bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒05‒12
39 papers selected by
Christian Frezza, Universität zu Köln
  1. Reprogrammed mitochondria: a central hub of cancer cell metabolism.
  2. Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.
  3. An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
  4. The mitochondrial tRNA-derived fragment, mt-tRF-LeuTAA, couples mitochondrial metabolism to insulin secretion.
  5. Targetable leukaemia dependency on noncanonical PI3Kγ signalling.
  6. Flavin-containing monooxygenase (FMO): Beyond xenobiotics.
  7. The intrinsic substrate specificity of the human tyrosine kinome.
  8. Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
  9. Branching out beyond canonical brown adipocyte function.
  10. Comprehensive proteogenomic characterization of rare kidney tumors.
  11. tauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data.
  12. Spatially resolved metabolomic dataset of distinct human kidney anatomic regions.
  13. Dodging death.
  14. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
  15. Nature of epigenetic aging from a single-cell perspective.
  16. Mapping genotypes to chromatin accessibility profiles in single cells.
  17. Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
  18. Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
  19. Dysregulated BH4 metabolism facilitates immunosuppression in pancreatic cancer.
  20. FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
  21. Dendrite architecture determines mitochondrial distribution patterns in vivo.
  22. Protein lipoylation: mitochondria, cuproptosis, and beyond.
  23. Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.
  24. Cell-intrinsic and microenvironmental determinants of metastatic colonization.
  25. Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.
  26. CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake.
  27. PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma.
  28. Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
  29. A systematic mutational framework for studying oxidative phosphorylation-related proteins.
  30. Hacking the immune system could slow ageing - here's how.
  31. Cell metabolism: Functional and phenotypic single cell approaches.
  32. Tubular CPT1A deletion minimally affects aging and chronic kidney injury.
  33. Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.
  34. ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis.
  35. Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart.
  36. Glucose and trehalose metabolism through the cyclic pentose phosphate pathway shapes pathogen resistance and host protection in Drosophila.
  37. Mutational robustness and the role of buffer genes in evolvability.
  38. Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
  39. Aging clocks based on accumulating stochastic variation.
  1. Biochem Soc Trans. 2024 May 08. pii: BST20231090. [Epub ahead of print]
    Reprogrammed mitochondria: a central hub of cancer cell metabolism.
    Fabio Ciccarone, Maria Rosa Ciriolo.
      Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.
    Keywords:  TCA cycle; metabolic disorders; mitochondrial dysfunction
    DOI:  https://doi.org/10.1042/BST20231090
  2. Elife. 2024 May 07. pii: RP92178. [Epub ahead of print]12
    Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.
    Mohammad Alfatah, Jolyn Jia Jia Lim, Yizhong Zhang, Arshia Naaz, Trishia Yi Ning Cheng, Sonia Yogasundaram, Nashrul Afiq Faidzinn, Jovian Jing Lin, Birgit Eisenhaber, Frank Eisenhaber.
      Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared genesets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralog RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Furthermore, we find that genetic- or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.
    Keywords:  S. cerevisiae; cellular aging; genetics; genomics; human; lifespan; mitochondria; nutrient signaling; target of rapamycin complex 1; uncharacterized genes
    DOI:  https://doi.org/10.7554/eLife.92178
  3. Nat Commun. 2024 May 07. 15(1): 3793
    An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
    Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.
      Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.
    DOI:  https://doi.org/10.1038/s41467-024-48189-1
  4. Mol Metab. 2024 May 03. pii: S2212-8778(24)00086-3. [Epub ahead of print] 101955
    The mitochondrial tRNA-derived fragment, mt-tRF-LeuTAA, couples mitochondrial metabolism to insulin secretion.
    Cecile Jacovetti, Chris Donnelly, Véronique Menoud, Mara Suleiman, Cristina Cosentino, Jonathan Sobel, Kejing Wu, Karim Bouzakri, Piero Marchetti, Claudiane Guay, Bengt Kayser, Romano Regazzi.
      OBJECTIVE: The contribution of the mitochondrial electron transfer system to insulin secretion involves more than just energy provision. We identified a small RNA fragment (mt-tRF-LeuTAA) derived from the cleavage of a mitochondrially-encoded tRNA that is conserved between mice and humans. The role of mitochondrially-encoded tRNA-derived fragments remains unknown. This study aimed to characterize the impact of mt-tRF-LeuTAA, on mitochondrial metabolism and pancreatic islet functions.METHODS: We used antisense oligonucleotides to reduce mt-tRF-LeuTAA levels in primary rat and human islet cells, as well as in insulin-secreting cell lines. We performed a joint transcriptome and proteome analysis upon mt-tRF-LeuTAA inhibition. Additionally, we employed pull-down assays followed by mass spectrometry to identify direct interactors of the fragment. Finally, we characterized the impact of mt-tRF-LeuTAA silencing on the coupling between mitochondrial metabolism and insulin secretion using high-resolution respirometry and insulin secretion assays.
    RESULTS: Our study unveils a modulation of mt-tRF-LeuTAA levels in pancreatic islets in different Type 2 diabetes models and in response to changes in nutritional status. The level of the fragment is finely tuned by the mechanistic target of rapamycin complex 1. Located within mitochondria, mt-tRF-LeuTAA interacts with core subunits and assembly factors of respiratory complexes of the electron transfer system. Silencing of mt-tRF-LeuTAA in islet cells limits the inner mitochondrial membrane potential and impairs mitochondrial oxidative phosphorylation, predominantly by affecting the Succinate (via Complex II)-linked electron transfer pathway. Lowering mt-tRF-LeuTAA impairs insulin secretion of rat and human pancreatic β-cells.
    CONCLUSIONS: Our findings indicate that mt-tRF-LeuTAA interacts with electron transfer system complexes and is a pivotal regulator of mitochondrial oxidative phosphorylation and its coupling to insulin secretion.
    Keywords:  Insulin secretion; Mitochondrial OXPHOS; Mitochondrial tRNA-derived fragments
    DOI:  https://doi.org/10.1016/j.molmet.2024.101955
  5. Nature. 2024 May 08.
    Targetable leukaemia dependency on noncanonical PI3Kγ signalling.
    Qingyu Luo, Evangeline G Raulston, Miguel A Prado, Xiaowei Wu, Kira Gritsman, Karley S Whalen, Kezhi Yan, Christopher A G Booth, Ran Xu, Peter van Galen, John G Doench, Shai Shimony, Henry W Long, Donna S Neuberg, Joao A Paulo, Andrew A Lane.
      Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.
    DOI:  https://doi.org/10.1038/s41586-024-07410-3
  6. Bioessays. 2024 May 07. e2400029
    Flavin-containing monooxygenase (FMO): Beyond xenobiotics.
    Ajay Bhat, Faith R Carranza, Angela M Tuckowski, Scott F Leiser.
      Flavin-containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo-2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo-2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S-adenosyl-methionine (SAM) to S-adenosyl-homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss how FMO-2-mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo-2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan.
    DOI:  https://doi.org/10.1002/bies.202400029
  7. Nature. 2024 May 08.
    The intrinsic substrate specificity of the human tyrosine kinome.
    Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson.
      Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07407-y
  8. Nat Metab. 2024 May 08.
    Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
    Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.
      Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01039-2
  9. Cell Metab. 2024 May 07. pii: S1550-4131(24)00131-1. [Epub ahead of print]36(5): 891-892
    Branching out beyond canonical brown adipocyte function.
    Helaina Von Bank, Judith Simcox.
      Brown adipose tissue has long been functionally characterized as an organ that regulates thermogenesis, body weight set point, and glucose homeostasis. In the May 9, 2024, issue of Cell, Verkerke et al. discover a novel function for brown adipose tissue in processing branched-chain amino acids into antioxidant metabolites that enter the circulation and regulate insulin signaling in the liver.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.011
  10. Cell Rep Med. 2024 Apr 26. pii: S2666-3791(24)00239-8. [Epub ahead of print] 101547
    Comprehensive proteogenomic characterization of rare kidney tumors.
    Clinical Proteomic Tumor Analysis Consortium
      Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.
    Keywords:  CPTAC; cell-of-origin; differential diagnosis biomarkers; glycoproteomics; metabolomics; non-clear cell renal cell carcinoma; phosphoproteomics; prognostic marker; proteogenomics; weighted genome instability index
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101547
  11. Nat Commun. 2024 May 07. 15(1): 3840
    tauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data.
    Junyan Duan, Michelle N Ngo, Satya Swaroop Karri, Lam C Tsoi, Johann E Gudjonsson, Babak Shahbaba, John Lowengrub, Bogi Andersen.
      As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.
    DOI:  https://doi.org/10.1038/s41467-024-48041-6
  12. Data Brief. 2024 Jun;54 110431
    Spatially resolved metabolomic dataset of distinct human kidney anatomic regions.
    Haikuo Li, Benjamin D Humphreys.
      Cortex, medulla and papilla are three major human kidney anatomic structures and they harbour unique metabolic functions, but the underlying metabolomic profiles are largely unknown at spatial resolution. Here, we generated a spatially resolved metabolomics dataset on human kidney cortex, medulla and papilla tissues dissected from the same donor. Matrix-Assisted Laser Desorption/Ionization-Imaging Mass Spectrometry (MALDI-IMS) was used to detect metabolite species over mass-to-charge ratios of 50 -1500 for each section at a resolution of 10 × 10 µm2 pixel size. We present raw data matrix of each sample, feature annotations, raw AnnData merged from three samples and processed AnnData files after quality control, dimensional reduction and data integration, which contains a total of 170,459 spatially resolved metabolomes with 562 features detected. This dataset can be either visualized through an interactive browser or further analyzed to study metabolomic heterogeneity across regional human kidney anatomy.
    Keywords:  Imaging mass spectrometry; Kidney anatomy; MALDI; Metabolism; Nephrology; Omics
    DOI:  https://doi.org/10.1016/j.dib.2024.110431
  13. Nat Chem Biol. 2024 May 08.
    Dodging death.
    Yuelong Yan, Boyi Gan.
      
    DOI:  https://doi.org/10.1038/s41589-024-01607-3
  14. Nat Commun. 2024 May 10. 15(1): 3982
    Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
    Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.
      The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-024-48272-7
  15. Nat Aging. 2024 May 09.
    Nature of epigenetic aging from a single-cell perspective.
    Andrei E Tarkhov, Thomas Lindstrom-Vautrin, Sirui Zhang, Kejun Ying, Mahdi Moqri, Bohan Zhang, Alexander Tyshkovskiy, Orr Levy, Vadim N Gladyshev.
      Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.
    DOI:  https://doi.org/10.1038/s43587-024-00616-0
  16. Nature. 2024 May 08.
    Mapping genotypes to chromatin accessibility profiles in single cells.
    Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, JoAnn Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau.
      In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.
    DOI:  https://doi.org/10.1038/s41586-024-07388-y
  17. bioRxiv. 2024 Apr 28. pii: 2024.04.25.591150. [Epub ahead of print]
    Lactate transport inhibition therapeutically reprograms fibroblast metabolism in experimental pulmonary fibrosis.
    David R Ziehr, Fei Li, K Mark Parnell, Nathan M Krah, Kevin J Leahy, Christelle Guillermier, Jack Varon, Rebecca M Baron, Bradley A Maron, Nancy J Philp, Lida P Hariri, Edy Y Kim, Matthew L Steinhauser, Rachel S Knipe, Jared Rutter, William M Oldham.
      Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist.SUMMARY: Small molecule inhibitors of lactate transporters, including the novel MCT4 inhibitor VB253, reprogram fibroblast metabolism to prevent myofibroblast differentiation and decrease bleomycin-induced pulmonary fibrosis.
    DOI:  https://doi.org/10.1101/2024.04.25.591150
  18. Cell Metab. 2024 May 07. pii: S1550-4131(24)00127-X. [Epub ahead of print]36(5): 884-886
    Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
    Qiang Cai, Yihao Tian, Quazi T H Shubhra.
      Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.007
  19. Cell Metab. 2024 May 07. pii: S1550-4131(24)00129-3. [Epub ahead of print]36(5): 886-888
    Dysregulated BH4 metabolism facilitates immunosuppression in pancreatic cancer.
    Shane J F Cronin.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive, malignant, and lethal cancers, displaying strong resistance to immunotherapy. In this issue of Cell Metabolism, a study by Liu et al. identifies tetrahydrobiopterin metabolic dysregulation as a key driver for the immunosuppressive PDAC environment in mouse and human.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.009
  20. Nat Commun. 2024 May 07. 15(1): 3805
    FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
    Yuanli Zhen, Kai Liu, Lei Shi, Simran Shah, Qin Xu, Haley Ellis, Eranga R Balasooriya, Johannes Kreuzer, Robert Morris, Albert S Baldwin, Dejan Juric, Wilhelm Haas, Nabeel Bardeesy.
      Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.
    DOI:  https://doi.org/10.1038/s41467-024-47514-y
  21. Cell Rep. 2024 May 06. pii: S2211-1247(24)00518-7. [Epub ahead of print]43(5): 114190
    Dendrite architecture determines mitochondrial distribution patterns in vivo.
    Eavan J Donovan, Anamika Agrawal, Nicole Liberman, Jordan I Kalai, Avi J Adler, Adam M Lamper, Hailey Q Wang, Nicholas J Chua, Elena F Koslover, Erin L Barnhart.
      Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules-which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness-predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.
    Keywords:  CP: Cell biology; CP: Neuroscience; dendrite scaling; in vivo imaging; mitochondrial motility; neuronal morphology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114190
  22. Trends Biochem Sci. 2024 May 06. pii: S0968-0004(24)00096-3. [Epub ahead of print]
    Protein lipoylation: mitochondria, cuproptosis, and beyond.
    Cheng-Han Lin, Yeh Chin, Ming Zhou, Robert W Sobol, Mien-Chie Hung, Ming Tan.
      Protein lipoylation, a crucial post-translational modification (PTM), plays a pivotal role in mitochondrial function and emerges as a key player in cell death through cuproptosis. This novel copper-driven cell death pathway is activated by excessive copper ions binding to lipoylated mitochondrial proteins, disrupting energy production and causing lethal protein aggregation and cell death. The intricate relationship among protein lipoylation, cellular energy metabolism, and cuproptosis offers a promising avenue for regulating essential cellular functions. This review focuses on the mechanisms of lipoylation and its significant impact on cell metabolism and cuproptosis, emphasizing the key genes involved and their implications for human diseases. It offers valuable insights into targeting dysregulated cellular metabolism for therapeutic purposes.
    Keywords:  cancer; cell death; iron-sulfur cluster; metabolism; metal ion; post-translational modification
    DOI:  https://doi.org/10.1016/j.tibs.2024.04.002
  23. Cell. 2024 May 02. pii: S0092-8674(24)00410-0. [Epub ahead of print]
    Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.
    Chen Wang, Qun Zeng, Zeynep Melis Gül, Sisi Wang, Robert Pick, Phil Cheng, Ruben Bill, Yan Wu, Stefan Naulaerts, Coline Barnoud, Pei-Chun Hsueh, Sofie Hedlund Moller, Mara Cenerenti, Mengzhu Sun, Ziyang Su, Stéphane Jemelin, Volodymyr Petrenko, Charna Dibner, Stéphanie Hugues, Camilla Jandus, Zhongwu Li, Olivier Michielin, Ping-Chih Ho, Abhishek D Garg, Federico Simonetta, Mikaël J Pittet, Christoph Scheiermann.
      The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.
    Keywords:  BMAL1; CAR T therapy; PD-1; chronotherapy; circadian; immune checkpoint blockade; immunology; melanoma; tumor-infiltrating leukocyte
    DOI:  https://doi.org/10.1016/j.cell.2024.04.015
  24. Nat Cell Biol. 2024 May 07.
    Cell-intrinsic and microenvironmental determinants of metastatic colonization.
    Arthur W Lambert, Yun Zhang, Robert A Weinberg.
      Cancer metastasis is a biologically complex process that remains a major challenge in the oncology clinic, accounting for nearly all of the mortality associated with malignant neoplasms. To establish metastatic growths, carcinoma cells must disseminate from the primary tumour, survive in unfamiliar tissue microenvironments, re-activate programs of proliferation, and escape innate and adaptive immunosurveillance. The entire process is extremely inefficient and can occur over protracted timescales, yielding only a vanishingly small number of carcinoma cells that are able to complete all of the required steps. Here we review both the cancer-cell-intrinsic mechanisms and microenvironmental interactions that enable metastatic colonization. In particular, we highlight recent work on the behaviour of already-disseminated tumour cells, since meaningful progress in treating metastatic disease will clearly require a better understanding of the cells that spawn metastases, which generally have disseminated by the time of initial diagnosis.
    DOI:  https://doi.org/10.1038/s41556-024-01409-8
  25. Cancer Discov. 2024 May 09.
    Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.
    Santiago Demajo, Joan Enric Ramis-Zaldivar, Ferran Muinos, Miguel L Grau, Maria Andrianova, Nuria Lopez-Bigas, Abel Gonzalez-Perez.
      Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. Here, we trained machine-learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1416
  26. Elife. 2024 May 07. pii: e83712. [Epub ahead of print]13
    CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake.
    Savvas Nikolaou, Amelie Juin, Jamie A Whitelaw, Nikki R Paul, Loic Fort, Colin Nixon, Heather J Spence, Sheila Bryson, Laura M Machesky.
      Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53-driven pancreatic cancer. Deletion of Cyrib (the gene encoding CYRI-B protein) accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a potential role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of the lysophosphatidic acid receptor-1. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.
    Keywords:  cancer biology; cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.83712
  27. EMBO Mol Med. 2024 May 10.
    PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma.
    Matilde Simoni, Chiara Menegazzi, Cristina Fracassi, Claudia C Biffi, Francesca Genova, Nazario Pio Tenace, Roberta Lucianò, Andrea Raimondi, Carlo Tacchetti, James Brugarolas, Davide Mazza, Rosa Bernardi.
      Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
    Keywords:  Arsenic Trioxide; PML; Senescence; ccRCC; p53
    DOI:  https://doi.org/10.1038/s44321-024-00077-3
  28. Nat Commun. 2024 May 04. 15(1): 3767
    Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
    Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam.
      Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs' biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.
    DOI:  https://doi.org/10.1038/s41467-024-48086-7
  29. Nat Metab. 2024 May 08.
    A systematic mutational framework for studying oxidative phosphorylation-related proteins.
      
    DOI:  https://doi.org/10.1038/s42255-024-01042-7
  30. Nature. 2024 May;629(8011): 276-278
    Hacking the immune system could slow ageing - here's how.
    Alison Abbott.
      
    Keywords:  Ageing; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-01274-3
  31. Methods Cell Biol. 2024 ;pii: S0091-679X(24)00055-4. [Epub ahead of print]186 151-187
    Cell metabolism: Functional and phenotypic single cell approaches.
    Sara De Biasi, Julien Paul Gigan, Rebecca Borella, Elena Santacroce, Domenico Lo Tartaro, Anita Neroni, Nikolaos Paschalidis, Katarzyna Piwocka, Rafael José Argüello, Lara Gibellini, Andrea Cossarizza.
      Several metabolic pathways are essential for the physiological regulation of immune cells, but their dysregulation can cause immune dysfunction. Hypermetabolic and hypometabolic states represent deviations in the magnitude and flexibility of effector cells in different contexts, for example in autoimmunity, infections or cancer. To study immunometabolism, most methods focus on bulk populations and rely on in vitro activation assays. Nowadays, thanks to the development of single-cell technologies, including multiparameter flow cytometry, mass cytometry, RNA cytometry, among others, the metabolic state of individual immune cells can be measured in a variety of samples obtained in basic, translational and clinical studies. Here, we provide an overview of different single-cell approaches that are employed to investigate both mitochondrial functions and cell dependence from mitochondria metabolism. Moreover, besides the description of the appropriate experimental settings, we discuss the strengths and weaknesses of different approaches with the aim to suggest how to study cell metabolism in the settings of interest.
    Keywords:  Function; Metabolism; Multiparametric flow cytometry; Single-cell
    DOI:  https://doi.org/10.1016/bs.mcb.2024.02.024
  32. JCI Insight. 2024 May 08. pii: e181816. [Epub ahead of print]9(9):
    Tubular CPT1A deletion minimally affects aging and chronic kidney injury.
    Safaa Hammoud, Alla Ivanova, Yosuke Osaki, Steven Funk, Haichun Yang, Olga Viquez, Rachel Delgado, Dongliang Lu, Melanie Phillips Mignemi, Jane Tonello, Selene Colon, Louise Lantier, David H Wasserman, Benjamin D Humphreys, Jeffrey Koenitzer, Justin Kern, Mark de Caestecker, Toren Finkel, Agnes Fogo, Nidia Messias, Irfan J Lodhi, Leslie S Gewin.
      
    DOI:  https://doi.org/10.1172/jci.insight.181816
  33. Nat Commun. 2024 May 09. 15(1): 3905
    Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.
    Ting Xie, Adi Danieli-Mackay, Mariachiara Buccarelli, Mariano Barbieri, Ioanna Papadionysiou, Q Giorgio D'Alessandris, Claudia Robens, Nadine Übelmesser, Omkar Suhas Vinchure, Liverana Lauretti, Giorgio Fotia, Roland F Schwarz, Xiaotao Wang, Lucia Ricci-Vitiani, Jay Gopalakrishnan, Roberto Pallini, Argyris Papantonis.
      Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41467-024-48053-2
  34. Cell Death Dis. 2024 May 06. 15(5): 319
    ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis.
    Wensong Luo, Zizheng Zou, Yuan Nie, Junli Luo, Zhengnan Ming, Xiyuan Hu, Tiao Luo, Min Ouyang, Mingquan Liu, Huicheng Tang, Yuanzhu Xie, Kunjian Peng, Ling Chen, Jiang Zhou, Zhiyong Luo.
      Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.
    DOI:  https://doi.org/10.1038/s41419-024-06672-z
  35. Sci Adv. 2024 May 10. 10(19): eadl3549
    Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart.
    Qingbo Lv, Duanbin Li, Liding Zhao, Pengcheng Yu, Yecheng Tao, Qiongjun Zhu, Yao Wang, Meihui Wang, Guosheng Fu, Min Shang, Wenbin Zhang.
      Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
    DOI:  https://doi.org/10.1126/sciadv.adl3549
  36. PLoS Biol. 2024 May 07. 22(5): e3002299
    Glucose and trehalose metabolism through the cyclic pentose phosphate pathway shapes pathogen resistance and host protection in Drosophila.
    Michalina Kazek, Lenka Chodáková, Katharina Lehr, Lukáš Strych, Pavla Nedbalová, Ellen McMullen, Adam Bajgar, Stanislav Opekar, Petr Šimek, Martin Moos, Tomáš Doležal.
      Activation of immune cells requires the remodeling of cell metabolism in order to support immune function. We study these metabolic changes through the infection of Drosophila larvae by parasitoid wasp. The parasitoid egg is neutralized by differentiating lamellocytes, which encapsulate the egg. A melanization cascade is initiated, producing toxic molecules to destroy the egg while the capsule also protects the host from the toxic reaction. We combined transcriptomics and metabolomics, including 13C-labeled glucose and trehalose tracing, as well as genetic manipulation of sugar metabolism to study changes in metabolism, specifically in Drosophila hemocytes. We found that hemocytes increase the expression of several carbohydrate transporters and accordingly uptake more sugar during infection. These carbohydrates are metabolized by increased glycolysis, associated with lactate production, and cyclic pentose phosphate pathway (PPP), in which glucose-6-phosphate is re-oxidized to maximize NADPH yield. Oxidative PPP is required for lamellocyte differentiation and resistance, as is systemic trehalose metabolism. In addition, fully differentiated lamellocytes use a cytoplasmic form of trehalase to cleave trehalose to glucose and fuel cyclic PPP. Intracellular trehalose metabolism is not required for lamellocyte differentiation, but its down-regulation elevates levels of reactive oxygen species, associated with increased resistance and reduced fitness. Our results suggest that sugar metabolism, and specifically cyclic PPP, within immune cells is important not only to fight infection but also to protect the host from its own immune response and for ensuring fitness of the survivor.
    DOI:  https://doi.org/10.1371/journal.pbio.3002299
  37. EMBO J. 2024 May 08.
    Mutational robustness and the role of buffer genes in evolvability.
    Mohammed T Tawfeeq, Karin Voordeckers, Pieter van den Berg, Sander K Govers, Jan Michiels, Kevin J Verstrepen.
      Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.
    Keywords:  Cryptic Genetic Variation; Evolvability; Genetic Buffering; Hsp90; Mutational Robustness
    DOI:  https://doi.org/10.1038/s44318-024-00109-1
  38. iScience. 2024 May 17. 27(5): 109775
    Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
    Nikhila S Bharadwaj, Nicholas A Zumwalde, Arvinder Kapur, Manish Patankar, Jenny E Gumperz.
      The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector T cells ultimately limits anti-tumor immunity. Memory phenotype (MP) T cells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4+ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4+ T cells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak T cell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.
    Keywords:  cell biology; immunity
    DOI:  https://doi.org/10.1016/j.isci.2024.109775
  39. Nat Aging. 2024 May 09.
    Aging clocks based on accumulating stochastic variation.
    David H Meyer, Björn Schumacher.
      Aging clocks have provided one of the most important recent breakthroughs in the biology of aging, and may provide indicators for the effectiveness of interventions in the aging process and preventive treatments for age-related diseases. The reproducibility of accurate aging clocks has reinvigorated the debate on whether a programmed process underlies aging. Here we show that accumulating stochastic variation in purely simulated data is sufficient to build aging clocks, and that first-generation and second-generation aging clocks are compatible with the accumulation of stochastic variation in DNA methylation or transcriptomic data. We find that accumulating stochastic variation is sufficient to predict chronological and biological age, indicated by significant prediction differences in smoking, calorie restriction, heterochronic parabiosis and partial reprogramming. Although our simulations may not explicitly rule out a programmed aging process, our results suggest that stochastically accumulating changes in any set of data that have a ground state at age zero are sufficient for generating aging clocks.
    DOI:  https://doi.org/10.1038/s43587-024-00619-x
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