular regulation and has been extensively studied for carbon but much less is known about nitrogen, which is another important building block for living organisms. For the tuberculosis pathogen, this is particularly important in informing the development of effective drugs targeting the pathogen's metabolism. Here we performed 13C15N dual isotopic labeling of Mycobacterium bovis BCG steady state cultures, quantified intracellular carbon and nitrogen fluxes and inferred reaction bidirectionalities. This was achieved by model scope extension and refinement, implemented in a multi-atom transition model, within the statistical framework of Bayesian model averaging (BMA). Using BMA-based 13C15N-metabolic flux analysis, we jointly resolve carbon and nitrogen fluxes quantitatively. We provide the first nitrogen flux distributions for amino acid and nucleotide biosynthesis in mycobacteria and establish glutamate as the central node for nitrogen metabolism. We improved resolution of the notoriously elusive anaplerotic node in central carbon metabolism and revealed possible operation modes. Our study provides a powerful and statistically rigorous platform to simultaneously infer carbon and nitrogen metabolism in any biological system.
    Keywords:  Bayesian metabolic flux analysis; Mycobacterium tuberculosis ; carbon metabolism; isotope labeling; nitrogen metabolism
    DOI:  https://doi.org/10.15252/msb.202211099
  22. Nat Cardiovasc Res. 2024 Oct 21.
    Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury.
    Farid F Kadyrov, Andrew L Koenig, Junedh M Amrute, Hao Dun, Wenjun Li, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Andrea L Bredemeyer, Steven Yang, Shibali Das, Vinay R Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J Kopecky, Daniel Kreisel, Kory J Lavine.
      Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia-reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.
    DOI:  https://doi.org/10.1038/s44161-024-00553-6
  23. Cell. 2024 Oct 14. pii: S0092-8674(24)01139-5. [Epub ahead of print]
    P-stalk ribosomes act as master regulators of cytokine-mediated processes.
    Anna Dopler, Ferhat Alkan, Yuval Malka, Rob van der Kammen, Kelly Hoefakker, Daniel Taranto, Naz Kocabay, Iris Mimpen, Christel Ramirez, Elke Malzer, Olga I Isaeva, Mandy Kerkhoff, Anastasia Gangaev, Joana Silva, Sofia Ramalho, Liesbeth Hoekman, Maarten Altelaar, Roderick Beijersbergen, Leila Akkari, Jonathan Wilson Yewdell, Pia Kvistborg, William James Faller.
      Inflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an "alert state" that enhances their visibility to the immune system. Here, we identified an alert-state subpopulation of ribosomes defined by the presence of the P-stalk. We show that P-stalk ribosomes (PSRs) are formed in response to cytokines linked to tumor immunity, and this is at least partially mediated by P-stalk phosphorylation. PSRs are involved in the preferential translation of mRNAs vital for the cytokine response via the more efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the PSR inhibits CD8+ T cell recognition and killing, and inhibitory cytokines like transforming growth factor β (TGF-β) hinder PSR formation, suggesting that the PSR is a central regulatory hub upon which multiple signals converge. Thus, the PSR is an essential mediator of the cellular rewiring that occurs following cytokine exposure via the translational regulation of this process.
    Keywords:  P-stalk; T cells; cytokines; melanoma; ribosome
    DOI:  https://doi.org/10.1016/j.cell.2024.09.039
  24. Biochem Soc Trans. 2024 Oct 24. pii: BST20231017. [Epub ahead of print]
    Using human disease mutations to understand de novo DNA methyltransferase function.
    Willow Rolls, Marcus D Wilson, Duncan Sproul.
      DNA methylation is a repressive epigenetic mark that is pervasive in mammalian genomes. It is deposited by DNA methyltransferase enzymes (DNMTs) that are canonically classified as having de novo (DNMT3A and DNMT3B) or maintenance (DNMT1) function. Mutations in DNMT3A and DNMT3B cause rare Mendelian diseases in humans and are cancer drivers. Mammalian DNMT3 methyltransferase activity is regulated by the non-catalytic region of the proteins which contain multiple chromatin reading domains responsible for DNMT3A and DNMT3B recruitment to the genome. Characterising disease-causing missense mutations has been central in dissecting the function and regulation of DNMT3A and DNMT3B. These observations have also motivated biochemical studies that provide the molecular details as to how human DNMT3A and DNMT3B mutations drive disorders. Here, we review progress in this area highlighting recent work that has begun dissecting the function of the disordered N-terminal regions of DNMT3A and DNMT3B. These studies have elucidated that the N-terminal regions of both proteins mediate novel chromatin recruitment pathways that are central in our understanding of human disease mechanisms. We also discuss how disease mutations affect DNMT3A and DNMT3B oligomerisation, a process that is poorly understood in the context of whole proteins in cells. This dissection of de novo DNMT function using disease-causing mutations provides a paradigm of how genetics and biochemistry can synergise to drive our understanding of the mechanisms through which chromatin misregulation causes human disease.
    Keywords:  cancer; epigenetics; genetic disease; methylation
    DOI:  https://doi.org/10.1042/BST20231017
  25. Oncogene. 2024 Oct 23.
    USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.
    Michaela Reissland, Oliver Hartmann, Saskia Tauch, Jeroen M Bugter, Cristian Prieto-Garcia, Clemens Schulte, Sinah Loebbert, Daniel Solvie, Eliya Bitman-Lotan, Ashwin Narain, Anne-Claire Jacomin, Christina Schuelein-Voelk, Carmina T Fuss, Nikolett Pahor, Carsten Ade, Viktoria Buck, Michael Potente, Vivian Li, Gerti Beliu, Armin Wiegering, Tom Grossmann, Martin Eilers, Elmar Wolf, Hans Maric, Mathias Rosenfeldt, Madelon M Maurice, Ivan Dikic, Peter Gallant, Amir Orian, Markus E Diefenbacher.
      The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.
    DOI:  https://doi.org/10.1038/s41388-024-03141-x
  26. Nat Commun. 2024 Oct 23. 15(1): 9114
    A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint.
    Xuetong Wang, Tongfeng Liu, Yifei Li, Ao Ding, Chang Zhang, Yinmin Gu, Xujie Zhao, Shuwen Cheng, Tianyou Cheng, Songzhe Wu, Liqiang Duan, Jihang Zhang, Rong Yin, Man Shang, Shan Gao.
      The immune checkpoint receptor, programmed cell death 1 (PD-1, encoded by PDCD1), mediates the immune escape of cancer, but whether PD-1 splicing isoforms contribute to this process is still unclear. Here, we identify an alternative splicing isoform of human PD-1, which carries a 28-base pairs extension retained from 5' region of intron 2 (PD-1^28), is expressed in peripheral T cells and tumor infiltrating lymphocytes. PD-1^28 expression is induced on T cells upon activation and is regulated by an RNA binding protein, TAF15. Functionally, PD-1^28 inhibits T cell proliferation, cytokine production, and tumor cell killing in vitro. In vivo, T cell-specific exogenous expression of PD-1^28 promotes tumor growth in both a syngeneic mouse tumor model and humanized NOG mice inoculated with human lung cancer cells. Our study thus demonstrates that PD-1^28 functions as an immune checkpoint, and may contribute to resistance to immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1038/s41467-024-53561-2
  27. Nature. 2024 Oct 23.
    Transgelin 2 guards T cell lipid metabolism and antitumour function.
    Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito A Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matías Marin Falco, Camilla Salvagno, Alexander Emmanuelli, Ian T McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana K Morales, Xiaoqing Yu, Paulo C Rodriguez, Jose R Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan R Cubillos-Ruiz.
      Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells4,5. However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8+ T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8+ T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8+ T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
    DOI:  https://doi.org/10.1038/s41586-024-08071-y
  28. Evolution. 2024 Oct 21. pii: qpae150. [Epub ahead of print]
    Allometric scaling of somatic mutation and epimutation rates in trees.
    Frank Johannes.
      How long-lived trees escape "mutational meltdown" despite centuries of continuous growth remains puzzling. Here we integrate recent studies to show that the yearly rate of somatic mutations and epimutations (μY) scales inversely with generation time (G), and follows the same allometric power law found in mammals (μY∝G-1). Deeper insights into the scaling function may permit predictions of somatic (epi)mutation rates from life-history traits without the need for genomic data.
    DOI:  https://doi.org/10.1093/evolut/qpae150
  29. Nat Commun. 2024 Oct 22. 15(1): 9110
    METASPACE-ML: Context-specific metabolite annotation for imaging mass spectrometry using machine learning.
    Bishoy Wadie, Lachlan Stuart, Christopher M Rath, Bernhard Drotleff, Sergii Mamedov, Theodore Alexandrov.
      Imaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.
    DOI:  https://doi.org/10.1038/s41467-024-52213-9
  30. Trends Cell Biol. 2024 Oct 21. pii: S0962-8924(24)00208-3. [Epub ahead of print]
    ERMCS Ca2+ transmission fuels cell division.
    Muniswamy Madesh, Neelanjan Vishnu, Dhanendra Tomar.
      Mitosis is a cellular process that demands high energy, but it was previously unclear how this process is linked with mitochondrial ATP production. Zhao et al. describe how during mitosis, the lamin B receptor migrates to the ER membrane to enhance ER-mitochondria contact sites, coordinating Ca2+ surges that increase ATP production necessary for cell division.
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.002
  31. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2401218121
    The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
    Yumei Yang, Baomin Wang, Haoru Dong, Huige Lin, Melody Yuen-Man Ho, Ke Hu, Na Zhang, Jing Ma, Rong Xie, Kenneth King-Yip Cheng, Xiaomu Li.
      Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.
    Keywords:  MDM2; cellular senescence; diabetes; p53; pyruvate carboxylase
    DOI:  https://doi.org/10.1073/pnas.2401218121
  32. Nat Rev Cancer. 2024 Oct 24.
    Convergent inducers and effectors of T cell paralysis in the tumour microenvironment.
    Douglas Hanahan, Olivier Michielin, Mikael J Pittet.
      Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.
    DOI:  https://doi.org/10.1038/s41568-024-00761-z
  33. Nat Commun. 2024 Oct 22. 15(1): 9098
    Dissected antiporter modules establish minimal proton-conduction elements of the respiratory complex I.
    Adel Beghiah, Patricia Saura, Sofia Badolato, Hyunho Kim, Johanna Zipf, Dirk Auman, Ana P Gamiz-Hernandez, Johan Berg, Grant Kemp, Ville R I Kaila.
      The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts in recent decades, its long-range energy transduction principles remain highly debated. We create here minimal proton-conducting membrane modules by engineering and dissecting the key elements of the bacterial Complex I. By combining biophysical, biochemical, and computational experiments, we show that the isolated antiporter-like modules of Complex I comprise all functional elements required for conducting protons across proteoliposome membranes. We find that the rate of proton conduction is controlled by conformational changes of buried ion-pairs that modulate the reaction barriers by electric field effects. The proton conduction is also modulated by bulky residues along the proton channels that are key for establishing a tightly coupled proton pumping machinery in Complex I. Our findings provide direct experimental evidence that the individual antiporter modules are responsible for the proton transport activity of Complex I. On a general level, our findings highlight electrostatic and conformational coupling mechanisms in the modular energy-transduction machinery of Complex I with distinct similarities to other enzymes.
    DOI:  https://doi.org/10.1038/s41467-024-53194-5
  34. Nature. 2024 Oct 23.
    Chromatin remodelling drives immune cell-fibroblast communication in heart failure.
    Michael Alexanian, Arun Padmanabhan, Tomohiro Nishino, Joshua G Travers, Lin Ye, Angelo Pelonero, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Kirsten Auclair, Ada Zhu, Yuqian An, Christina A Ekstrand, Cassandra Martinez, Barbara Gonzalez Teran, Will R Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Zachary Gardner, Li Li, Mauro W Costa, Rajan Jain, Israel Charo, Alexis J Combes, Saptarsi M Haldar, Katherine S Pollard, Ronald J Vagnozzi, Timothy A McKinsey, Pawel F Przytycki, Deepak Srivastava.
      Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.
    DOI:  https://doi.org/10.1038/s41586-024-08085-6
  35. Curr Protoc. 2024 Oct;4(10): e70037
    Generation of Murine Cancer Cell Lines.
    Cheryl Zhang, Anthony Lin, Xiang Chen, Yi-Chieh Nancy Du.
      Cancer cell lines are important tools to investigate the biology of cancer and test hypotheses to improve cancer treatments. A major challenge in establishing epithelial cancer cell lines is the removal of cancer-associated fibroblasts (CAFs). CAFs are abundant within the tumor microenvironment. CAFs generally proliferate faster than epithelial cancer cells in culture. CAFs can be mistakenly identified as cancer cells, especially when cancer cells display spindle-shaped morphology. Among all cancer types, pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. Here, we describe protocols for establishing epithelial cancer cell lines from mouse models of PDAC and verifying that they are not CAFs. The approach is cost-effective and can be used for other types of cancer. If needed, CAF cell lines can also be established and preserved using this protocol. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Isolation of cells from tumors Basic Protocol 2: Isolation and cryopreservation of cancer cell clones Basic Protocol 3: Assessment of the identity of cancer cell lines and CAFs by western blotting.
    Keywords:  cell culture; cell line; epithelial cancer cells; fibroblast; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/cpz1.70037
  36. Mol Biol Rep. 2024 Oct 19. 51(1): 1071
    Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues.
    E M Sadeesh, Anuj Malik, Madhuri S Lahamge, Pratiksha Singh.
       BACKGROUND: Buffaloes are crucial to agriculture, yet mitochondrial biology in these animals is less studied compared to humans and laboratory animals. This research examines tissue-specific variations in mitochondrial succinate dehydrogenase (SDH) gene expression across buffalo kidneys, hearts, brains, and ovaries. Understanding these variations sheds light on mitochondrial energy metabolism and its impact on buffalo health and productivity, revealing insights into enzyme regulation and potential improvements in livestock management.
    MATERIALS AND METHODS: RNA-seq data from buffalo kidney, heart, brain, and ovary tissues were reanalyzed to explore mitochondrial SDH gene expression. The expression of SDH subunits (SDHA, SDHB, SDHC, SDHD) and assembly factors (SDHAF1, SDHAF2, SDHAF3, SDHAF4) was assessed using a log2 fold-change threshold of + 1 for up-regulated and - 1 for down-regulated transcripts, with significance set at p < 0.05. Hierarchical clustering and differential expression analyses were performed to identify tissue-specific expression patterns and regulatory mechanisms, while Gene Ontology and KEGG pathway analyses were conducted to uncover functional attributes and pathway enrichments across different tissues.
    RESULTS: Reanalysis of RNA-seq data from different tissues of healthy female buffaloes revealed distinct expression patterns for SDH subunits and assembly factors. While SDHA, SDHB, and SDHC showed variable expression across tissues, SDHAF2, SDHAF3, and SDHAF4 exhibited tissue-specific profiles. Significant up-regulation of SDHA, SDHB, and several assembly factors was observed in specific tissue comparisons, with fewer down-regulated transcripts. Gene ontology and KEGG pathway analyses linked the up-regulated transcripts to mitochondrial ATP synthesis and the respiratory electron transport chain. Notably, tissue-specific variations in mitochondrial function were particularly evident in the ovary.
    CONCLUSION: This study identifies distinct SDH gene expression patterns in buffalo tissues, highlighting significant down-regulation of SDHA, SDHB, SDHC, and assembly factors in the ovary. These findings underscore the critical role of mitochondria in tissue-specific energy production and metabolic regulation, suggest potential metabolic adaptations, and emphasize the importance of mitochondrial complex II. The insights gained offer valuable implications for improving feed efficiency and guiding future research and therapies for energy metabolism disorders.
    Keywords:   SDH expression; Buffalo tissues; Energy production; Metabolic insights; Mitochondria
    DOI:  https://doi.org/10.1007/s11033-024-10022-9
  37. Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549
    Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
    Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.
      Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.
    Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.arr.2024.102549
  38. Nat Cell Biol. 2024 Oct 24.
    Differential stiffness between brain vasculature and parenchyma promotes metastatic infiltration through vessel co-option.
    Marina Uroz, Amy E Stoddard, Bryan P Sutherland, Olivia Courbot, Roger Oria, Linqing Li, Cara R Ravasio, Mai T Ngo, Jinling Yang, Juliann B Tefft, Jeroen Eyckmans, Xue Han, Alberto Elosegui-Artola, Valerie M Weaver, Christopher S Chen.
      In brain metastasis, cancer cells remain in close contact with the existing vasculature and can use vessels as migratory paths-a process known as vessel co-option. However, the mechanisms regulating this form of migration are poorly understood. Here we use ex vivo brain slices and an organotypic in vitro model for vessel co-option to show that cancer cell invasion along brain vasculature is driven by the difference in stiffness between vessels and the brain parenchyma. Imaging analysis indicated that cells move along the basal surface of vessels by adhering to the basement membrane extracellular matrix. We further show that vessel co-option is enhanced by both the stiffness of brain vasculature, which reinforces focal adhesions through a talin-dependent mechanism, and the softness of the surrounding environment that permits cellular movement. Our work reveals a mechanosensing mechanism that guides cell migration in response to the tissue's intrinsic mechanical heterogeneity, with implications in cancer invasion and metastasis.
    DOI:  https://doi.org/10.1038/s41556-024-01532-6
  39. Sci Adv. 2024 Oct 25. 10(43): eadp2622
    Single-cell chemoproteomics identifies metastatic activity signatures in breast cancer.
    Kavya Smitha Pillai, Olivia Laxton, Gang Li, Jing Lin, Olga Karginova, Rita Nanda, Olufunmilayo I Olopade, Savaş Tay, Raymond E Moellering.
      Protein activity state, rather than protein or mRNA abundance, is a biologically regulated and relevant input to many processes in signaling, differentiation, development, and diseases such as cancer. While there are numerous methods to detect and quantify mRNA and protein abundance in biological samples, there are no general approaches to detect and quantify endogenous protein activity with single-cell resolution. Here, we report the development of a chemoproteomic platform, single-cell activity-dependent proximity ligation, which uses automated, microfluidics-based single-cell capture and nanoliter volume manipulations to convert the interactions of family-wide chemical activity probes with native protein targets into multiplexed, amplifiable oligonucleotide barcodes. We demonstrate accurate, reproducible, and multiplexed quantitation of a six-enzyme (Ag-6) panel with known ties to cancer cell aggressiveness directly in single cells. We further identified increased Ag-6 enzyme activity across breast cancer cell lines of increasing metastatic potential, as well as in primary patient-derived tumor cells and organoids from patients with breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.adp2622
  40. Cell Death Differ. 2024 Oct 23.
    Oncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer.
    Letizia Lanzetti.
      By the time a tumor reaches clinical detectability, it contains around 108-109 cells. However, during tumor formation, significant cell loss occurs due to cell death. In some estimates, it could take up to a thousand cell generations, over a ~ 20-year life-span of a tumor, to reach clinical detectability, which would correspond to a "theoretical" generation of ~1030 cells. These rough calculations indicate that cancers are under negative selection. The fact that they thrive implies that they "evolve", and that their evolutionary trajectories are shaped by the pressure of the environment. Evolvability of a cancer is a function of its heterogeneity, which could be at the genetic, epigenetic, and ecological/microenvironmental levels [1]. These principles were summarized in a proposed classification in which Evo (evolutionary) and Eco (ecological) indexes are used to label cancers [1]. The Evo index addresses cancer cell-autonomous heterogeneity (genetic/epigenetic). The Eco index describes the ecological landscape (non-cell-autonomous) in terms of hazards to cancer survival and resources available. The reciprocal influence of Evo and Eco components is critical, as it can trigger self-sustaining loops that shape cancer evolvability [2]. Among the various hallmarks of cancer [3], metabolic alterations appear unique in that they intersect with both Evo and Eco components. This is partly because altered metabolism leads to the accumulation of oncometabolites. These oncometabolites have traditionally been viewed as mediators of non-cell-autonomous alterations in the cancer microenvironment. However, they are now increasingly recognized as inducers of genetic and epigenetic modifications. Thus, oncometabolites are uniquely positioned at the crossroads of genetic, epigenetic and ecological alterations in cancer. In this review, the mechanisms of action of oncometabolites will be summarized, together with their roles in the Evo and Eco phenotypic components of cancer evolvability. An evolutionary perspective of the impact of oncometabolites on the natural history of cancer will be presented.
    DOI:  https://doi.org/10.1038/s41418-024-01402-6
  41. J Biol Rhythms. 2024 Oct 24. 7487304241286573
    Hierarchy or Heterarchy of Mammalian Circadian Timekeepers?
    William Bechtel.
      Mammalian circadian biologists commonly characterize the relation between circadian clocks as hierarchical, with the clock in the suprachiasmatic nucleus at the top of the hierarchy. The lineage of research since the suprachiasmatic nucleus (SCN) was first identified as the clock in mammals has challenged this perspective, revealing clocks in peripheral tissues, showing that they respond to their own zeitgebers, coordinate oscillations among themselves, and in some cases modify the behavior of the SCN. Increasingly circadian timekeepers appear to constitute a heterarchical network, with control distributed and operating along multiple pathways. One reason for the continued invocation of hierarchy in mammalian circadian biology is that it is difficult to understand how a heterarchical system could operate effectively so as to maintain the organism. Evolved mechanisms, however, need not respect hierarchy and those that have survived have demonstrated the ability of heterarchical organizaton to maintain organisms.
    Keywords:  heterarchy; hierarchy; peripheral clocks; suprachiasmatic nucleus; zeitgebers
    DOI:  https://doi.org/10.1177/07487304241286573
  42. Curr Biol. 2024 Oct 17. pii: S0960-9822(24)01335-6. [Epub ahead of print]
    Crosstalk between the circatidal and circadian clocks mediates behavioral adaptation to tidal patterns.
    Erica R Kwiatkowski, Joshua J C Rosenthal, Patrick Emery.
      The ability to anticipate tides is critical for a wide range of marine organisms, but this task is complicated by the diversity of tidal patterns on Earth. Previous findings suggest that organisms whose geographic range spans multiple types of tidal cycles can produce distinct patterns of rhythmic behavior that correspond to the tidal cycles they experience. How this behavioral plasticity is achieved, however, is unclear. Here, we show that Parhyale hawaiensis adapts its rhythmic behavior to various naturally occurring tidal regimens through the plastic contribution of its circatidal and circadian clocks. After entrainment to a tidal cycle that deviated only mildly from a regular 12.4 h tidal cycle, animals exhibited strong circatidal rhythms. By contrast, following entrainment to more irregularly spaced tides or to tides that occurred every 24.8 h, a significant fraction of animals instead synchronized to the light/dark (LD) cycle and exhibited circadian behavior, while others showed rhythmic behavior with both circatidal and circadian traits. We also show that the circatidal clock, while able to entrain to various naturally occurring tidal patterns, does not entrain to an unnatural one. We propose that Parhyale hawaiensis's ecological success around the world relies in part on the plastic interactions between the circatidal and circadian clocks, which shape its rhythmic behavior appropriately according to tidal patterns.
    Keywords:  Parhyale hawaiensis; chronobiology; circadian rhythms; circatidal rhythms; diurnal tides; marine biology; mixed tides
    DOI:  https://doi.org/10.1016/j.cub.2024.09.067
  43. Trends Cancer. 2024 Oct 21. pii: S2405-8033(24)00212-7. [Epub ahead of print]
    Mitochondrial DNA damage, repair, and replacement in cancer.
    Pavel Vodicka, Sona Vodenkova, Natalie Danesova, Ludmila Vodickova, Renata Zobalova, Kristyna Tomasova, Stepana Boukalova, Michael V Berridge, Jiri Neuzil.
      Mitochondria are vital organelles with their own DNA (mtDNA). mtDNA is circular and composed of heavy and light chains that are structurally more accessible than nuclear DNA (nDNA). While nDNA is typically diploid, the number of mtDNA copies per cell is higher and varies considerably during development and between tissues. Compared with nDNA, mtDNA is more prone to damage that is positively linked to many diseases, including cancer. Similar to nDNA, mtDNA undergoes repair processes, although these mechanisms are less well understood. In this review, we discuss the various forms of mtDNA damage and repair and their association with cancer initiation and progression. We also propose horizontal mitochondrial transfer as a novel mechanism for replacing damaged mtDNA.
    Keywords:  DNA stability; base excision repair; cancer; horizontal mitochondrial transfer; mitochondrial DNA; mitochondrial DNA damage repair; nuclear DNA
    DOI:  https://doi.org/10.1016/j.trecan.2024.09.010
  44. Sci Signal. 2024 Oct 22. 17(859): eadi8753
    Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.
    Teresa Rosenlehner, Stefanie Pennavaria, Batuhan Akçabozan, Shiva Jahani, Thomas J O'Neill, Daniel Krappmann, Tobias Straub, Jan Kranich, Reinhard Obst.
      Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.
    DOI:  https://doi.org/10.1126/scisignal.adi8753
  45. Science. 2024 Oct 25. 386(6720): eadk9167
    Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function.
    Manojit M Swamynathan, Shan Kuang, Kaitlin E Watrud, Mary R Doherty, Charlotte Gineste, Grinu Mathew, Grace Q Gong, Hilary Cox, Eileen Cheng, David Reiss, Jude Kendall, Diya Ghosh, Colleen R Reczek, Xiang Zhao, Tali Herzka, Saulė Špokaitė, Antoine N Dessus, Seung Tea Kim, Olaf Klingbeil, Juan Liu, Dawid G Nowak, Habeeb Alsudani, Tse-Luen Wee, Youngkyu Park, Francesca Minicozzi, Keith Rivera, Ana S Almeida, Kenneth Chang, Ram P Chakrabarty, John E Wilkinson, Phyllis A Gimotty, Sarah D Diermeier, Mikala Egeblad, Christopher R Vakoc, Jason W Locasale, Navdeep S Chandel, Tobias Janowitz, James B Hicks, Michael Wigler, Darryl J Pappin, Roger L Williams, Paolo Cifani, David A Tuveson, Jocelyn Laporte, Lloyd C Trotman.
      Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1-the phosphatase antagonist of VPS34-we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.
    DOI:  https://doi.org/10.1126/science.adk9167
  46. Nature. 2024 Oct 23.
    Nuclear release of eIF1 restricts start-codon selection during mitosis.
    Jimmy Ly, Kehui Xiang, Kuan-Chung Su, Gunter B Sissoko, David P Bartel, Iain M Cheeseman.
      Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08088-3
  47. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2318767121
    The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
    Eri Oguro-Igashira, Mari Murakami, Ryota Mori, Ryuichi Kuwahara, Takako Kihara, Masaharu Kohara, Makoto Fujiwara, Daisuke Motooka, Daisuke Okuzaki, Mitsuru Arase, Hironobu Toyota, Siyun Peng, Takayuki Ogino, Yasuji Kitabatake, Eiichi Morii, Seiichi Hirota, Hiroki Ikeuchi, Eiji Umemoto, Atsushi Kumanogoh, Kiyoshi Takeda.
      The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues.
    Keywords:  G protein-coupled receptors; GPR31; antigen recognition; dendritic cell; transepithelial dendrite formation
    DOI:  https://doi.org/10.1073/pnas.2318767121
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