bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–07–28
fifty-five papers selected by
Christian Frezza, Universität zu Köln
  1. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  2. Complex roles for mitochondrial complexes in microglia.
  3. 100 years of the Warburg effect: A cancer metabolism endeavor.
  4. Germline regulation of the somatic mitochondrial stress response.
  5. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
  6. VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.
  7. SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
  8. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  9. Unravelling the origins and forces that shape mtDNA mutations in human cells.
  10. Metabolic Messengers: itaconate.
  11. Separation of reproductive decline from lifespan extension during methionine restriction.
  12. Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
  13. The HuMet Repository: Watching human metabolism at work.
  14. SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.
  15. Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.
  16. Autocrine glutamate signaling drives cell competition in Drosophila.
  17. Ring around the mitochondria.
  18. Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
  19. Parameter Estimation and Identifiability in Kinetic Flux Profiling Models of Metabolism.
  20. Metabolism and HSC fate: what NADPH is made for.
  21. Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.
  22. PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
  23. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
  24. The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
  25. Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
  26. Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
  27. Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells.
  28. 3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.
  29. Germline loss in C. elegans enhances longevity by disrupting adhesion between niche and stem cells.
  30. Metabolic determinants of germinal center B cell formation and responses.
  31. Cancer and Our Body Clock: Disrupting circadian rhythms is tied to cancer. Bolstering them might prevent it.
  32. HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.
  33. Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
  34. Detection of ROS in Dormant Breast Cancer Cell.
  35. Higher central circadian temperature amplitude is associated with greater metabolite rhythmicity in humans.
  36. Lactate: a missing link between metabolism and inflammation in CKD progression?
  37. 13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
  38. Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations.
  39. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
  40. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
  41. Metabolic heterogeneity in humans.
  42. Iron scavenging and myeloid cell polarization.
  43. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
  44. Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
  45. STING: Stay near to STIM(1) neuroprotection.
  46. Nuclear pyruvate dehydrogenase complex regulates histone acetylation and transcriptional regulation in the ethylene response.
  47. Metabolic Regulation in the Induction of Trained Immunity.
  48. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
  49. 50 years of metabolism research at Cell.
  50. The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.
  51. MetalinksDB: a flexible and contextualizable resource of metabolite-protein interactions.
  52. Mitochondrial DNA mosaicism in normal human somatic cells.
  53. An intestinal TH17 cell-derived subset can initiate cancer.
  54. Multi-omic characterization of antibody-producing CHO cell lines elucidates metabolic reprogramming and nutrient uptake bottlenecks.
  55. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  1. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  2. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
  3. Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828
    100 years of the Warburg effect: A cancer metabolism endeavor.
    Sarah-Maria Fendt.
      If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?
    DOI:  https://doi.org/10.1016/j.cell.2024.06.026
  4. Trends Cell Biol. 2024 Jul 20. pii: S0962-8924(24)00142-9. [Epub ahead of print]
    Germline regulation of the somatic mitochondrial stress response.
    Liankui Zhou, Ying Liu.
      Mitochondria are pivotal organelles for cellular energy production and the regulation of stress responses. Recent research has elucidated complex mechanisms through which mitochondrial stress in one tissue can impact distant tissues, thereby promoting overall organismal health. Two recent studies by Shen et al. and Charmpilas et al. have demonstrated that an intact germline serves as a crucial signaling hub for the activation of the somatic mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans.
    Keywords:  UPR(mt); cell-nonautonomous; germline; mitochondria; stress response
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.004
  5. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496
    Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
    Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.
      The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
    Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114496
  6. iScience. 2024 Jul 19. 27(7): 110285
    VHL loss enhances antitumor immunity by activating the anti-viral DNA-sensing pathway.
    Meng Jiao, Mengjie Hu, Dong Pan, Xinjian Liu, Xuhui Bao, Jonathan Kim, Fang Li, Chuan-Yuan Li.
      von Hippel-Lindau (VHL), known as a tumor suppressor gene, is frequently mutated in clear cell renal cell carcinoma (ccRCC). However, VHL mutation is not sufficient to promote tumor formation. In most cases other than ccRCC, VHL loss alters cellular homeostasis and causes cell stress and metabolic changes by stabilizing hypoxia-inducible factor (HIF) levels, resulting in a fitness disadvantage. In addition, the function of VHL in regulating immune response is still not well established. In this study, we demonstrate that VHL loss enhances the efficacy of anti-programmed death 1 (PD1) treatment in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α/2α induced by VHL loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA, which triggered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation and induced type I interferons. Our study thus provided mechanistic insights into the role of VHL gene loss in boosting antitumor immunity.
    Keywords:  Cancer; Cell biology; Immunity; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110285
  7. Mol Genet Metab. 2024 Jun 20. pii: S1096-7192(24)00402-5. [Epub ahead of print]143(1-2): 108518
    SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
    David J Bernard, Faith Pangilinan, Caitlin Mendina, Tara Desporte, Stephen M Wincovitch, Darren J Walsh, Richard K Porter, Anne M Molloy, Barry Shane, Lawrence C Brody.
      Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.
    Keywords:  Betaine; Choline; Inner mitochondrial membrane transport; Mitochondria; One carbon metabolism; SLC25A48
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108518
  8. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  9. Nat Genet. 2024 Jul 26.
    Unravelling the origins and forces that shape mtDNA mutations in human cells.
      
    DOI:  https://doi.org/10.1038/s41588-024-01837-0
  10. Nat Metab. 2024 Jul 26.
    Metabolic Messengers: itaconate.
    A F McGettrick, L A Bourner, F C Dorsey, L A J O'Neill.
      The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01092-x
  11. Nat Aging. 2024 Jul 26.
    Separation of reproductive decline from lifespan extension during methionine restriction.
    Fangchao Wei, Shiyu Liu, Juan Liu, Yudong Sun, Annamarie E Allen, Michael A Reid, Jason W Locasale.
      Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline.
    DOI:  https://doi.org/10.1038/s43587-024-00674-4
  12. Nat Chem Biol. 2024 Jul 26.
    Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
    Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye.
      Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.
    DOI:  https://doi.org/10.1038/s41589-024-01689-z
  13. Cell Rep. 2024 Jul 20. pii: S2211-1247(24)00745-9. [Epub ahead of print]43(8): 114416
    The HuMet Repository: Watching human metabolism at work.
    Patrick Weinisch, Johannes Raffler, Werner Römisch-Margl, Matthias Arnold, Robert P Mohney, Manuela J Rist, Cornelia Prehn, Thomas Skurk, Hans Hauner, Hannelore Daniel, Karsten Suhre, Gabi Kastenmüller.
      Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.
    Keywords:  CP: Metabolism; dynamic metabolic responses in health; exercise metabolism; metabolic flexibility; metabolomics platform comparison; oral glucose tolerance test; oral lipid tolerance test; postprandial metabolism; prolonged/extended fasting; standardized physiological challenge tests; time-series metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114416
  14. Nature. 2024 Jul 24.
    SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.
    Juhyung Park, Jibo Wu, Krzysztof J Szkop, Jinho Jeong, Predrag Jovanovic, Dylan Husmann, Natasha M Flores, Joel W Francis, Ying-Jiun C Chen, Ana Morales Benitez, Emily Zahn, Shumei Song, Jaffer A Ajani, Linghua Wang, Kamini Singh, Ola Larsson, Benjamin A Garcia, Ivan Topisirovic, Or Gozani, Pawel K Mazur.
      Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.
    DOI:  https://doi.org/10.1038/s41586-024-07718-0
  15. Int J Mol Sci. 2024 Jul 09. pii: 7544. [Epub ahead of print]25(14):
    Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.
    Junichi Fujii, Hirotaka Imai.
      Ferroptosis is a type of nonapoptotic cell death that is characteristically caused by phospholipid peroxidation promoted by radical reactions involving iron. Researchers have identified many of the protein factors that are encoded by genes that promote ferroptosis. Glutathione peroxidase 4 (GPX4) is a key enzyme that protects phospholipids from peroxidation and suppresses ferroptosis in a glutathione-dependent manner. Thus, the dysregulation of genes involved in cysteine and/or glutathione metabolism is closely associated with ferroptosis. From the perspective of cell dynamics, actively proliferating cells are more prone to ferroptosis than quiescent cells, which suggests that radical species generated during oxygen-involved metabolism are responsible for lipid peroxidation. Herein, we discuss the initial events involved in ferroptosis that dominantly occur in the process of energy metabolism, in association with cysteine deficiency. Accordingly, dysregulation of the tricarboxylic acid cycle coupled with the respiratory chain in mitochondria are the main subjects here, and this suggests that mitochondria are the likely source of both radical electrons and free iron. Since not only carbohydrates, but also amino acids, especially glutamate, are major substrates for central metabolism, dealing with nitrogen derived from amino groups also contributes to lipid peroxidation and is a subject of this discussion.
    Keywords:  glycolysis; metabolic remodeling; tricarboxylic acid cycle; urea cycle
    DOI:  https://doi.org/10.3390/ijms25147544
  16. Dev Cell. 2024 Jul 17. pii: S1534-5807(24)00400-3. [Epub ahead of print]
    Autocrine glutamate signaling drives cell competition in Drosophila.
    Carmo Castilho Soares, Alberto Rizzo, Marta Forés Maresma, Pascal Meier.
      Cell competition is an evolutionarily conserved quality control process that eliminates suboptimal or potentially dangerous cells. Although differential metabolic states act as direct drivers of competition, how these are measured across tissues is not understood. Here, we demonstrate that vesicular glutamate transporter (VGlut) and autocrine glutamate signaling are required for cell competition and Myc-driven super-competition in the Drosophila epithelia. We find that the loss of glutamate-stimulated VGlut>NMDAR>CaMKII>CrebB signaling triggers loser status and cell death under competitive settings via the autocrine induction of TNF. This in turn drives TNFR>JNK activation, triggering loser cell elimination and PDK/LDH-dependent metabolic reprogramming. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbors nullifies cell competition. Further, in a Drosophila model for premalignancy, Myc-overexpressing clones co-opt this signaling circuit to acquire super-competitor status. Targeting glutamate signaling converts Myc "super-competitor" clones into "losers," highlighting new therapeutic opportunities to restrict the evolution of fitter clones.
    Keywords:  Myc; NMDAR; TNF-JNK; VGlut; cell competition; glutamate; lactate
    DOI:  https://doi.org/10.1016/j.devcel.2024.06.022
  17. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  18. Redox Biol. 2024 Jul 20. pii: S2213-2317(24)00254-4. [Epub ahead of print]75 103276
    Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
    Marco Biondini, Camille Lehuédé, Sébastien Tabariès, Matthew G Annis, Alain Pacis, Eric H Ma, Christine Tam, Brian E Hsu, Yannick Audet-Delage, Afnan Abu-Thuraia, Charlotte Girondel, Valerie Sabourin, Stephanie P Totten, Mariana de Sá Tavares Russo, Gaëlle Bridon, Daina Avizonis, Marie-Christine Guiot, Julie St-Pierre, Josie Ursini-Siegel, Russell Jones, Peter M Siegel.
      Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.
    Keywords:  Breast cancer; GCLC; Glutathione; Glycolysis; HIF-1α; Liver metastasis; Metabolism; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2024.103276
  19. ArXiv. 2024 Jul 11. pii: arXiv:2407.08844v1. [Epub ahead of print]
    Parameter Estimation and Identifiability in Kinetic Flux Profiling Models of Metabolism.
    Breanna Guppy, Colleen Mitchell, Eric Taylor.
      Metabolic fluxes are the rates of life-sustaining chemical reactions within a cell and metabolites are the components. Determining the changes in these fluxes is crucial to understanding diseases with metabolic causes and consequences. Kinetic flux profiling (KFP) is a method for estimating flux that utilizes data from isotope tracing experiments. In these experiments, the isotope-labeled nutrient is metabolized through a pathway and integrated into the downstream metabolite pools. Measurements of proportion labeled for each metabolite in the pathway are taken at multiple time points and used to fit an ordinary differential equations model with fluxes as parameters. We begin by generalizing the process of converting diagrams of metabolic pathways into mathematical models composed of differential equations and algebraic constraints. The scaled differential equations for proportions of unlabeled metabolite contain parameters related to the metabolic fluxes in the pathway. We investigate flux parameter identifiability given data collected only at the steady state of the differential equation. Next, we give criteria for valid parameter estimations in the case of a large separation of timescales with fast-slow analysis. Bayesian parameter estimation on simulated data from KFP experiments containing both irreversible and reversible reactions illustrates the accuracy and reliability of flux estimations. These analyses provide constraints that serve as guidelines for the design of KFP experiments to estimate metabolic fluxes.
  20. Trends Cell Biol. 2024 Jul 24. pii: S0962-8924(24)00141-7. [Epub ahead of print]
    Metabolism and HSC fate: what NADPH is made for.
    Claudia Morganti, Massimo Bonora, Keisuke Ito.
      Mitochondrial metabolism plays a central role in the regulation of hematopoietic stem cell (HSC) biology. Mitochondrial fatty acid oxidation (FAO) is pivotal in controlling HSC self-renewal and differentiation. Herein, we discuss recent evidence suggesting that NADPH generated in the mitochondria can influence the fate of HSCs. Although NADPH has multiple functions, HSCs show high levels of NADPH that are preferentially used for cholesterol biosynthesis. Endogenous cholesterol supports the biogenesis of extracellular vesicles (EVs), which are essential for maintaining HSC properties. We also highlight the significance of EVs in hematopoiesis through autocrine signaling. Elucidating the mitochondrial NADPH-cholesterol axis as part of the metabolic requirements of healthy HSCs will facilitate the development of new therapies for hematological disorders.
    Keywords:  FAO; HSC self-renewal; cholesterol; exosome; hematopoiesis; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.07.003
  21. Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00852-0. [Epub ahead of print]43(8): 114523
    Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks.
    Victoria A Acosta-Rodríguez, Filipa Rijo-Ferreira, Laura van Rosmalen, Mariko Izumo, Noheon Park, Chryshanthi Joseph, Chelsea Hepler, Anneke K Thorne, Jeremy Stubblefield, Joseph Bass, Carla B Green, Joseph S Takahashi.
      Extended food consumption during the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain, leading to adverse health effects. Beyond the liver, how metabolic organs respond to a timed hypocaloric diet is largely unexplored. We investigated how feeding schedules impacted circadian gene expression in epididymal white and brown adipose tissue (eWAT and BAT) compared to the liver and hypothalamus. We restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. Unlike the liver and eWAT, rhythmic clock genes in the BAT remained insensitive to feeding time, similar to the hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating tissue-specific responses on circadian transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at unusual times.
    Keywords:  CP: Metabolism; brown adipose tissue; caloric restriction; circadian clocks; dietary interventions; liver; misaligned feeding; mouse behavior; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2024.114523
  22. Int J Mol Sci. 2024 Jul 15. pii: 7738. [Epub ahead of print]25(14):
    PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
    Fedho Kusuma, Soyoung Park, Kim Anh Nguyen, Rosalie Elvira, Duckgue Lee, Jaeseok Han.
      Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.
    Keywords:  PKR; UPRMT; integrated stress response; mitochondrial dsRNAs; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms25147738
  23. Nat Commun. 2024 Jul 21. 15(1): 6152
    Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
    Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P Duncan, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary R Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Joshua Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.
      Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
    DOI:  https://doi.org/10.1038/s41467-024-50454-2
  24. Nucleic Acids Res. 2024 Jul 22. pii: gkae645. [Epub ahead of print]
    The human mitochondrial translation factor TACO1 alleviates mitoribosome stalling at polyproline stretches.
    Michele Brischigliaro, Annika Krüger, J Conor Moran, Hana Antonicka, Ahram Ahn, Eric A Shoubridge, Joanna Rorbach, Antoni Barrientos.
      The prokaryotic translation elongation factor P (EF-P) and the eukaryotic/archaeal counterparts eIF5A/aIF5A are proteins that serve a crucial role in mitigating ribosomal stalling during the translation of specific sequences, notably those containing consecutive proline residues (1,2). Although mitochondrial DNA-encoded proteins synthesized by mitochondrial ribosomes also contain polyproline stretches, an EF-P/eIF5A mitochondrial counterpart remains unidentified. Here, we show that the missing factor is TACO1, a protein causative of a juvenile form of neurodegenerative Leigh's syndrome associated with cytochrome c oxidase deficiency, until now believed to be a translational activator of COX1 mRNA. By using a combination of metabolic labeling, puromycin release and mitoribosome profiling experiments, we show that TACO1 is required for the rapid synthesis of the polyproline-rich COX1 and COX3 cytochrome c oxidase subunits, while its requirement is negligible for other mitochondrial DNA-encoded proteins. In agreement with a role in translation efficiency regulation, we show that TACO1 cooperates with the N-terminal extension of the large ribosomal subunit bL27m to provide stability to the peptidyl-transferase center during elongation. This study illuminates the translation elongation dynamics within human mitochondria, a TACO1-mediated biological mechanism in place to mitigate mitoribosome stalling at polyproline stretches during protein synthesis, and the pathological implications of its malfunction.
    DOI:  https://doi.org/10.1093/nar/gkae645
  25. Nat Genet. 2024 Jul 24.
    Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
    Amin Abedini, Jonathan Levinsohn, Konstantin A Klötzer, Bernhard Dumoulin, Ziyuan Ma, Julia Frederick, Poonam Dhillon, Michael S Balzer, Rojesh Shrestha, Hongbo Liu, Steven Vitale, Andi M Bergeson, Kishor Devalaraja-Narashimha, Paola Grandi, Tanmoy Bhattacharyya, Erding Hu, Steven S Pullen, Carine M Boustany-Kari, Paolo Guarnieri, Anil Karihaloo, Daniel Traum, Hanying Yan, Kyle Coleman, Matthew Palmer, Lea Sarov-Blat, Lori Morton, Christopher A Hunter, Klaus H Kaestner, Mingyao Li, Katalin Susztak.
      Kidneys are intricate three-dimensional structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. We generated high-quality datasets for 81 samples, including single-cell, single-nuclear, spot-level (Visium) and single-cell resolution (CosMx) spatial-RNA expression and single-nuclear open chromatin, capturing cells from healthy, diabetic and hypertensive diseased human kidneys. Combining these data, we identify cell types and map them to their locations within the tissue. Unbiased deconvolution of the spatial data identifies the following four distinct microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex organization of microenvironments in health and disease and find that the fibrotic microenvironment is able to molecularly classify human kidneys and offers an improved prognosis compared to traditional histopathology. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
    DOI:  https://doi.org/10.1038/s41588-024-01802-x
  26. Immunity. 2024 Jul 16. pii: S1074-7613(24)00320-0. [Epub ahead of print]
    Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
    Frank A Buquicchio, Raissa Fonseca, Patrick K Yan, Fangyi Wang, Maximilien Evrard, Andreas Obers, Jacob C Gutierrez, Colin J Raposo, Julia A Belk, Bence Daniel, Pirooz Zareie, Kathryn E Yost, Yanyan Qi, Yajie Yin, Katherine F Nico, Flora M Tierney, Michael R Howitt, Caleb A Lareau, Ansuman T Satpathy, Laura K Mackay.
      The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
    Keywords:  chromatin accessibility; development; epigenetics; regulatory elements; single-cell genomics; tissue immunity; tissue-resident memory T cells; transcriptional regulators
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.014
  27. Int J Mol Sci. 2024 Jul 16. pii: 7797. [Epub ahead of print]25(14):
    Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells.
    Olga Cela, Rosella Scrima, Consiglia Pacelli, Michela Rosiello, Claudia Piccoli, Nazzareno Capitanio.
      Circadian oscillations of several physiological and behavioral processes are an established process in all the organisms anticipating the geophysical changes recurring during the day. The time-keeping mechanism is controlled by a transcription translation feedback loop involving a set of well-characterized transcription factors. The synchronization of cells, controlled at the organismal level by a brain central clock, can be mimicked in vitro, pointing to the notion that all the cells are endowed with an autonomous time-keeping system. Metabolism undergoes circadian control, including the mitochondrial terminal catabolic pathways, culminating under aerobic conditions in the electron transfer to oxygen through the respiratory chain coupled to the ATP synthesis according to the oxidative phosphorylation chemiosmotic mechanism. In this study, we expanded upon previous isolated observations by utilizing multiple cell types, employing various synchronization protocols and different methodologies to measure mitochondrial oxygen consumption rates under conditions simulating various metabolic stressors. The results obtained clearly demonstrate that mitochondrial respiratory activity undergoes rhythmic oscillations in all tested cell types, regardless of their individual respiratory proficiency, indicating a phenomenon that can be generalized. However, notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes. This observation confirms on the one hand the dysregulation of the circadian control of the oxidative metabolism observed in cancer, likely contributing to its development, and on the other hand underscores the necessity of personalized chronotherapy, which necessitates a detailed characterization of the cancer chronotype.
    Keywords:  Cosinor analysis; circadian rhythms; in vitro synchronization; mitochondrial respiration; oxygen consumption measurement
    DOI:  https://doi.org/10.3390/ijms25147797
  28. Nat Commun. 2024 Jul 20. 15(1): 6130
    3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression.
    Katelyn L Mortenson, Courtney Dawes, Emily R Wilson, Nathan E Patchen, Hailey E Johnson, Jason Gertz, Swneke D Bailey, Yang Liu, Katherine E Varley, Xiaoyang Zhang.
      Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC's enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.
    DOI:  https://doi.org/10.1038/s41467-024-50387-w
  29. EMBO J. 2024 Jul 25.
    Germline loss in C. elegans enhances longevity by disrupting adhesion between niche and stem cells.
    Meng Liu, Jiehui Chen, Guizhong Cui, Yumin Dai, Mengjiao Song, Chunyu Zhou, Qingyuan Hu, Qingxia Chen, Hongwei Wang, Wanli Chen, Jingdong Jackie Han, Guangdun Peng, Naihe Jing, Yidong Shen.
      Ageing and fertility are intertwined. Germline loss extends the lifespan in various organisms, termed gonadal longevity. However, the original longevity signal from the somatic gonad remains poorly understood. Here, we focused on the interaction between germline stem cells (GSCs) and their niche, the distal tip cells (DTCs), to explore the barely known longevity signal from the somatic gonad in C. elegans. We found that removing germline disrupts the cell adhesions between GSC and DTC, causing a significant transcriptomic change in DTC through hmp-2/β-catenin and two GATA transcription factors, elt-3 and pqm-1 in this niche cell. Inhibiting elt-3 and pqm-1 in DTC suppresses gonadal longevity. Moreover, we further identified the TGF-β ligand, tig-2, as the cytokine from DTC upon the loss of germline, which evokes the downstream gonadal longevity signalling throughout the body. Our findings thus reveal the source of the longevity signalling in response to germline removal, highlighting the stem cell niche as a critical signalling hub in ageing.
    Keywords:   C. elegans ; Cell Adhesion; Gonadal Longevity; Niche
    DOI:  https://doi.org/10.1038/s44318-024-00185-3
  30. Nat Chem Biol. 2024 Jul 26.
    Metabolic determinants of germinal center B cell formation and responses.
    Jun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Chen Xiang, Haiyan Chen, Peng Jiang.
      Germinal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione. MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway. Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination.
    DOI:  https://doi.org/10.1038/s41589-024-01690-6
  31. Sci Am. 2023 Jul 01. 329(1): 22
    Cancer and Our Body Clock: Disrupting circadian rhythms is tied to cancer. Bolstering them might prevent it.
    Lydia Denworth.
      
    DOI:  https://doi.org/10.1038/scientificamerican0723-22
  32. Cell Death Discov. 2024 Jul 24. 10(1): 338
    HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.
    J Contenti, Y Guo, M Larcher, L Mirabal-Ortega, M Rouleau, M Irondelle, V Tiroille, A Mazzu, V Duranton-Tanneur, F Pedeutour, I Ben-Sahra, C Lago, G Leva, L Tiberi, G Robert, C Pouponnot, F Bost, N M Mazure.
      Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.
    DOI:  https://doi.org/10.1038/s41420-024-02100-5
  33. Nat Commun. 2024 Jul 23. 15(1): 6213
    Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots.
    Pallavi Kompella, Guliang Wang, Russell E Durrett, Yanhao Lai, Celeste Marin, Yuan Liu, Samy L Habib, John DiGiovanni, Karen M Vasquez.
      Obesity is associated with increased cancer risk, yet the underlying mechanisms remain elusive. Obesity-associated cancers involve disruptions in metabolic and cellular pathways, which can lead to genomic instability. Repetitive DNA sequences capable of adopting alternative DNA structures (e.g., H-DNA) stimulate mutations and are enriched at mutation hotspots in human cancer genomes. However, it is not known if obesity impacts DNA repeat-mediated endogenous mutation hotspots. We address this gap by measuring mutation frequencies in obese and normal-weight transgenic reporter mice carrying either a control human B-DNA- or an H-DNA-forming sequence (from a translocation hotspot in c-MYC in Burkitt lymphoma). Here, we discover that H-DNA-induced DNA damage and mutations are elevated in a tissue-specific manner, and DNA repair efficiency is reduced in obese mice compared to those on the control diet. These findings elucidate the impact of obesity on cancer-associated endogenous mutation hotspots, providing mechanistic insight into the link between obesity and cancer.
    DOI:  https://doi.org/10.1038/s41467-024-50006-8
  34. Methods Mol Biol. 2024 ;2811 185-193
    Detection of ROS in Dormant Breast Cancer Cell.
    Patrizia Romani, Sirio Dupont.
      Reactive oxygen species (ROS) production can occur both as a physiological response and because of oxidative stress. ROS are not only the end product of nonfunctional cell processes but also signaling molecules that can regulate cell and tissue homeostasis. Recently, we have discovered that metastatic breast cancer cells that lay dormant in the lung microenvironment activate mitochondrial ROS production in response to the mechanical properties of the ECM, which triggers an antioxidant response mediated by the NRF2 transcription factor. In turn, this response protects dormant metastatic cells from cisplatin chemotherapy. Many tools have been developed to monitor ROS production in cells in culture, while our ability to detect this in vivo remains limited. Here we describe a detailed protocol for determination of ROS in metastatic cells in the mouse lung tissue by detecting 4-hydroxy-2-noneal (4HNE) adducts formation in fixed tissues.
    Keywords:  4HNE; Frozen tissue; Immunostaining; Lipid peroxidation; ROS
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_14
  35. Sci Rep. 2024 Jul 22. 14(1): 16796
    Higher central circadian temperature amplitude is associated with greater metabolite rhythmicity in humans.
    Daniel P Windred, Clare Anderson, Katherine J Jeppe, Suzanne Ftouni, Leilah K Grant, Brunda Nijagal, Shantha M W Rajaratnam, Malcolm McConville, Dedreia Tull, Steven W Lockley, Sean W Cain, Andrew J K Phillips.
      Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body. We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-h constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [± SD] age = 25.4 ± 5.7 years, 5 women). Valid core body temperature data were available in 17/23 (mean [± SD] age = 25.6 ± 6.3 years, 1 woman). Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R2 = 0.37, p = .009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R2 = 0.47, p = .002). These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock.
    Keywords:  Biological rhythms; Circadian clock; Circadian organization; Core body temperature; Peripheral oscillators
    DOI:  https://doi.org/10.1038/s41598-024-67297-y
  36. Kidney Int. 2024 Aug;pii: S0085-2538(24)00390-9. [Epub ahead of print]106(2): 183-185
    Lactate: a missing link between metabolism and inflammation in CKD progression?
    Nobuaki Nishima, Shinji Tanaka.
      Persistent enhancement of glycolysis in kidney tubular epithelial cells has been linked to the progression of chronic kidney disease, although the underlying mechanisms are largely unknown. In this issue of Kidney International, Wang et al. report that the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 plays a crucial role in kidney fibrosis by enhancing histone H4 lysine 12 lactylation through lactate accumulation. This increases the transcription of nuclear factor-κB-related genes and promotes inflammation and fibrosis. Inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 reduces these effects, indicating therapeutic potential for kidney fibrosis.
    DOI:  https://doi.org/10.1016/j.kint.2024.05.016
  37. Methods Mol Biol. 2024 ;2811 195-206
    13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
    Patricia Altea-Manzano, Sarah-Maria Fendt, Laura Vera-Ramirez.
      Over the last two decades, major advances in the field of tumor dormancy have been made. Yet, it is not completely understood how dormant disseminated tumor cells survive and transition to a proliferative state to generate a metastatic lesion. On the other hand, metabolic rewiring has been shown to influence metastasis development through the modulation of both intracellular signaling and the crosstalk between metastatic cells and their microenvironment. Thus, studying the metabolic features of dormant disseminated tumor cells has gained importance in understanding the dormancy process. Here, we describe a method to perform metabolomics and 13C tracer analysis in 3D cultures of dormant breast cancer cells.
    Keywords:  13C tracing; 3D cell culture; Cancer; Disseminated tumor cells; Mass spectrometry; Metabolomics; Metastasis; Tumor cell dormancy
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_15
  38. Nat Commun. 2024 Jul 20. 15(1): 6139
    Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations.
    Elizaveta Besedina, Fran Supek.
      Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations.
    DOI:  https://doi.org/10.1038/s41467-024-50552-1
  39. Nat Commun. 2024 Jul 22. 15(1): 6172
    Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
    Benjamin S Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A Adair, Ajit Elhance, Moemen Eltobgy, Francesca M Coan, Lexie Chafin, Jessica A Joseph, Alex Cornwell, Finny J Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S Bednash, James D Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S Lee, Bill B Chen, Rama K Mallampalli.
      The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50031-7
  40. Nat Metab. 2024 Jul 24.
    Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
    Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.
      Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
    DOI:  https://doi.org/10.1038/s42255-024-01081-0
  41. Cell. 2024 Jul 25. pii: S0092-8674(24)00708-6. [Epub ahead of print]187(15): 3821-3823
    Metabolic heterogeneity in humans.
    Heather Christofk, Christian Metallo, Guanghui Liu, Joshua Rabinowitz, Lauren Sparks, David James.
      Recent advancements in technology, especially the emergence of single-cell technologies, genomic sequencing, metabolomics, and artificial intelligence, have enabled us to understand the distinct metabolic changes in different cell types, tissues, genders, disease states, ages, and populations. Six scientists whose work intersects with metabolism in various capacities tell us about their vision for human metabolic heterogeneity.
    DOI:  https://doi.org/10.1016/j.cell.2024.06.033
  42. Trends Immunol. 2024 Jul 24. pii: S1471-4906(24)00155-8. [Epub ahead of print]
    Iron scavenging and myeloid cell polarization.
    Natalie Ludwig, Stefania Cucinelli, Simon Hametner, Martina U Muckenthaler, Lucas Schirmer.
      Myeloid cells that populate all human organs and blood are a versatile class of innate immune cells. They are crucial for sensing and regulating processes as diverse as tissue homeostasis and inflammation and are frequently characterized by their roles in either regulating or promoting inflammation. Recent studies in cultured cells and mouse models highlight the role of iron in skewing the functional properties of myeloid cells in tissue damage and repair. Here, we review certain emerging concepts on how iron influences and determines myeloid cell polarization in the context of its uptake, storage, and metabolism, including in conditions such as multiple sclerosis (MS), sickle cell disease, and tumors.
    Keywords:  hemolysis; macrophages; multiple sclerosis; neuroinflammation; sickle cell disease; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2024.06.006
  43. Nat Commun. 2024 Jul 22. 15(1): 6162
    Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
    Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A Stewart, Karine A Atlan, Gideon Zamir, Ben Z Stanger, Michael Berger, Ittai Ben-Porath.
      Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-50441-7
  44. Sci Adv. 2024 Jul 26. 10(30): eado5103
    Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
    Ashley L Kiemen, Pei-Hsun Wu, Alicia M Braxton, Toby C Cornish, Ralph H Hruban, Laura D Wood, Denis Wirtz, David Zwicker.
      Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence suggests that pancreatic intraepithelial neoplasia (PanIN), a microscopic precursor lesion that gives rise to pancreatic cancer, is larger and more prevalent than previously believed. Better understanding of the growth-law dynamics of PanINs may improve our ability to understand how a miniscule fraction makes the transition to invasive cancer. Here, using three-dimensional tissue mapping, we analyzed >1000 PanINs and found that lesion size is distributed according to a power law. Our data suggest that in bulk, PanIN size can be predicted by general growth behavior without consideration for the heterogeneity of the pancreatic microenvironment or an individual's age, history, or lifestyle. Our models suggest that intraductal spread and fusing of lesions drive our observed size distribution. This analysis lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, and molecular features to understand tumorigenesis and demonstrates the utility of combining experimental measurement with dynamic modeling in understanding tumorigenesis.
    DOI:  https://doi.org/10.1126/sciadv.ado5103
  45. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00541-0. [Epub ahead of print]84(14): 2596-2597
    STING: Stay near to STIM(1) neuroprotection.
    Hong-Gyun Lee, Francisco J Quintana.
      In a recent publication in Cell, Woo et al.1 report that stimulator of interferon genes (STING) links inflammation with glutamate-driven excitotoxicity to induce ferroptosis, identifying a mechanism of inflammation-induced neurodegeneration and also a novel candidate therapeutic target for multiple sclerosis.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.034
  46. Sci Adv. 2024 Jul 26. 10(30): eado2825
    Nuclear pyruvate dehydrogenase complex regulates histone acetylation and transcriptional regulation in the ethylene response.
    Zhengyao Shao, Liangqiao Bian, Shyon K Ahmadi, Tyler J Daniel, Miguel A Belmonte, Jackson G Burns, Prashanth Kotla, Yang Bi, Zhouxin Shen, Shou-Ling Xu, Zhi-Yong Wang, Steven P Briggs, Hong Qiao.
      Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesizes nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme-mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
    DOI:  https://doi.org/10.1126/sciadv.ado2825
  47. Semin Immunopathol. 2024 Jul 25. 46(3-4): 7
    Metabolic Regulation in the Induction of Trained Immunity.
    Anaisa V Ferreira, Jorge Domínguez-Andrés, Laura M Merlo Pich, Leo A B Joosten, Mihai G Netea.
      The innate immune system exhibits features of memory, termed trained immunity, which promote faster and more robust responsiveness to heterologous challenges. Innate immune memory is sustained through epigenetic modifications, affecting gene accessibility, and promoting a tailored gene transcription for an enhanced immune response. Alterations in the epigenetic landscape are intertwined with metabolic rewiring. Here, we review the metabolic pathways that underscore the induction and maintenance of trained immunity, including glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, and amino acid and lipid metabolism. The intricate interplay of these pathways is pivotal for establishing innate immune memory in distinct cellular compartments. We explore in particular the case of resident lung alveolar macrophages. We propose that leveraging the memory of the innate immune system may present therapeutic potential. Specifically, targeting the metabolic programs of innate immune cells is an emerging strategy for clinical interventions, either to boost immune responses in immunosuppressed conditions or to mitigate maladaptive activation in hyperinflammatory diseases.
    Keywords:  Epigenetics; Metabolism; Therapy; Trained immunity
    DOI:  https://doi.org/10.1007/s00281-024-01015-8
  48. Nature. 2024 Jul 24.
    Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
    Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Naveen Sharma, Tian-Tian Liu, Vladimir Sukhov, Maria Firulyova, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Andres M Salazar, Robert Burns, Helio A Costa, Kelly D Moynihan, Yik Andy Yeung, Ivana Djuretic, Ton N Schumacher, Kathleen C F Sheehan, Marco Colonna, James P Allison, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber.
      CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
    DOI:  https://doi.org/10.1038/s41586-024-07752-y
  49. Cell. 2024 Jul 25. pii: S0092-8674(24)00714-1. [Epub ahead of print]187(15): 3787-3788
    50 years of metabolism research at Cell.
    Cell editorial team
      This 50th Anniversary Focus on Metabolism highlights several foundational and current themes of interest in metabolism research.
    DOI:  https://doi.org/10.1016/j.cell.2024.06.040
  50. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2407472121
    The ISR downstream target ATF4 represses long-term memory in a cell type-specific manner.
    Niaz Mahmood, Jung-Hyun Choi, Pei You Wu, Sean W Dooling, Trent A Watkins, Ziying Huang, Jesse Lipman, Hanjie Zhao, Anqi Yang, Jake Silversmith, Yanis Inglebert, Constantinos Koumenis, Vijendra Sharma, Jean-Claude Lacaille, Wayne S Sossin, Arkady Khoutorsky, R Anne McKinney, Mauro Costa-Mattioli, Nahum Sonenberg.
      The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.
    Keywords:  integrated stress response; learning and memory; protein synthesis; synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2407472121
  51. Brief Bioinform. 2024 May 23. pii: bbae347. [Epub ahead of print]25(4):
    MetalinksDB: a flexible and contextualizable resource of metabolite-protein interactions.
    Elias Farr, Daniel Dimitrov, Christina Schmidt, Denes Turei, Sebastian Lobentanzer, Aurelien Dugourd, Julio Saez-Rodriguez.
      From the catalytic breakdown of nutrients to signaling, interactions between metabolites and proteins play an essential role in cellular function. An important case is cell-cell communication, where metabolites, secreted into the microenvironment, initiate signaling cascades by binding to intra- or extracellular receptors of neighboring cells. Protein-protein cell-cell communication interactions are routinely predicted from transcriptomic data. However, inferring metabolite-mediated intercellular signaling remains challenging, partially due to the limited size of intercellular prior knowledge resources focused on metabolites. Here, we leverage knowledge-graph infrastructure to integrate generalistic metabolite-protein with curated metabolite-receptor resources to create MetalinksDB. MetalinksDB is an order of magnitude larger than existing metabolite-receptor resources and can be tailored to specific biological contexts, such as diseases, pathways, or tissue/cellular locations. We demonstrate MetalinksDB's utility in identifying deregulated processes in renal cancer using multi-omics bulk data. Furthermore, we infer metabolite-driven intercellular signaling in acute kidney injury using spatial transcriptomics data. MetalinksDB is a comprehensive and customizable database of intercellular metabolite-protein interactions, accessible via a web interface (https://metalinks.omnipathdb.org/) and programmatically as a knowledge graph (https://github.com/biocypher/metalinks). We anticipate that by enabling diverse analyses tailored to specific biological contexts, MetalinksDB will facilitate the discovery of disease-relevant metabolite-mediated intercellular signaling processes.
    Keywords:  cell–cell communication; database; metabolomics; single-cell; spatial; transcriptomics
    DOI:  https://doi.org/10.1093/bib/bbae347
  52. Nat Genet. 2024 Jul 22.
    Mitochondrial DNA mosaicism in normal human somatic cells.
    Jisong An, Chang Hyun Nam, Ryul Kim, Yunah Lee, Hyein Won, Seongyeol Park, Won Hee Lee, Hansol Park, Christopher J Yoon, Yohan An, Jie-Hyun Kim, Jong Kwan Jun, Jeong Mo Bae, Eui-Cheol Shin, Bun Kim, Yong Jun Cha, Hyun Woo Kwon, Ji Won Oh, Jee Yoon Park, Min Jung Kim, Young Seok Ju.
      Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.
    DOI:  https://doi.org/10.1038/s41588-024-01838-z
  53. Nat Immunol. 2024 Jul 26.
    An intestinal TH17 cell-derived subset can initiate cancer.
    Olivier Fesneau, Valentin Thevin, Valérie Pinet, Chloe Goldsmith, Baptiste Vieille, Saïdi M'Homa Soudja, Rossano Lattanzio, Michael Hahne, Valérie Dardalhon, Hector Hernandez-Vargas, Nicolas Benech, Julien C Marie.
      Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.
    DOI:  https://doi.org/10.1038/s41590-024-01909-7
  54. Metab Eng. 2024 Jul 22. pii: S1096-7176(24)00099-5. [Epub ahead of print]
    Multi-omic characterization of antibody-producing CHO cell lines elucidates metabolic reprogramming and nutrient uptake bottlenecks.
    Saratram Gopalakrishnan, William Johnson, Miguel A Valderrama-Gomez, Elcin Icten, Jasmine Tat, Fides Lay, Jonathan Diep, Natalia Gomez, Jennitte Stevens, Fabrice Schlegel, Pablo Rolandi, Cleo Kontoravdi, Nathan E Lewis.
      Characterizing the phenotypic diversity and metabolic capabilities of industrially relevant manufacturing cell lines is critical to bioprocess optimization and cell line development. Metabolic capabilities of production hosts limit nutrient and resource channeling into desired cellular processes and can have a profound impact on productivity. These limitations cannot be directly inferred from measured data such as spent media concentrations or transcriptomics. Here, we present an integrated multi-omic analysis pipeline combining exo-metabolomics, transcriptomics, and genome-scale metabolic network analysis and apply it to three antibody-producing Chinese Hamster Ovary cell lines to identify reprogramming features associated with high-producer clones and metabolic bottlenecks limiting product formation in an industrial bioprocess. Analysis of individual datatypes revealed a decreased nitrogenous byproduct secretion in high-producing clones and the topological changes in peripheral metabolic pathway expression associated with phase shifts. An integrated omics analysis in the context of the genome-scale metabolic model elucidated the differences in central metabolism and identified amino acid utilization bottlenecks limiting cell growth and antibody production that were not evident from exo-metabolomics or transcriptomics alone. Thus, we demonstrate the utility of a multi-omics characterization in providing an in-depth understanding of cellular metabolism, which is critical to efforts in cell engineering and bioprocess optimization.
    Keywords:  Biopharmaceuticals; CHO cells; Industrial bioproduction; Metabolic modeling; Multi-omics analysis; Process optimization
    DOI:  https://doi.org/10.1016/j.ymben.2024.07.009
  55. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
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