bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒09‒29
67 papers selected by
Christian Frezza, Universität zu Köln
  1. CALHM2 is a mitochondrial protein import channel that regulates fatty acid metabolism.
  2. Identifying targetable metabolic dependencies across colorectal cancer progression.
  3. Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
  4. Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium.
  5. Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
  6. Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
  7. Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
  8. A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
  9. Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
  10. Exercise inhibits cellular senescence in pancreatic islets.
  11. Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution.
  12. Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.
  13. Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
  14. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  15. Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.
  16. Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites.
  17. Time bomb.
  18. Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.
  19. MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer.
  20. AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.
  21. Universal and tissue-specific fibroblasts in chronic inflammation and cancer.
  22. Metabolic footprint and logic through the T cell life cycle.
  23. Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.
  24. Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
  25. The inositol phosphate signalling network in physiology and disease.
  26. Mitochondrial Dysfunction-Evoked DHODH Acetylation is Involved in Renal Cell Ferroptosis during Cisplatin-Induced Acute Kidney Injury.
  27. Identification and characterization of human GDF15 knockouts.
  28. Causal drivers of human proteome variation in health and disease.
  29. Activation of automethylated PRC2 by dimerization on chromatin.
  30. Single cell genome and epigenome co-profiling reveals hardwiring and plasticity in breast cancer.
  31. Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.
  32. The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.
  33. Host physiology shapes the mutational landscape of normal and carcinogenic tissue.
  34. HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions.
  35. Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape.
  36. Vitessce: integrative visualization of multimodal and spatially resolved single-cell data.
  37. Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention.
  38. The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.
  39. Humans without GDF15 reassure drug developers.
  40. BACH to the ferroptosis.
  41. Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
  42. Aberrant pre-mRNA processing in cancer.
  43. Bringing carbon to life via one-carbon metabolism.
  44. HDAC3 integrates TGF-β and microbial cues to program tuft cell biogenesis and diurnal rhythms in mucosal immune surveillance.
  45. Spatial organization of adenylyl cyclase and its impact on dopamine signaling in neurons.
  46. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  47. USF2 and TFEB compete in regulating lysosomal and autophagy genes.
  48. Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer.
  49. Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity.
  50. GTP before ATP: The energy currency at the origin of genes.
  51. An ILK/STAT3 pathway controls glioblastoma stem cell plasticity.
  52. Sensor systems of KEAP1 uniquely detecting oxidative and electrophilic stresses separately In vivo.
  53. Scar/WAVE drives actin protrusions independently of its VCA domain using proline-rich domains.
  54. Anaesthetics disrupt complex I-linked respiration and reverse the ATP synthase.
  55. ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer.
  56. Quality control of mitochondria involves lysosomes in multiple definitive ways.
  57. Neural control of tumor immunity.
  58. Swimming through the fear.
  59. Orthogonal redox control.
  60. Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
  61. Exploring the role of macromolecular crowding and TNFR1 in cell volume control.
  62. Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease.
  63. How DNA Sensing Drives Inflammation.
  64. Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related naive T cell remodeling.
  65. Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia.
  66. Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations.
  67. Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer.
  1. Res Sq. 2024 Sep 13. pii: rs.3.rs-4985689. [Epub ahead of print]
    CALHM2 is a mitochondrial protein import channel that regulates fatty acid metabolism.
    Elizabeth Jonas, Nelli Mnatsakanyan, Felix Rivera-Molina, Andrew Robson, Alexandra MacColl Garfinkel, Amrendra Kumar, Stephen Batter, Valeria Padovano, Kaitlin Webster, Rebecca Cardone, Justin Berg, Derek Toomre, Richard Kibbey Iv, Michael Caplan, Mustafa Khokha.
      For mitochondrial metabolism to occur in the matrix, multiple proteins must be imported across the two (inner and outer) mitochondrial membranes. Classically, two protein import channels, TIM/TOM, are known to perform this function, but whether other protein import channels exist is not known. Here, using super-resolution microscopy, proteomics, and electrophysiological techniques, we identify CALHM2 as the import channel for the ECHA subunit of the mitochondrial trifunctional protein (mTFP), which catalyzes β-oxidation of fatty acids in the mitochondrial matrix. We find that CALHM2 sits specifically at the inner mitochondrial and cristae membranes and is critical for membrane morphology. Depletion of CALHM2 leads to a mislocalization of ECHA outside of the mitochondria leading to severe cellular metabolic defects. These defects include cytosolic accumulation of fatty acids, depletion of tricarboxylic acid cycle enzymes and intermediates, and reduced cellular respiration. Our data identify CALHM2 as an essential protein import channel that is critical for fatty acid- and glucose-dependent aerobic metabolism. .
    DOI:  https://doi.org/10.21203/rs.3.rs-4985689/v1
  2. Mol Metab. 2024 Sep 25. pii: S2212-8778(24)00168-6. [Epub ahead of print] 102037
    Identifying targetable metabolic dependencies across colorectal cancer progression.
    Danny N Legge, Tracey J Collard, Ewelina Stanko, Ashley J Hoskin, Amy K Holt, Caroline J Bull, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C Williams, Nicholas Jones, Emma E Vincent.
      Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.
    Keywords:  Colorectal cancer; adenocarcinoma; adenoma; asparagine; asparagine synthetase; oncometabolism
    DOI:  https://doi.org/10.1016/j.molmet.2024.102037
  3. Cell Rep. 2024 Sep 20. pii: S2211-1247(24)01126-4. [Epub ahead of print]43(10): 114775
    Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
    Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.
      Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.
    Keywords:  CP: Cancer; CP: Metabolism; PTEN; cancer metabolism; cancer therapies; glioma; metabolic state vulnerabilities; mitochondrial electron transport chain; multivariate modeling; oxidative phosphorylation; synthetic lethality
    DOI:  https://doi.org/10.1016/j.celrep.2024.114775
  4. Nat Genet. 2024 Sep 23.
    Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium.
    Albert Herms, David Fernandez-Antoran, Maria P Alcolea, Argyro Kalogeropoulou, Ujjwal Banerjee, Gabriel Piedrafita, Emilie Abby, Jose Antonio Valverde-Lopez, Inês S Ferreira, Irene Caseda, Maria T Bejar, Stefan C Dentro, Sara Vidal-Notari, Swee Hoe Ong, Bartomeu Colom, Kasumi Murai, Charlotte King, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Alan R Lowe, Moritz Gerstung, Philip H Jones.
      Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least 1 year, maintaining a three-dimensional structure with proliferative basal cells that differentiate into suprabasal cells, which eventually shed and retain genomic stability. Live imaging over 5 months showed that epithelioids replicate in vivo cell dynamics. Epithelioids support genetic manipulation and enable the study of mutant cell competition and selection in three-dimensional epithelia, and show how anti-cancer treatments modulate competition between transformed and wild-type cells. Finally, a targeted CRISPR-Cas9 screen shows that epithelioids recapitulate mutant gene selection in aging human esophagus and identifies additional drivers of clonal expansion, resolving the genetic networks underpinning competitive fitness.
    DOI:  https://doi.org/10.1038/s41588-024-01875-8
  5. J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643
    Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
    Kailash Venkatraman, Christopher T Lee, Itay Budin.
      Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.
    Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols
    DOI:  https://doi.org/10.1016/j.jlr.2024.100643
  6. Sci Adv. 2024 Sep 20. 10(38): eadn2806
    Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.
    Carlos Galvan, Aimee A Flores, Victoria Cerrilos, Itzetl Avila, Conor Murphy, Wilson Zheng, Heather R Christofk, William E Lowry.
      We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)-initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the up-regulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found the abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma.
    DOI:  https://doi.org/10.1126/sciadv.adn2806
  7. Res Sq. 2024 Sep 16. pii: rs.3.rs-4875322. [Epub ahead of print]
    Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
    Peter McGuire, Tatiana Tarasenko, Emily Warren, Amanda Fuchs, Bharati Singh, Jose Marin, Marten Szibor.
      T cell activation, proliferation, and differentiation are fundamentally driven by shifts in cellular metabolism, with mitochondria playing a central role. Cytochrome c oxidase (COX, complex IV) is a key player in this process, as its activity is crucial for apoptosis, mtDNA maintenance, mitochondrial transcription, and mitochondrial respiration (MR), all of which influence T cell fate and function. Despite its known roles, the specific functions of COX required for T cell activity in vivo remain unclear. To isolate the role of MR in T cell function, we reintroduced this capability in COX-deficient T cells using an alternative oxidase (AOX) from Ciona intestinalis. Our findings demonstrate that MR is vital for maintaining metabolic balance during T cell activation by alleviating electron pressure from metabolic reprogramming and preserving redox homeostasis. We further showed that AOX mitigates apoptosis, prevents metabolic disruptions in glycolysis and the tricarboxylic acid cycle, and improves mtDNA maintenance and transcription, indicating that these disturbances are secondary to impaired MR in the absence of COX. Most importantly, the introduction of AOX restored robust effector and memory T cell generation and function in COX-deficient cells. These results highlight the essential role of COX-dependent MR in ensuring cellular health and underscore its pivotal role in T cell proliferation and differentiation.
    DOI:  https://doi.org/10.21203/rs.3.rs-4875322/v2
  8. bioRxiv. 2024 Sep 09. pii: 2024.09.09.612087. [Epub ahead of print]
    A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
    Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.
      β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.
    DOI:  https://doi.org/10.1101/2024.09.09.612087
  9. Sci Immunol. 2024 Sep 20. 9(99): eadp3475
    Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation.
    Darren R Heintzman, Rachael C Sinard, Emilie L Fisher, Xiang Ye, Andrew R Patterson, Joel H Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J Rodriguez-Garcia, Nowrin U Chowdhury, Emily N Arner, Evan S Krystoviak, Frank M Mason, Yasmine T Toudji, KayLee K Steiner, Wasay Khan, Lana M Olson, Angela L Jones, Hanna S Hong, Lindsay Bass, Katherine L Beier, Wentao Deng, Costas A Lyssiotis, Dawn C Newcomb, Alexander G Bick, W Kimryn Rathmell, John T Wilson, Jeffrey C Rathmell.
      Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
    DOI:  https://doi.org/10.1126/sciimmunol.adp3475
  10. Nat Metab. 2024 Sep 24.
    Exercise inhibits cellular senescence in pancreatic islets.
    Gregory D Cartee.
      
    DOI:  https://doi.org/10.1038/s42255-024-01132-6
  11. Nat Genet. 2024 Sep 24.
    Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution.
    Joshua S Schiffman, Andrew R D'Avino, Tamara Prieto, Yakun Pang, Yilin Fan, Srinivas Rajagopalan, Catherine Potenski, Toshiro Hara, Mario L Suvà, Charles Gawad, Dan A Landau.
      Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.
    DOI:  https://doi.org/10.1038/s41588-024-01920-6
  12. J Cell Physiol. 2024 Sep 26. e31441
    Mitochondrial metabolism: A moving target in hepatocellular carcinoma therapy.
    Monika Komza, Jerry Edward Chipuk.
      Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.
    Keywords:  cancer; hepatocytes; metabolism; mitochondria; oncogenes; therapeutics
    DOI:  https://doi.org/10.1002/jcp.31441
  13. Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780
    Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
    Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.
      Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.
    Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114780
  14. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
  15. JCI Insight. 2024 Aug 13. pii: e180114. [Epub ahead of print]9(18):
    Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.
    Monica E Bonilla, Megan D Radyk, Matthew D Perricone, Ahmed M Elhossiny, Alexis C Harold, Paola I Medina-Cabrera, Padma Kadiyala, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Michael D Green, Cristina Mitrea, Costas A Lyssiotis, Marina Pasca di Magliano.
      Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.
    Keywords:  Bioinformatics; Cancer; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.180114
  16. Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00163-7. [Epub ahead of print] 102032
    Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites.
    Anna-Sophia Egger, Eva Rauch, Suraj Sharma, Tobias Kipura, Madlen Hotze, Thomas Mair, Alina Hohenegg, Philipp Kobler, Ines Heiland, Marcel Kwiatkowski.
      Histone acetylation is an important epigenetic modification that regulates various biological processes and cell homeostasis. Acetyl-CoA, a hub molecule of metabolism, is the substrate for histone acetylation, thus linking metabolism with epigenetic regulation. However, still relatively little is known about the dynamics of histone acetylation and its dependence on metabolic processes, due to the lack of integrated methods that can capture site-specific histone acetylation and deacetylation reactions together with the dynamics of acetyl-CoA synthesis. In this study, we present a novel proteo-metabo-flux approach that combines mass spectrometry-based metabolic flux analysis of acetyl-CoA and histone acetylation with computational modelling. We developed a mathematical model to describe metabolic label incorporation into acetyl-CoA and histone acetylation based on experimentally measured relative abundances. We demonstrate that our approach is able to determine acetyl-CoA synthesis dynamics and site-specific histone acetylation and deacetylation reaction rate constants, and that consideration of the metabolically labelled acetyl-CoA fraction is essential for accurate determination of histone acetylation dynamics. Furthermore, we show that without correction, changes in metabolic fluxes would be misinterpreted as changes in histone acetylation dynamics, whereas our proteo-metabo-flux approach allows to distinguish between the two processes.
    Keywords:  Computational modelling; Epigenetics; Histone modifications; LC-MS; Metabolic flux analysis; Metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2024.102032
  17. EMBO Rep. 2024 Sep 25.
    Time bomb.
    Howy Jacobs.
      
    DOI:  https://doi.org/10.1038/s44319-024-00273-9
  18. Nat Commun. 2024 Sep 27. 15(1): 8390
    Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.
    Yuqin Wu, Ashish Foollee, Andrea Y Chan, Susanne Hille, Jana Hauke, Matthew P Challis, Jared L Johnson, Tomer M Yaron, Victoria Mynard, Okka H Aung, Maria Almira S Cleofe, Cheng Huang, Terry C C Lim Kam Sian, Mohammad Rahbari, Suchira Gallage, Mathias Heikenwalder, Lewis C Cantley, Ralf B Schittenhelm, Luke E Formosa, Greg C Smith, Jürgen G Okun, Oliver J Müller, Patricia M Rusu, Adam J Rose.
      The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal "membrane trafficking" as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action.
    DOI:  https://doi.org/10.1038/s41467-024-52703-w
  19. Drug Discov Today. 2024 Sep 19. pii: S1359-6446(24)00314-3. [Epub ahead of print]29(11): 104189
    MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer.
    Fadi E Pulous, Barbara Steurer, Frank W Pun, Man Zhang, Feng Ren, Alex Zhavoronkov.
      Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.
    Keywords:  MAT2A and MTAP synthetic lethality; MAT2A-driven tumor progression; MTAP-null cancers; cancer cell metabolism; methionine synthesis
    DOI:  https://doi.org/10.1016/j.drudis.2024.104189
  20. Nature. 2024 Sep 25.
    AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.
    Heyu Li, Chao Liu, Ran Li, Lili Zhou, Yu Ran, Qiqing Yang, Huizhe Huang, Huasong Lu, Hai Song, Bing Yang, Heng Ru, Shixian Lin, Long Zhang.
      L-lactate modifies proteins through lactylation1, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensors required for L-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of L-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular L-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.
    DOI:  https://doi.org/10.1038/s41586-024-07992-y
  21. Cancer Cell. 2024 Sep 12. pii: S1535-6108(24)00346-5. [Epub ahead of print]
    Universal and tissue-specific fibroblasts in chronic inflammation and cancer.
    Simon Koplev, Sarah A Teichmann.
      In this issue of Cancer Cell, Gao et al. map fibroblast diversity across tumors and chronic inflammatory tissues. The authors uncover universal fibroblast subtypes such as LRRC15+ and MMP1+ myofibroblasts along with specialized tissue-specific subtypes. They reveal cellular roles of fibroblasts in immunosuppression through stromal niches and cell-cell interactions.
    DOI:  https://doi.org/10.1016/j.ccell.2024.08.022
  22. Curr Opin Immunol. 2024 Sep 21. pii: S0952-7915(24)00077-3. [Epub ahead of print]91 102487
    Metabolic footprint and logic through the T cell life cycle.
    Tingting Fan, Rushil Shah, Ruoning Wang.
      A simple definition of life is a system that can self-replicate (proliferation) and self-sustain (metabolism). At the cellular level, metabolism has evolved to drive proliferation, which requires energy and building blocks to duplicate cellular biomass before division. T lymphocytes (or T cells) are required for adaptive immune responses, protecting us against invading and malignant agents capable of hyper-replication. To gain a competitive advantage over these agents, activated T cells can duplicate their biomass and divide into two daughter cells in as short as 2-6 hours, considered the fastest cell division among all cell types in vertebrates. Thus, the primary task of cellular metabolism has evolved to commit available resources to drive T cell hyperproliferation. Beyond that, the T cell life cycle involves an ordered series of fate-determining events that drive cells to transition between discrete cell states. At the life stages not involved in hyperproliferation, T cells engage metabolic programs that are more flexible to sustain viability and maintenance and sometimes are fine-tuned to support specific cellular activities. Here, we focus on the central carbon metabolism, which is most relevant to cell proliferation. We provide examples of how the changes in the central carbon metabolism may or may not change the fate of T cells and further explore a few conceptual frameworks, such as metabolic flexibility, the Goldilocks Principle, overflow metabolism, and effector-signaling metabolites, in the context of T cell fate transitions.
    DOI:  https://doi.org/10.1016/j.coi.2024.102487
  23. Nat Metab. 2024 Sep 27.
    Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.
    Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton McKinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom.
      The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.
    DOI:  https://doi.org/10.1038/s42255-024-01134-4
  24. Nat Commun. 2024 Sep 27. 15(1): 8301
    Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
    Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.
      The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.
    DOI:  https://doi.org/10.1038/s41467-024-52538-5
  25. Trends Biochem Sci. 2024 Sep 23. pii: S0968-0004(24)00192-0. [Epub ahead of print]
    The inositol phosphate signalling network in physiology and disease.
    Seyun Kim, Rashna Bhandari, Charles A Brearley, Adolfo Saiardi.
      Combinatorial substitution of phosphate groups on the inositol ring gives rise to a plethora of inositol phosphates (InsPs) and inositol pyrophosphates (PP-InsPs). These small molecules constitute an elaborate metabolic and signalling network that influences nearly every cellular function. This review delves into the knowledge accumulated over the past decades regarding the biochemical principles and significance of InsP metabolism. We focus on the biological actions of InsPs in mammals, with an emphasis on recent findings regarding specific target proteins. We further discuss the roles of InsP metabolism in contributing to physiological homeostasis and pathological conditions. A deeper understanding of InsPs and their metabolic pathways holds the potential to address unresolved questions and propel advances towards therapeutic applications.
    Keywords:  kinase; metabolism; phosphatase; physiology; signal transduction
    DOI:  https://doi.org/10.1016/j.tibs.2024.08.005
  26. Adv Sci (Weinh). 2024 Sep 20. e2404753
    Mitochondrial Dysfunction-Evoked DHODH Acetylation is Involved in Renal Cell Ferroptosis during Cisplatin-Induced Acute Kidney Injury.
    Nan-Nan Liang, Yue-Yue Guo, Xiao-Yi Zhang, Ya-Hui Ren, Yi-Zhang He, Zhi-Bing Liu, De-Xiang Xu, Shen Xu.
      Several studies have observed renal cell ferroptosis during cisplatin-induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin-treated HK-2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin-treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH2, are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin-induced CoQH2 depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin-exposed mice. Mitochondrial SIRT3 is reduced in cisplatin-treated mouse kidneys and HK-2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin-induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria-target antioxidant MitoQ alleviated cisplatin-caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin-caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction-evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin-induced AKI.
    Keywords:  DHODH acetylation; SIRT3 SUMOylation; acute kidney injury; cisplatin; ferroptosis
    DOI:  https://doi.org/10.1002/advs.202404753
  27. Nat Metab. 2024 Sep 26.
    Identification and characterization of human GDF15 knockouts.
    Allan M Gurtan, Shareef Khalid, Christopher Koch, Maleeha Zaman Khan, Lindsey B Lamarche, Igor Splawski, Elizabeth Dolan, Ana M Carrion, Richard Zessis, Matthew E Clement, Zhiping Chen, Loren D Lindsley, Yu-Hsin Chiu, Ryan S Streeper, Daniel P Denning, Allison B Goldfine, Brian Doyon, Ali Abbasi, Jennifer L Harrow, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Alan R Shuldiner, Juan L Rodriguez-Flores, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Syed Shahzaib Raza, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, John E Dominy, Danish Saleheen.
      Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.
    DOI:  https://doi.org/10.1038/s42255-024-01135-3
  28. Nat Metab. 2024 Sep 26.
    Causal drivers of human proteome variation in health and disease.
    Paul W Franks, Daniel E Coral.
      
    DOI:  https://doi.org/10.1038/s42255-024-01138-0
  29. Mol Cell. 2024 Sep 13. pii: S1097-2765(24)00702-0. [Epub ahead of print]
    Activation of automethylated PRC2 by dimerization on chromatin.
    Paul V Sauer, Egor Pavlenko, Trinity Cookis, Linda C Zirden, Juliane Renn, Ankush Singhal, Pascal Hunold, Michaela N Hoehne-Wiechmann, Olivia van Ray, Farnusch Kaschani, Markus Kaiser, Robert Hänsel-Hertsch, Karissa Y Sanbonmatsu, Eva Nogales, Simon Poepsel.
      Polycomb repressive complex 2 (PRC2) is an epigenetic regulator that trimethylates lysine 27 of histone 3 (H3K27me3) and is essential for embryonic development and cellular differentiation. H3K27me3 is associated with transcriptionally repressed chromatin and is established when PRC2 is allosterically activated upon methyl-lysine binding by the regulatory subunit EED. Automethylation of the catalytic subunit enhancer of zeste homolog 2 (EZH2) stimulates its activity by an unknown mechanism. Here, we show that human PRC2 forms a dimer on chromatin in which an inactive, automethylated PRC2 protomer is the allosteric activator of a second PRC2 that is poised to methylate H3 of a substrate nucleosome. Functional assays support our model of allosteric trans-autoactivation via EED, suggesting a previously unknown mechanism mediating context-dependent activation of PRC2. Our work showcases the molecular mechanism of auto-modification-coupled dimerization in the regulation of chromatin-modifying complexes.
    Keywords:  PRC2; chromatin; cryo-EM; development; epigenetics; gene regulation; histone methyltransferase; trans-activation
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.025
  30. bioRxiv. 2024 Sep 10. pii: 2024.09.06.611519. [Epub ahead of print]
    Single cell genome and epigenome co-profiling reveals hardwiring and plasticity in breast cancer.
    Kaile Wang, Yun Yan, Heba Elgamal, Jianzhuo Li, Chenling Tang, Shanshan Bai, Zhenna Xiao, Emi Sei, Yiyun Lin, Junke Wang, Jessica Montalvan, Changandeep Nagi, Alastair M Thompson, Nicholas Navin.
      Understanding the impact of genetic alterations on epigenomic phenotypes during breast cancer progression is challenging with unimodal measurements. Here, we report wellDA-seq, the first high-genomic resolution, high-throughput method that can simultaneously measure the whole genome and chromatin accessibility profiles of thousands of single cells. Using wellDA-seq, we profiled 22,123 single cells from 2 normal and 9 tumors breast tissues. By directly mapping the epigenomic phenotypes to genetic lineages across cancer subclones, we found evidence of both genetic hardwiring and epigenetic plasticity. In 6 estrogen-receptor positive breast cancers, we directly identified the ancestral cancer cells, and found that their epithelial cell-of-origin was Luminal Hormone Responsive cells. We also identified cell types with copy number aberrations (CNA) in normal breast tissues and discovered non-epithelial cell types in the microenvironment with CNAs in breast cancers. These data provide insights into the complex relationship between genetic alterations and epigenomic phenotypes during breast tumor evolution.
    DOI:  https://doi.org/10.1101/2024.09.06.611519
  31. Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00162-5. [Epub ahead of print]89 102031
    Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.
    Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Naveen Kumar Tangudu, Apoorva Uboveja, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird.
      Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.
    Keywords:  ACSS2; Cell cycle; G0 phase; Metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2024.102031
  32. Elife. 2024 Sep 26. pii: RP90293. [Epub ahead of print]12
    The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.
    Vineeth Vengayil, Shreyas Niphadkar, Swagata Adhikary, Sriram Varahan, Sunil Laxman.
      Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing ∆ubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in ∆ubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic flux-dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.
    Keywords:  GAPDH; S. cerevisiae; biochemistry; cancer biology; chemical biology; glycolysis; inorganic phosphate; metabolic flux; mitochondria; trehalose
    DOI:  https://doi.org/10.7554/eLife.90293
  33. Nat Genet. 2024 Sep 26.
    Host physiology shapes the mutational landscape of normal and carcinogenic tissue.
    Nadia Nasreddin, Owen J Sansom.
      
    DOI:  https://doi.org/10.1038/s41588-024-01922-4
  34. Hepatol Commun. 2024 Oct 01. pii: e0533. [Epub ahead of print]8(10):
    HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions.
    Chenyue Lu, Amaya Pankaj, Michael Raabe, Cole Nawrocki, Ann Liu, Nova Xu, Bidish K Patel, Matthew J Emmett, Avril K Coley, Cristina R Ferrone, Vikram Deshpande, Irun Bhan, Yujin Hoshida, David T Ting, Martin J Aryee, Joseph W Franses.
      BACKGROUND: HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions.METHODS: We utilized computational deconvolution and cell-cell interaction analyses to cell type-specific (tumor-enriched and vessel-enriched) spatial transcriptomic data collected from 41 resected HCC tissue specimens.
    RESULTS: We report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner.
    CONCLUSIONS: Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous signaling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer-endothelial cell interactions and related drug targets.
    DOI:  https://doi.org/10.1097/HC9.0000000000000533
  35. Adv Sci (Weinh). 2024 Sep 26. e2403629
    Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape.
    Xinyi Zhou, Zhiqiang Chen, Yijiang Yu, Mengjiao Li, Yu Cao, Edward V Prochownik, Youjun Li.
      Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti-tumor immunity mediated by CD8+ T cells. In HCCs, depletion of PMVK is required to facilitate CD8+ T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ-aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl-CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4-acetaminobutyric acid (4-Ac-GABA), which is released into the TME. There, 4-Ac-GABA activates the GABAA receptor (GABAAR) on CD8+ T cells, which inhibits AKT1 signaling. This in turn suppresses CD8+ T cell activation, intratumoral infiltration, and the anti-tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti-PD-1 immune checkpoint therapy. These findings reveal non-canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8+ T cell inhibitor 4-Ac-GABA. Blocking 4-Ac-GABA signaling in CD8+ T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.
    Keywords:  4‐Acetaminobutyric acids; GABAA receptors; PMVK; immune escapes; tumor metabolisms
    DOI:  https://doi.org/10.1002/advs.202403629
  36. Nat Methods. 2024 Sep 27.
    Vitessce: integrative visualization of multimodal and spatially resolved single-cell data.
    Mark S Keller, Ilan Gold, Chuck McCallum, Trevor Manz, Peter V Kharchenko, Nils Gehlenborg.
      Multiomics technologies with single-cell and spatial resolution make it possible to measure thousands of features across millions of cells. However, visual analysis of high-dimensional transcriptomic, proteomic, genome-mapped and imaging data types simultaneously remains a challenge. Here we describe Vitessce, an interactive web-based visualization framework for exploration of multimodal and spatially resolved single-cell data. We demonstrate integrative visualization of millions of data points, including cell-type annotations, gene expression quantities, spatially resolved transcripts and cell segmentations, across multiple coordinated views. The open-source software is available at http://vitessce.io .
    DOI:  https://doi.org/10.1038/s41592-024-02436-x
  37. Curr Genomics. 2024 ;25(5): 358-379
    Emerging Multi-omic Approaches to the Molecular Diagnosis of Mitochondrial Disease and Available Strategies for Treatment and Prevention.
    Faeze Khaghani, Mahboobeh Hemmati, Masoumeh Ebrahimi, Arash Salmaninejad.
      Mitochondria are semi-autonomous organelles present in several copies within most cells in the human body that are controlled by the precise collaboration of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoding mitochondrial proteins. They play important roles in numerous metabolic pathways, such as the synthesis of adenosine triphosphate (ATP), the predominant energy substrate of the cell generated through oxidative phosphorylation (OXPHOS), intracellular calcium homeostasis, metabolite biosynthesis, aging, cell cycles, and so forth. Previous studies revealed that dysfunction of these multi-functional organelles, which may arise due to mutations in either the nuclear or mitochondrial genome, leads to a diverse group of clinically and genetically heterogeneous disorders. These diseases include neurodegenerative and metabolic disorders as well as cardiac and skeletal myopathies in both adults and newborns. The plethora of phenotypes and defects displayed leads to challenges in the diagnosis and treatment of mitochondrial diseases. In this regard, the related literature proposed several diagnostic options, such as high throughput mitochondrial genomics and omics technologies, as well as numerous therapeutic options, such as pharmacological approaches, manipulating the mitochondrial genome, increasing the mitochondria content of the affected cells, and recently mitochondrial diseases transmission prevention. Therefore, the present article attempted to review the latest advances and challenges in diagnostic and therapeutic options for mitochondrial diseases.
    Keywords:  Mitochondrial disease; genomic; metabolomics; omics; proteomics; transcriptomics
    DOI:  https://doi.org/10.2174/0113892029308327240612110334
  38. Nature. 2024 Sep 25.
    The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer.
    Bing Feng, Zhiliang Bai, Xiaolei Zhou, Yang Zhao, Yu-Qing Xie, Xinyi Huang, Yang Liu, Tom Enbar, Rongrong Li, Yi Wang, Min Gao, Lucia Bonati, Mei-Wen Peng, Weilin Li, Bo Tao, Mélanie Charmoy, Werner Held, J Joseph Melenhorst, Rong Fan, Yugang Guo, Li Tang.
      Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc-IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc-IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc-IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc-IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc-IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.
    DOI:  https://doi.org/10.1038/s41586-024-07962-4
  39. Nat Metab. 2024 Sep 26.
    Humans without GDF15 reassure drug developers.
    Samuel N Breit, Stephen O'Rahilly.
      
    DOI:  https://doi.org/10.1038/s42255-024-01136-2
  40. J Biochem. 2024 Sep 24. pii: mvae064. [Epub ahead of print]
    BACH to the ferroptosis.
    Fuminori Tokunaga.
      Ferroptosis is regulated cell death characterized by iron-dependent phospholipid peroxidation, and is closely related to various diseases. System Xc -, a cystine/glutamate antiporter, and glutathione peroxidase 4 (GPX4) are the key molecules in ferroptosis. Erastin and RSL3, known as inhibitors of system Xc - and GPX4, respectively, are commonly used as ferroptosis inducers. BTB and CNC homology 1 (BACH1), a heme-binding transcription repressor, promotes pro-ferroptotic signaling, and therefore, Bach1-deficient cells are resistant to ferroptosis. Irikura et al. constructed Bach1-re-expressing immortalized mouse embryonic fibroblasts (iMEFs) from Bach1-/- mice, which induce ferroptosis simply by the depletion of 2-mercaptoethanol from the culture medium (J. Biochem. 2023; 174:239-252). Transcriptional repression by re-expressed BACH1 induces suppressed glutathione synthesis and increases labile iron. Furthermore, the ferroptosis initiated by BACH1-re-expressing iMEFs is propagated to surrounding cells. Thus, the BACH1-re-expression system is a novel and powerful tool to investigate the cellular basis of ferroptosis.
    Keywords:  BACH1; ferroptosis; glutathione; system Xc−; transcriptional repression
    DOI:  https://doi.org/10.1093/jb/mvae064
  41. FASEB J. 2024 Sep 30. 38(18): e70066
    Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
    Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.
      Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.
    Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species
    DOI:  https://doi.org/10.1096/fj.202400313R
  42. J Exp Med. 2024 Nov 04. pii: e20230891. [Epub ahead of print]221(11):
    Aberrant pre-mRNA processing in cancer.
    Jeetayu Biswas, Leora Boussi, Eytan Stein, Omar Abdel-Wahab.
      Dysregulation of the flow of information from genomic DNA to RNA to protein occurs within all cancer types. In this review, we described the current state of understanding of how RNA processing is dysregulated in cancer with a focus on mutations in the RNA splicing factor machinery that are highly prevalent in hematologic malignancies. We discuss the downstream effects of these mutations highlighting both individual genes as well as common pathways that they perturb. We highlight examples of how alterations in RNA processing have been harnessed for therapeutic intent as well as to promote the selective toxicity of cancer cells.
    DOI:  https://doi.org/10.1084/jem.20230891
  43. Trends Biotechnol. 2024 Sep 20. pii: S0167-7799(24)00243-9. [Epub ahead of print]
    Bringing carbon to life via one-carbon metabolism.
    Samantha O'Keeffe, Lilly Garcia, Yi Chen, Richard C Law, Chong Liu, Junyoung O Park.
      One-carbon (C1) compounds found in greenhouse gases and industrial waste streams are underutilized carbon and energy sources. While various biological and chemical means exist for converting C1 substrates into multicarbon products, major challenges of C1 conversion lie in creating net value. Here, we review metabolic strategies to utilize carbon across oxidation states. Complications arise in biochemical C1-utilization approaches because of the need for cellular energy currency ATP. ATP supports cell maintenance and proliferation and drives thermodynamically challenging reactions by coupling them with ATP hydrolysis. Powering metabolism through substrate cofeeding and energy transduction from light and electricity improves ATP availability, relieves metabolic bottlenecks, and upcycles carbon. We present a bioenergetic, engineering, and technoeconomic outlook for bringing elements to life.
    Keywords:  carbon upcycling; metabolic engineering; one-carbon compounds; systems biology
    DOI:  https://doi.org/10.1016/j.tibtech.2024.08.014
  44. Sci Immunol. 2024 Sep 27. 9(99): eadk7387
    HDAC3 integrates TGF-β and microbial cues to program tuft cell biogenesis and diurnal rhythms in mucosal immune surveillance.
    Jianglin Zhang, Guoxun Wang, Junjie Ma, Yiran Duan, Samskrathi A Sharma, Sarah Oladejo, Xianda Ma, Giselle Arellano, Robert C Orchard, Tiffany A Reese, Zheng Kuang.
      The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota and feeding schedule. Disruption of epithelial HDAC3 decreases tuft cell numbers, impairing antihelminth immunity and norovirus infection. Mechanistically, HDAC3 functions noncanonically to activate transforming growth factor-β (TGF-β) signaling, which promotes rhythmic expression of Pou2f3, a lineage-defining transcription factor of tuft cells. Our findings reveal an environmental-epigenetic link that controls the diurnal differentiation of tuft cells and promotes rhythmic mucosal surveillance and immune responses in anticipation of exogenous challenges.
    DOI:  https://doi.org/10.1126/sciimmunol.adk7387
  45. Nat Commun. 2024 Sep 27. 15(1): 8297
    Spatial organization of adenylyl cyclase and its impact on dopamine signaling in neurons.
    Léa Ripoll, Yong Li, Carmen W Dessauer, Mark von Zastrow.
      The cAMP cascade is increasingly recognized to transduce physiological effects locally through spatially limited cAMP gradients. However, little is known about how adenylyl cyclase enzymes that initiate cAMP gradients are localized. Here we address this question in physiologically relevant striatal neurons and investigate how AC localization impacts downstream signaling function. We show that the major striatal AC isoforms are differentially sorted between ciliary and extraciliary domains of the plasma membrane, and that one isoform, AC9, is uniquely concentrated in endosomes. We identify key sorting determinants in the N-terminal cytoplasmic domain responsible for isoform-specific localization. We further show that AC9-containing endosomes accumulate activated dopamine receptors and form an elaborately intertwined network with juxtanuclear PKA stores bound to Golgi membranes. Finally, we provide evidence that endosomal localization enables AC9 to selectively elevate PKA activity in the nucleus relative to the cytoplasm. Together, these results reveal a precise spatial landscape of the cAMP cascade in neurons and a key role of AC localization in directing downstream PKA signaling to the nucleus.
    DOI:  https://doi.org/10.1038/s41467-024-52575-0
  46. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  47. Nat Commun. 2024 Sep 27. 15(1): 8334
    USF2 and TFEB compete in regulating lysosomal and autophagy genes.
    Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim, Sung Hee Baek.
      Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52600-2
  48. Sci Adv. 2024 Sep 27. 10(39): eado1458
    Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer.
    Rachel C Fellows, Sung Kook Chun, Natalie Larson, Bridget M Fortin, Alisa L Mahieu, Wei A Song, Marcus M Seldin, Nicholas R Pannunzio, Selma Masri.
      Diet is a robust entrainment cue that regulates diurnal rhythms of the gut microbiome. We and others have shown that disruption of the circadian clock drives the progression of colorectal cancer (CRC). While certain bacterial species have been suggested to play driver roles in CRC, it is unknown whether the intestinal clock impinges on the microbiome to accelerate CRC pathogenesis. To address this, genetic disruption of the circadian clock, in an Apc-driven mouse model of CRC, was used to define the impact on the gut microbiome. When clock disruption is combined with CRC, metagenomic sequencing identified dysregulation of many bacterial genera including Bacteroides, Helicobacter, and Megasphaera. We identify functional changes to microbial pathways including dysregulated nucleic acid, amino acid, and carbohydrate metabolism, as well as disruption of intestinal barrier function. Our findings suggest that clock disruption impinges on microbiota composition and intestinal permeability that may contribute to CRC pathogenesis.
    DOI:  https://doi.org/10.1126/sciadv.ado1458
  49. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2410356121
    Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity.
    Muhannad Abu-Remaileh, Nicole S Persky, Yenarae Lee, David E Root, William G Kaelin.
      Loss-of-function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain-of-function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2-dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.
    Keywords:  hypoxia; neuroblastoma; paraganglioma; pheochromocytoma; von Hippel–Lindau
    DOI:  https://doi.org/10.1073/pnas.2410356121
  50. Biochim Biophys Acta Bioenerg. 2024 Sep 24. pii: S0005-2728(24)00484-5. [Epub ahead of print] 149514
    GTP before ATP: The energy currency at the origin of genes.
    Natalia Mrnjavac, William F Martin.
      Life is an exergonic chemical reaction. Many individual reactions in metabolism entail slightly endergonic steps that are coupled to free energy release, typically as ATP hydrolysis, in order to go forward. ATP is almost always supplied by the rotor-stator ATP synthase, which harnesses chemiosmotic ion gradients. Because the ATP synthase is a protein, it arose after the ribosome did. What was the energy currency of metabolism before the origin of the ATP synthase and how (and why) did ATP come to be the universal energy currency? About 27 % of a cell's energy budget is consumed as GTP during translation. The universality of GTP-dependence in ribosome function indicates that GTP was the ancestral energy currency of protein synthesis. The use of GTP in translation and ATP in small molecule synthesis are conserved across all lineages, representing energetic compartments that arose in the last universal common ancestor, LUCA. And what came before GTP? Recent findings indicate that the energy supporting the origin of LUCA's metabolism stemmed from H2-dependent CO2 reduction along routes that strongly resemble the reactions and transition metal catalysts of the acetyl-CoA pathway.
    Keywords:  ATP synthase; Acetyl-CoA pathway; Acyl phosphates; Origin of life; Origin of translation; Ribosome
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149514
  51. Dev Cell. 2024 Sep 20. pii: S1534-5807(24)00531-8. [Epub ahead of print]
    An ILK/STAT3 pathway controls glioblastoma stem cell plasticity.
    Alexander E P Loftus, Marianna S Romano, Anh Nguyen Phuong, Ben J McKinnel, Morwenna T Muir, Muhammad Furqan, John C Dawson, Lidia Avalle, Adam T Douglas, Richard L Mort, Adam Byron, Neil O Carragher, Steven M Pollard, Valerie G Brunton, Margaret C Frame.
      Glioblastoma (GBM) is driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drive tumor progression and therapeutic resistance. Here, we show that the extracellular matrix-cell adhesion protein integrin-linked kinase (ILK) stimulates phenotypic plasticity and mesenchymal-like, invasive behavior in a murine GBM stem cell model. ILK is required for the interconversion of GBM stem cells between malignancy-associated glial-like states, and its loss produces cells that are unresponsive to multiple cell state transition cues. We further show that an ILK/STAT3 signaling pathway controls the plasticity that enables transition of GBM stem cells to an astrocyte-like state in vitro and in vivo. Finally, we find that ILK expression correlates with expression of STAT3-regulated proteins and protein signatures describing astrocyte-like and mesenchymal states in patient tumors. This work identifies ILK as a pivotal regulator of multiple malignancy-associated GBM phenotypes, including phenotypic plasticity and mesenchymal state.
    Keywords:  STAT3; adhesion; astrocytes; cancer; glioblastoma; integrin-linked kinase; plasticity; stem cells
    DOI:  https://doi.org/10.1016/j.devcel.2024.09.003
  52. Redox Biol. 2024 Sep 17. pii: S2213-2317(24)00333-1. [Epub ahead of print]77 103355
    Sensor systems of KEAP1 uniquely detecting oxidative and electrophilic stresses separately In vivo.
    Miu Sato, Nahoko Yaguchi, Takuya Iijima, Aki Muramatsu, Liam Baird, Takafumi Suzuki, Masayuki Yamamoto.
      In the KEAP1-NRF2 stress response system, KEAP1 acts as a sensor for oxidative and electrophilic stresses through formation of S-S bond and C-S bond, respectively. Of the many questions left related to the sensor activity, following three appear important; whether these KEAP1 sensor systems are operating in vivo, whether oxidative and electrophilic stresses are sensed by the similar or distinct systems, and how KEAP1 equips highly sensitive mechanisms detecting oxidative and electrophilic stresses in vivo. To address these questions, we conducted a series of analyses utilizing KEAP1-cysteine substitution mutant mice, conditional selenocysteine-tRNA (Trsp) knockout mice, and human cohort whole genome sequence (WGS) data. Firstly, the Trsp-knockout provokes severe deficiency of selenoproteins and compensatory activation of NRF2. However, mice lacking homozygously a pair of critical oxidative stress sensor cysteine residues of KEAP1 fail to activate NRF2 in the Trsp-knockout livers. Secondly, this study provides evidence for the differential utilization of KEAP1 sensors for oxidative and electrophilic stresses in vivo. Thirdly, theoretical calculations show that the KEAP1 dimer equips quite sensitive sensor machinery in which modification of a single molecule of KEAP1 within the dimer is sufficient to affect the activity. WGS examinations of rare variants identified seven non-synonymous variants in the oxidative stress sensors in human KEAP1, while no variant was found in electrophilic sensor cysteine residues, supporting the fail-safe nature of the KEAP1 oxidative stress sensor activity. These results provide valuable information for our understanding how mammals respond to oxidative and electrophilic stresses efficiently.
    DOI:  https://doi.org/10.1016/j.redox.2024.103355
  53. Curr Biol. 2024 Sep 19. pii: S0960-9822(24)01125-4. [Epub ahead of print]
    Scar/WAVE drives actin protrusions independently of its VCA domain using proline-rich domains.
    Simona Buracco, Hermann Döring, Stefanie Engelbart, Shashi Prakash Singh, Peggy Paschke, Jamie Whitelaw, Peter A Thomason, Nikki R Paul, Luke Tweedy, Sergio Lilla, Lynn McGarry, Ryan Corbyn, Sophie Claydon, Magdalena Mietkowska, Laura M Machesky, Klemens Rottner, Robert H Insall.
      Cell migration requires the constant modification of cellular shape by reorganization of the actin cytoskeleton. Fine-tuning of this process is critical to ensure new actin filaments are formed only at specific times and in defined regions of the cell. The Scar/WAVE complex is the main catalyst of pseudopod and lamellipodium formation during cell migration. It is a pentameric complex highly conserved through eukaryotic evolution and composed of Scar/WAVE, Abi, Nap1/NCKAP1, Pir121/CYFIP, and HSPC300/Brk1. Its function is usually attributed to activation of the Arp2/3 complex through Scar/WAVE's VCA domain, while other parts of the complex are expected to mediate spatial-temporal regulation and have no direct role in actin polymerization. Here, we show in both B16-F1 mouse melanoma and Dictyostelium discoideum cells that Scar/WAVE without its VCA domain still induces the formation of morphologically normal, actin-rich protrusions, extending at comparable speeds despite a drastic reduction of Arp2/3 recruitment. However, the proline-rich regions in Scar/WAVE and Abi subunits are essential, though either is sufficient for the generation of actin protrusions in B16-F1 cells. We further demonstrate that N-WASP can compensate for the absence of Scar/WAVE's VCA domain and induce lamellipodia formation, but it still requires an intact WAVE complex, even if without its VCA domain. We conclude that the Scar/WAVE complex does more than directly activating Arp2/3, with proline-rich domains playing a central role in promoting actin protrusions. This implies a broader function for the Scar/WAVE complex, concentrating and simultaneously activating many actin-regulating proteins as a lamellipodium-producing core.
    Keywords:  Arp2/3; Dictyostelium discoideum; N-WASP; Scar/WAVE; VCA domain; WAVE regulatory complex; WRC; actin; lamellipodium; polyproline
    DOI:  https://doi.org/10.1016/j.cub.2024.08.013
  54. Biochim Biophys Acta Bioenerg. 2024 Sep 24. pii: S0005-2728(24)00481-X. [Epub ahead of print] 149511
    Anaesthetics disrupt complex I-linked respiration and reverse the ATP synthase.
    Enrique Rodriguez, Bella Peng, Nick Lane.
      The mechanism of volatile general anaesthetics has long been a mystery. Anaesthetics have no structural motifs in common, beyond lipid solubility, yet all exert a similar effect. The fact that the inert gas xenon is an anaesthetic suggests their common mechanism might relate to physical rather than chemical properties. Electron transfer through chiral proteins can induce spin polarization. Recent work suggests that anaesthetics dissipate spin polarization during electron transfer to oxygen, slowing respiration. Here we show that the volatile anaesthetics isoflurane and sevoflurane specifically disrupt complex I-linked respiration in the thoraces of Drosophila melanogaster, with less effect on maximal respiration. Suppression of complex I-linked respiration was greatest with isoflurane. Using high-resolution tissue fluorespirometry, we show that these anaesthetics simultaneously increase mitochondrial membrane potential, implying reversal of the ATP synthase. Inhibition of ATP synthase with oligomycin prevented respiration and increased membrane potential back to the maximal (LEAK state) potential. Magnesium-green fluorescence predicted a collapse in ATP availability following a single anaesthetic dose, consistent with ATP hydrolysis through reversal of the ATP synthase. Raised membrane potential corresponded to a rise in ROS flux, especially with isoflurane. Anaesthetic doses causing respiratory suppression were in the same range as those that induce anaesthesia, although we could not establish tissue concentrations. Our findings show that anaesthetics suppress complex I-linked respiration with concerted downstream effects. But we cannot explain why only mutations in complex I, and not elsewhere in the electron-transfer system, confer hypersensitivity to anaesthetics.
    Keywords:  Anaesthetic; Complex I; Isoflurane; Mitochondria; Respiration; Sevoflurane
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149511
  55. Sci Adv. 2024 Sep 27. 10(39): eado4618
    ATR inhibition activates cancer cell cGAS/STING-interferon signaling and promotes antitumor immunity in small-cell lung cancer.
    Hirokazu Taniguchi, Subhamoy Chakraborty, Nobuyuki Takahashi, Avisek Banerjee, Rebecca Caeser, Yingqian A Zhan, Sam E Tischfield, Andrew Chow, Evelyn M Nguyen, Álvaro Quintanal Villalonga, Parvathy Manoj, Nisargbhai S Shah, Samantha Rosario, Omar Hayatt, Rui Qu, Elisa de Stanchina, Joseph Chan, Hiroshi Mukae, Anish Thomas, Charles M Rudin, Triparna Sen.
      Patients with small-cell lung cancer (SCLC) have poor prognosis and typically experience only transient benefits from combined immune checkpoint blockade (ICB) and chemotherapy. Here, we show that inhibition of ataxia telangiectasia and rad3 related (ATR), the primary replication stress response activator, induces DNA damage-mediated micronuclei formation in SCLC models. ATR inhibition in SCLC activates the stimulator of interferon genes (STING)-mediated interferon signaling, recruits T cells, and augments the antitumor immune response of programmed death-ligand 1 (PD-L1) blockade in mouse models. We demonstrate that combined ATR and PD-L1 inhibition causes improved antitumor response than PD-L1 alone as the second-line treatment in SCLC. This study shows that targeting ATR up-regulates major histocompatibility class I expression in preclinical models and SCLC clinical samples collected from a first-in-class clinical trial of ATR inhibitor, berzosertib, with topotecan in patients with relapsed SCLC. Targeting ATR represents a transformative vulnerability of SCLC and is a complementary strategy to induce STING-interferon signaling-mediated immunogenicity in SCLC.
    DOI:  https://doi.org/10.1126/sciadv.ado4618
  56. Autophagy. 2024 Sep 26.
    Quality control of mitochondria involves lysosomes in multiple definitive ways.
    Xiaowen Ma, Wen-Xing Ding.
      Mitochondria are crucial organelles in maintaining cellular homeostasis. They are involved in processes such as energy production, metabolism of lipids and glucose, and cell death regulation. Mitochondrial dysfunction can lead to various health issues such as aging, cancer, neurodegenerative diseases, and chronic liver diseases. While mitophagy is the main process for getting rid of excess or damaged mitochondria, there are additional mechanisms for preserving mitochondrial quality. One such alternative mechanism we have discovered is a hybrid organelle called mitochondrial-lysosome-related-organelle (MLRO), which functions independently of the typical autophagy process. More recently, another type of vesicle called vesicle derived from the inner mitochondrial membrane (VDIM) has been identified to break down the inner mitochondrial membrane without involving the standard autophagy pathway. In this article, we will delve into the similarities and differences between MLRO and VDIM, including their structure, regulation, and relevance to human diseases.
    Keywords:  Autophagy; DNM1L/DRP1; MLRO; VDIM; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2408712
  57. FEBS J. 2024 Sep 20.
    Neural control of tumor immunity.
    Burak Kizil, Francesco De Virgiliis, Christoph Scheiermann.
      Communication between the nervous system and the immune system has evolved to optimally respond to potentially dangerous stimuli both from within and outside the body. Tumors pose a severe threat to an organism and current therapies are insufficient for tumor regression in the majority of cases. Studies show that tumors are innervated by peripheral nerves from the sensory, parasympathetic and sympathetic nervous systems. Interactions between cancer cells, nerves and immune cells regulate overall tumor progression. Clinical studies have indicated the potential of targeting the peripheral nervous system for promoting anti-tumor immune responses. This view point provides an opinion on the current evidence and therapeutic potential of manipulating neuro-immune communications in cancer.
    Keywords:  cancer; cancer neuroimmunology; immune system; nervous system; neuroimmunology; tumor immunology
    DOI:  https://doi.org/10.1111/febs.17280
  58. Science. 2024 Sep 27. 385(6716): 1498
    Swimming through the fear.
    Virginia Manner.
      
    DOI:  https://doi.org/10.1126/science.adt3041
  59. Nat Chem Biol. 2024 Sep 24.
    Orthogonal redox control.
    Lena M Hümmler, Steffen N Lindner.
      
    DOI:  https://doi.org/10.1038/s41589-024-01728-9
  60. Nat Immunol. 2024 Oct;25(10): 1884-1899
    Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy.
    Geoffrey J Markowitz, Yi Ban, Diamile A Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T Martin, Michael J P Crowley, Tito A Sandoval, Dingcheng Gao, M Laura Martin, Olivier Elemento, Juan R Cubillos-Ruiz, Timothy E McGraw, Nasser K Altorki, Vivek Mittal.
      TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.
    DOI:  https://doi.org/10.1038/s41590-024-01963-1
  61. Elife. 2024 Sep 19. pii: e92719. [Epub ahead of print]13
    Exploring the role of macromolecular crowding and TNFR1 in cell volume control.
    Parijat Biswas, Priyanka Roy, Subhamoy Jana, Dipanjan Ray, Jibitesh Das, Bipasa Chaudhuri, Ridita Ray Basunia, Bidisha Sinha, Deepak Kumar Sinha.
      The excessive cosolute densities in the intracellular fluid create a physicochemical condition called macromolecular crowding (MMC). Intracellular MMC entropically maintains the biochemical thermodynamic equilibria by favouring associative reactions while hindering transport processes. Rapid cell volume shrinkage during extracellular hypertonicity elevates the MMC and disrupts the equilibria, potentially ushering cell death. Consequently, cells actively counter the hypertonic stress through regulatory volume increase (RVI) and restore the MMC homeostasis. Here, we establish fluorescence anisotropy of EGFP as a reliable tool for studying cellular MMC and explore the spatiotemporal dynamics of MMC during cell volume instabilities under multiple conditions. Our studies reveal that the actin cytoskeleton enforces spatially varying MMC levels inside adhered cells. Within cell populations, MMC is uncorrelated with nuclear DNA content but anti-correlated with the cell spread area. Although different cell lines have statistically similar MMC distributions, their responses to extracellular hypertonicity vary. The intensity of the extracellular hypertonicity determines a cell's ability for RVI, which correlates with Nuclear Factor Kappa Beta (NFkB) activation. Pharmacological inhibition and knockdown experiments reveal that Tumour Necrosis Factor Receptor 1 (TNFR1) initiates the hypertonicity induced NFkB signalling and RVI. At severe hypertonicities, the elevated MMC amplifies cytoplasmic microviscosity and hinders Receptor Interacting Protein Kinase 1 (RIPK1) recruitment at the TNFR1 complex, incapacitating the TNFR1-NFkB signalling and consequently, RVI. Together, our studies unveil the involvement of TNFR1-NFkB signalling in modulating RVI and demonstrate the pivotal role of MMC in determining cellular osmoadaptability.
    Keywords:  cell biology
    DOI:  https://doi.org/10.7554/eLife.92719
  62. Nat Cancer. 2024 Sep 20.
    Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease.
    Lea Lemaitre, Nia Adeniji, Akanksha Suresh, Reshma Reguram, Josephine Zhang, Jangho Park, Amit Reddy, Alexandro E Trevino, Aaron T Mayer, Anja Deutzmann, Aida S Hansen, Ling Tong, Vinodhini Arjunan, Neeraja Kambham, Brendan C Visser, Monica M Dua, C Andrew Bonham, Nishita Kothary, H Blaize D'Angio, Ryan Preska, Yanay Rosen, James Zou, Vivek Charu, Dean W Felsher, Renumathy Dhanasekaran.
      Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD.
    DOI:  https://doi.org/10.1038/s43018-024-00828-8
  63. N Engl J Med. 2024 Sep 19.
    How DNA Sensing Drives Inflammation.
    Russell E Vance.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2410049
  64. Immunity. 2024 Sep 17. pii: S1074-7613(24)00418-7. [Epub ahead of print]
    Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related naive T cell remodeling.
    Pavla Bohacova, Marina Terekhova, Petr Tsurinov, Riley Mullins, Kamila Husarcikova, Irina Shchukina, Alina Ulezko Antonova, Barbora Echalar, Jan Kossl, Adam Saidu, Thomas Francis, Chelsea Mannie, Laura Arthur, Stephen D R Harridge, Daniel Kreisel, Philip A Mudd, Angela M Taylor, Coleen A McNamara, Marina Cella, Sidharth V Puram, Theo van den Broek, Femke van Wijk, Pirooz Eghtesady, Maxim N Artyomov.
      Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38hi expression universally identified CD8+ and CD4+ RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8+ and CD4+ T cells: (1) a decrease in CD38++ cells (RTEs) and (2) an increase in CXCR3hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging.
    Keywords:  PBMC; aging; human; naive T cells; recent thymic emigrants
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.019
  65. Blood. 2024 Sep 24. pii: blood.2024024300. [Epub ahead of print]
    Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia.
    Sunniyat Rahman, Gianna Bloye, Nadine Farah, Jonas Demeulemeester, Joana R Costa, David O'Connor, Rachael Pocock, Tanya Rapoz-D'Silva, Adam Turna, Lingyi Wang, Soo Wah Lee, Adele K Fielding, Juliette Roels, Roman Jaksik, Małgorzata Dawidowska, Pieter Van Vlierberghe, Suzana Hadjur, Jim R Hughes, James Davies, Alejandro Gutierrez, Michelle Kelliher, Peter Van Loo, Mark A Dawson, Marc R Mansour.
      Oncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T cell acute lymphoblastic leukemia (T-ALL). Loss of this CTCF bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (-644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that 'promoter tethering' of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.
    DOI:  https://doi.org/10.1182/blood.2024024300
  66. Nat Commun. 2024 Sep 27. 15(1): 8310
    Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations.
    Yufan Zhou, Tian Li, Lavanya Choppavarapu, Kun Fang, Shili Lin, Victor X Jin.
      An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We find the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.
    DOI:  https://doi.org/10.1038/s41467-024-52440-0
  67. Mol Cell. 2024 Sep 14. pii: S1097-2765(24)00731-7. [Epub ahead of print]
    Hydrogen sulfide-mediated persulfidation regulates homocysteine metabolism and enhances ferroptosis in non-small cell lung cancer.
    Hualei Zheng, Huidi Chen, Yunjie Cai, Min Shen, Xilin Li, Yi Han, Xusheng Deng, Hongjie Cao, Junjia Liu, Hao Li, Benchao Liu, Ganlin Li, Xindong Wang, Hui Chen, Jingjing Hou, Shu-Hai Lin, Lili Zong, Yongyou Zhang.
      Hydrogen sulfide (H₂S), a metabolite of the transsulfuration pathway, has been implicated in ferroptosis, a unique form of cell death caused by lipid peroxidation. While the exact mechanisms controlling ferroptosis remain unclear, our study reveals that H₂S sensitizes human non-small cell lung cancer (NSCLC) cells to this process, particularly when cysteine levels are low. Combining H₂S with cystine depletion significantly enhances the effectiveness of ferroptosis-based cancer therapy. Mechanistically, H₂S persulfidates the 195th cysteine on S-adenosyl homocysteine hydrolase (SAHH), reducing its enzymatic activity. This leads to decreased homocysteine levels, subsequently lowering cysteine and glutathione concentrations under cystine depletion conditions. These changes ultimately increase the vulnerability of NSCLC cells to ferroptosis. Our findings establish H₂S as a key regulator of homocysteine metabolism and a critical factor in determining NSCLC cell susceptibility to ferroptosis. These results highlight the potential of H₂S-based therapies to improve the efficacy of ferroptosis-targeted cancer treatments for NSCLC.
    Keywords:  S-adenosyl homocysteine hydrolase; ferroptosis; homocysteine; hydrogen sulfide; persulfidation; transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.035
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