bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023‒12‒17
72 papers selected by
Christian Frezza, Universität zu Köln
  1. The interplay of the circadian clock and metabolic tumorigenesis.
  2. Phenotypic profiling of solute carriers characterizes serine transport in cancer.
  3. The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
  4. Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
  5. Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
  6. The critical roles of STING in mitochondrial homeostasis.
  7. VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response.
  8. Metabolic Messengers: ketone bodies.
  9. MYC protein helps cancer to take its vitamins.
  10. Mitochondrial temperature homeostasis resists external metabolic stresses.
  11. Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
  12. Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.
  13. AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress.
  14. Efferocyte-Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1-Mediated Activation of Glycolysis.
  15. Spatial metabolic patterns.
  16. Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
  17. Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
  18. Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.
  19. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  20. Ferroptosis and cuproptposis in kidney Diseases: dysfunction of cell metabolism.
  21. An oncogenic phenoscape of colonic stem cell polarization.
  22. Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival.
  23. Sugar-free synapses run on mitochondrial Sirtuin 3.
  24. Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
  25. Re-"Formate" T-cell Antitumor Responses.
  26. Modulation of Subcellular Redox Homeostasis with Trialkylphosphines.
  27. SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.
  28. Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
  29. Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis.
  30. Boundary flux analysis: an emerging strategy for investigating metabolic pathway activity in large cohorts.
  31. The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
  32. Mitochondrial Cation Signalling in the Control of Inflammatory Processes.
  33. A metabolic perspective on nitric oxide function in melanoma.
  34. CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
  35. A single-nucleus pan-cancer epigenetic and transcriptomic landscape.
  36. A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
  37. Targeting cancer cell dormancy.
  38. Glutamine addiction and therapeutic strategies in pancreatic cancer.
  39. Control of lipolysis by a population of oxytocinergic sympathetic neurons.
  40. Serine metabolism in macrophage polarization.
  41. Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
  42. CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity.
  43. Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features.
  44. Mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3-LAG3 axis.
  45. Organelle morphology and positioning orchestrate physiological and disease-associated processes.
  46. Trans-vaccenic Acid Reprograms CD8+ T Cells and Enhances Antitumor Immunity.
  47. ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
  48. B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.
  49. A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.
  50. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
  51. Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
  52. Epinephrine inhibits PI3Kα via the Hippo kinases.
  53. An integrated workflow for quantitative analysis of the newly synthesized proteome.
  54. A class of secreted mammalian peptides with potential to expand cell-cell communication.
  55. Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
  56. Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
  57. The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
  58. Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.
  59. cGAS-STING signalling regulates microglial chemotaxis in genome instability.
  60. Are your organs ageing well? The blood holds clues.
  61. ROS production by mitochondria: function or dysfunction?
  62. Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.
  63. Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
  64. Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake.
  65. Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function.
  66. Is space the final frontier for mitochondrial study?
  67. In vivo protein turnover rates in varying oxygen tensions nominate MYBBP1A as a mediator of the hyperoxia response.
  68. Enzyme-Catalyzed Oxidative Degradation of Ergothioneine.
  69. A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.
  70. Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.
  71. Spatial segregation and aging of metabolic processes underlie phenotypic heterogeneity in mycobacteria.
  72. Why we need an academic career path that combines science and art.
  1. Trends Cell Biol. 2023 Dec 06. pii: S0962-8924(23)00237-4. [Epub ahead of print]
    The interplay of the circadian clock and metabolic tumorigenesis.
    Zheng Wang, Leina Ma, Ying Meng, Jing Fang, Daqian Xu, Zhimin Lu.
      The circadian clock and cell metabolism are both dysregulated in cancer cells through intrinsic cell-autonomous mechanisms and external influences from the tumor microenvironment. The intricate interplay between the circadian clock and cancer cell metabolism exerts control over various metabolic processes, including aerobic glycolysis, de novo nucleotide synthesis, glutamine and protein metabolism, lipid metabolism, mitochondrial metabolism, and redox homeostasis in cancer cells. Importantly, oncogenic signaling can confer a moonlighting function on core clock genes, effectively reshaping cellular metabolism to fuel cancer cell proliferation and drive tumor growth. These interwoven regulatory mechanisms constitute a distinctive feature of cancer cell metabolism.
    Keywords:  cancer metabolism; dysregulated circadian clock; moonlighting function
    DOI:  https://doi.org/10.1016/j.tcb.2023.11.004
  2. Nat Metab. 2023 Dec 08.
    Phenotypic profiling of solute carriers characterizes serine transport in cancer.
    Vasileios Papalazarou, Alice C Newman, Alejandro Huerta-Uribe, Nathalie M Legrave, Mattia Falcone, Tong Zhang, Lynn McGarry, Dimitris Athineos, Emma Shanks, Karen Blyth, Karen H Vousden, Oliver D K Maddocks.
      Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
    DOI:  https://doi.org/10.1038/s42255-023-00936-2
  3. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303713120
    The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore.
    Ryan Pekson, Felix G Liang, Joshua L Axelrod, Jaehoon Lee, Dongze Qin, Andre J H Wittig, Victor M Paulino, Min Zheng, Pablo M Peixoto, Richard N Kitsis.
      The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.
    Keywords:  mitochondrial ATP synthase; mitochondrial permeability transition pore; necrosis
    DOI:  https://doi.org/10.1073/pnas.2303713120
  4. bioRxiv. 2023 Nov 29. pii: 2023.11.28.569098. [Epub ahead of print]
    Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
    Cara Abecunas, Mohammad Fallahi-Sichani.
      Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.
    DOI:  https://doi.org/10.1101/2023.11.28.569098
  5. J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2290911
    Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
    Rajath Cyriac, Kwangho Lee.
      Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression.
    Keywords:  GLS; KEAP1 mutation; anticancer; cancer metabolism; glutaminase
    DOI:  https://doi.org/10.1080/14756366.2023.2290911
  6. Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938
    The critical roles of STING in mitochondrial homeostasis.
    Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
    Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING
    DOI:  https://doi.org/10.1016/j.bcp.2023.115938
  7. bioRxiv. 2023 Nov 30. pii: 2023.11.28.569047. [Epub ahead of print]
    VHL loss enables immune checkpoint blockade therapy by boosting type I interferon response.
    Meng Jiao, Xuhui Bao, Mengjie Hu, Dong Pan, Xinjian Liu, Jonathan Kim, Fang Li, Chuan-Yuan Li.
      Despite a moderate mutation burden, clear cell renal cell carcinoma (ccRCC) responds well to immune checkpoint blockade (ICB) therapy. Here we report that loss-of-function mutations in the von Hippel-Lindau (VHL) gene, the most frequent in ccRCC, underlies its responsiveness to ICB therapy. We demonstrate that genetic knockout of the VHL gene enhanced the efficacy of anti-PD-1 therapy in multiple murine tumor models in a T cell-dependent manner. Mechanistically, we discovered that upregulation of HIF1α and HIF2α induced by VHL gene loss decreased mitochondrial outer membrane potential and caused the cytoplasmic leakage of mitochondrial DNA (mtDNA), which triggered cGAS-STING activation and induced type I interferons. Our study thus provided novel mechanistic insights into the role of VHL gene loss in potentiating ccRCC immunotherapy.
    DOI:  https://doi.org/10.1101/2023.11.28.569047
  8. Nat Metab. 2023 Dec 13.
    Metabolic Messengers: ketone bodies.
    Alisa B Nelson, Eric D Queathem, Patrycja Puchalska, Peter A Crawford.
      Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.
    DOI:  https://doi.org/10.1038/s42255-023-00935-3
  9. Nature. 2023 Dec;624(7991): 258-260
    MYC protein helps cancer to take its vitamins.
    Martina Wallace.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-03764-2
  10. Elife. 2023 Dec 11. pii: RP89232. [Epub ahead of print]12
    Mitochondrial temperature homeostasis resists external metabolic stresses.
    Mügen Terzioglu, Kristo Veeroja, Toni Montonen, Teemu O Ihalainen, Tiina S Salminen, Paule Bénit, Pierre Rustin, Young-Tae Chang, Takeharu Nagai, Howard T Jacobs.
      Based on studies with a fluorescent reporter dye, Mito Thermo Yellow (MTY), and the genetically encoded gTEMP ratiometric fluorescent temperature indicator targeted to mitochondria, the temperature of active mitochondria in four mammalian and one insect cell line was estimated to be up to 15°C above that of the external environment to which the cells were exposed. High mitochondrial temperature was maintained in the face of a variety of metabolic stresses, including substrate starvation or modification, decreased ATP demand due to inhibition of cytosolic protein synthesis, inhibition of the mitochondrial adenine nucleotide transporter and, if an auxiliary pathway for electron transfer was available via the alternative oxidase, even respiratory poisons acting downstream of oxidative phosphorylation (OXPHOS) complex I. We propose that the high temperature of active mitochondria is an inescapable consequence of the biochemistry of OXPHOS and is homeostatically maintained as a primary feature of mitochondrial metabolism.
    Keywords:  D. melanogaster; OXPHOS; biochemistry; bioenergetics; cell biology; chemical biology; human; mitochondria; mouse; organelle; temperature; thermogenesis
    DOI:  https://doi.org/10.7554/eLife.89232
  11. Nat Commun. 2023 Dec 13. 14(1): 8075
    Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.
    Yu Muta, Juan F Linares, Anxo Martinez-Ordoñez, Angeles Duran, Tania Cid-Diaz, Hiroto Kinoshita, Xiao Zhang, Qixiu Han, Yuki Nakanishi, Naoko Nakanishi, Thekla Cordes, Gurpreet K Arora, Marc Ruiz-Martinez, Miguel Reina-Campos, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Christian M Metallo, Timothy F Osborne, Maria T Diaz-Meco, Jorge Moscat.
      The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
    DOI:  https://doi.org/10.1038/s41467-023-43690-5
  12. Cell Rep. 2023 Dec 07. pii: S2211-1247(23)01551-6. [Epub ahead of print]42(12): 113539
    Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.
    Yao Rong, Alicia M Darnell, Kiera M Sapp, Matthew G Vander Heiden, Sabrina L Spencer.
      Amino acids are required for cell growth and proliferation, but it remains unclear when and how amino acid availability impinges on the proliferation-quiescence decision. Here, we used time-lapse microscopy and single-cell tracking of cyclin-dependent kinase 2 (CDK2) activity to assess the response of individual cells to withdrawal of single amino acids and found strikingly different cell-cycle effects depending on the amino acid. For example, upon leucine withdrawal, MCF10A cells complete two cell cycles and then enter a CDK2-low quiescence, whereas lysine withdrawal causes immediate cell-cycle stalling. Methionine withdrawal triggers a restriction point phenotype similar to serum starvation or Mek inhibition: upon methionine withdrawal, cells complete their current cell cycle and enter a CDK2-low quiescence after mitosis. Modulation of restriction point regulators p21/p27 or cyclin D1 enables short-term rescue of proliferation under methionine and leucine withdrawal, and to a lesser extent lysine withdrawal, revealing a checkpoint connecting nutrient signaling to cell-cycle entry.
    Keywords:  CDK2; CP: Cell biology; amino acid withdrawal; cyclin D1; leucine; lysine; methionine; p21; p27; proliferation-quiescence decision; restriction point
    DOI:  https://doi.org/10.1016/j.celrep.2023.113539
  13. bioRxiv. 2023 Dec 01. pii: 2023.11.29.568904. [Epub ahead of print]
    AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress.
    Manuel A Torres Acosta, Nurbek Mambetsariev, Carla P Reyes Flores, Kathryn A Helmin, Qianli Liu, Anthony M Joudi, Luisa Morales-Nebreda, Jonathan Gurkan, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E Weinberg, Benjamin D Singer.
      CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury in the lung and other organs. Treg cells require mitochondrial metabolism to exert their function, but how Treg cells adapt their metabolic programs to sustain and optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMP-activated protein kinase (AMPK) to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during acute lung injury caused by influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In the lung during viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking DNA methylation with AMPK function and mitochondrial metabolism. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
    DOI:  https://doi.org/10.1101/2023.11.29.568904
  14. Adv Sci (Weinh). 2023 Dec 08. e2304690
    Efferocyte-Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1-Mediated Activation of Glycolysis.
    Duco Steven Koenis, Roberta de Matteis, Vinothini Rajeeve, Pedro Cutillas, Jesmond Dalli.
      Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12-lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add-back of MCTRs. Mechanistically, MCTR-mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR-mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.
    Keywords:  efferocytosis; macrophages; metabolism; specialized pro-resolving mediators (SPM); tissue repair
    DOI:  https://doi.org/10.1002/advs.202304690
  15. Nat Rev Cancer. 2023 Dec 11.
    Spatial metabolic patterns.
    Anna Dart.
      
    DOI:  https://doi.org/10.1038/s41568-023-00654-7
  16. Cell. 2023 Nov 28. pii: S0092-8674(23)01228-X. [Epub ahead of print]
    Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.
    Cesar A Perez-Ramirez, Haruko Nakano, Richard C Law, Nedas Matulionis, Jennifer Thompson, Andrew Pfeiffer, Junyoung O Park, Atsushi Nakano, Heather R Christofk.
      Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using 13C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing 13C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
    Keywords:  development; diabetes; fetal metabolism; isotope tracing; metabolism; metabolomics; pregnancy
    DOI:  https://doi.org/10.1016/j.cell.2023.11.011
  17. bioRxiv. 2023 Nov 28. pii: 2023.11.28.568893. [Epub ahead of print]
    Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
    Dylan J Duerre, Julia K Hansen, Steven John, Annie Jen, Noah Carrillo, Hoang Bui, Yutong Bao, Matias Fabregat, Katherine Overmeyer, Evgenia Shishkova, Mark P Keller, Richard A Anderson, Vincent L Cryns, Alan D Attie, Joshua J Coon, Jing Fan, Andrea Galmozzi.
      With age, people tend to accumulate body fat and reduce energy expenditure 1 . Brown (BAT) and beige adipose tissue dissipate heat and increase energy expenditure via the activity of the uncoupling protein UCP1 and other thermogenic futile cycles 2,3 . The activity of brown and beige depots inversely correlates with BMI and age 4-11 , suggesting that promoting thermogenesis may be an effective approach for combating age-related metabolic disease 12-15 . Heme is an enzyme cofactor and signaling molecule that we recently showed to regulate BAT function 16 . Here, we show that heme biosynthesis is the primary contributor to intracellular heme levels in brown adipocytes. Inhibition of heme biosynthesis leads to mitochondrial dysfunction and reduction in UCP1. Although supplementing heme can restore mitochondrial function in heme-synthesis-deficient cells, the downregulation of UCP1 persists due to the accumulation of the heme precursors, particularly propionyl-CoA, which is a product of branched-chain amino acids (BCAA) catabolism. Cold exposure promotes BCAA uptake in BAT, and defects in BCAA catabolism in this tissue hinder thermogenesis 17 . However, BCAAs' contribution to the TCA cycle in BAT and WAT never exceeds 2% of total TCA flux 18 . Our work offers a way to integrate current literature by describing heme biosynthesis as an important metabolic sink for BCAAs.
    DOI:  https://doi.org/10.1101/2023.11.28.568893
  18. Nat Commun. 2023 Dec 13. 14(1): 8095
    Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.
    Miyuki Nomura, Mai Ohuchi, Yoshimi Sakamoto, Kei Kudo, Keisuke Yaku, Tomoyoshi Soga, Yuki Sugiura, Mami Morita, Kayoko Hayashi, Shuko Miyahara, Taku Sato, Yoji Yamashita, Shigemi Ito, Naohiko Kikuchi, Ikuro Sato, Rintaro Saito, Nobuo Yaegashi, Tatsuro Fukuhara, Hidekazu Yamada, Hiroshi Shima, Keiichi I Nakayama, Atsushi Hirao, Kenta Kawasaki, Yoichi Arai, Shusuke Akamatsu, Sei-Ichi Tanuma, Toshiro Sato, Takashi Nakagawa, Nobuhiro Tanuma.
      Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.
    DOI:  https://doi.org/10.1038/s41467-023-43630-3
  19. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  20. Apoptosis. 2023 Dec 14.
    Ferroptosis and cuproptposis in kidney Diseases: dysfunction of cell metabolism.
    Tingting Chen, Lifei Liang, Yuzhu Wang, Xiaoyu Li, Cheng Yang.
      Metal ions play an important role in living organisms and are involved in essential physiological activities. However, the overload state of ions can cause excess free radicals, cell damage, and even cell death. Ferroptosis and cuproptosis are specific forms of cell death that are distinct from apoptosis, necroptosis, and other regulated cell death. These unique modalities of cell death, dependent on iron and copper, are regulated by multiple cellular metabolic pathways, including steady-state metal redox treatment mitochondrial activity of lipid, amino acid and glucose metabolism, and various signaling pathways associated with disease. Although the mechanisms of ferroptosis and cuproptosis are not yet fully understood, there is no doubt that ion overload plays a crucial act in these metal-dependent cell deaths. In this review, we discussed the core roles of ion overload in ferroptosis and cuproptosis, the association between metabolism imbalance and ferroptosis and cuproptosis, the extract the diseases caused by ion overload and current treatment modalities.
    Keywords:  Cell death; Cuproptosis; Ferroptosis; Kidney fibrosis; Kidney ischemia-reperfusion injury; Kidney transplantation; Metal ions; Renal cancer
    DOI:  https://doi.org/10.1007/s10495-023-01928-z
  21. Cell. 2023 Dec 07. pii: S0092-8674(23)01221-7. [Epub ahead of print]186(25): 5554-5568.e18
    An oncogenic phenoscape of colonic stem cell polarization.
    Xiao Qin, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Jeroen Claus, Christopher J Tape.
      Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.
    Keywords:  CRC; cell plasticity; cell-cell signaling; cell-fate polarization; colonic stem cell; colorectal cancer; cue-signal-response; organoid; single-cell analysis; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2023.11.004
  22. bioRxiv. 2023 Dec 01. pii: 2023.11.30.569407. [Epub ahead of print]
    Chronic metabolic stress drives developmental programs and loss of tissue functions in non-transformed liver that mirror tumor states and stratify survival.
    Constantine N Tzouanas, Marc S Sherman, Jessica E S Shay, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Evelyn Y Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Georg M Lauer, Ömer H Yilmaz, Wolfram Goessling, Alex K Shalek.
      Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi-omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi-omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.
    DOI:  https://doi.org/10.1101/2023.11.30.569407
  23. J Cell Biol. 2024 Jan 01. pii: e202312035. [Epub ahead of print]223(1):
    Sugar-free synapses run on mitochondrial Sirtuin 3.
    Alexander P Walsh, David J Simon.
      Metabolic plasticity of neurons ensures their activity continues when glucose is limited. Walsh and Simon discuss new work by Ashrafi and colleagues (https://doi.org/10.1083/jcb.202305048) that finds Sirtuin 3 directs local metabolic adaptation at synapses during sustained glucose deprivation.
    DOI:  https://doi.org/10.1083/jcb.202312035
  24. Cell Death Dis. 2023 Dec 08. 14(12): 805
    Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
    Doni Davide, Cavion Federica, Bortolus Marco, Baschiera Elisa, Muccioli Silvia, Tombesi Giulia, d'Ettorre Federica, Daniele Ottaviani, Marchesan Elena, Leanza Luigi, Greggio Elisa, Ziviani Elena, Russo Antonella, Bellin Milena, Sartori Geppo, Carbonera Donatella, Salviati Leonardo, Costantini Paola.
      Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease caused by an expanded GAA repeat in the first intron of the FXN gene, leading to transcriptional silencing and reduced expression of frataxin. Frataxin participates in the mitochondrial assembly of FeS clusters, redox cofactors of the respiratory complexes I, II and III. To date it is still unclear how frataxin deficiency culminates in the decrease of bioenergetics efficiency in FRDA patients' cells. We previously demonstrated that in healthy cells frataxin is closely attached to the mitochondrial cristae, which contain both the FeS cluster assembly machinery and the respiratory chain complexes, whereas in FRDA patients' cells with impaired respiration the residual frataxin is largely displaced in the matrix. To gain novel insights into the function of frataxin in the mitochondrial pathophysiology, and in the upstream metabolic defects leading to FRDA disease onset and progression, here we explored the potential interaction of frataxin with the FeS cluster-containing respiratory complexes I, II and III. Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells. Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for FRDA targeted to this respiratory complex.
    DOI:  https://doi.org/10.1038/s41419-023-06320-y
  25. Cancer Discov. 2023 Dec 12. 13(12): 2507-2509
    Re-"Formate" T-cell Antitumor Responses.
    Mei-Chun Lin, Sofie Hedlund Moller, Ping-Chih Ho.
      SUMMARY: Rowe and colleagues discover that one-carbon (1C) metabolism rewiring occurs upon T-cell activation to support proliferation and cytolytic activity in CD8+ T cells and that supplementation of 1C donor formate rescues the dysfunctional T cells and their responsiveness to anti-PD-1 in selective tumor-infiltrated T-cell subsets. This finding represents an attractive strategy to overcome a metabolic vulnerability in the tumor microenvironment and improve the efficacy of immune checkpoint blockade. See related article by Rowe et al., p. 2566 (8).
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1059
  26. Chimia (Aarau). 2022 Apr 27. 76(4): 308-311
    Modulation of Subcellular Redox Homeostasis with Trialkylphosphines.
    Jade Nguyen.
      Redox homeostasis is essential for cell function and its disruption is associated with multiple pathologies. Redox balance is largely regulated by the relative concentrations of reduced (GSH) and oxidized (GSSG) glutathione. In eukaryotic cells, this ratio is different in each cell compartment. There is a lack of chemical probes able to modulate GSH/GSSG in order to study the impact of redox stress in an organelle specific manner. Here, we highlight the importance of trialkylphosphines to induce reductive stress and how it can be targeted to a specific organelle. Our probe is selectively activated by endogenous nitroreductases, and releases tributylphosphine to trigger redox stress in mitochondria. Mechanistic studies revealed that the induced stress activates a cellular response orchestrated by transcription factor ATF4, which upregulates genes involved in glutathione catabolism.
    Keywords:  Glutathione; Mitochondria; Redox homeostatis; Reductive stress; Tryalkylphosphine
    DOI:  https://doi.org/10.2533/chimia.2022.308
  27. Int Immunopharmacol. 2023 Dec 12. pii: S1567-5769(23)01656-9. [Epub ahead of print]127 111329
    SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages.
    Wenqiang Zhu, Lina Liu, Jinjing Wu, Renzhuo Gao, Liying Fu, Xiaohong Yang, Yang Zou, Shuhua Zhang, Daya Luo.
      BACKGROUND: SMYD3 refers to a histone lysine methyltransferase from the SMYD family, which acts as a gene transcriptional regulator chiefly through catalysis of the histone subunit 3 at lysine 4 trimethylation (H3K4me3). Great progress has been made that epigenetic modification plays a pivotal role in regulating macrophage polarization. However, the effects of the histone lysine methyltransferase SMYD3 on macrophage polarization and phenotypic switching are unclear.RESULTS: We found that LPS/IFN-γ-stimulated macrophages gradually transformed from M1 to M2 in the late stage, and SMYD3 played a key role in this process. As demonstrated by RNA-seq assessment, SMYD3 prominently activated a metabolic pathway known as TCA cycle inside macrophages during M1-M2 conversion. Besides, by modifying H3K4me3 histone, the target genes regulated by SMYD3 were identified via the ChIP-seq assessment, including citrate synthase (CS), succinate dehydrogenase complex subunit C (SDHC) and pyruvate carboxylase (PC). SMYD3 activated the transcriptional activities of the metabolic enzymes CS, SDHC and PC through H3K4me3 by causing the aggregation of citrate, an intramacrophage metabolite, and the depletion of succinate. And additionally, it facilitated the generation of ROS, as well as the expressions of genes associated with mitochondrial respiratory chain complexes. This increased ROS production ultimately induced mitophagy, triggering the M1 to M2 phenotype switch in the macrophages.
    CONCLUSIONS: Our study provides a detailed intrinsic mechanism in the macrophage phenotypic transition process, in short, SMYD3 promotes the M1-M2 conversion of macrophages by activating the TCA cycle through the simultaneous regulation of the transcriptional activities of the metabolic enzymes CS, SDHC and PC.
    Keywords:  Histone modification; Macrophage phenotype conversion; Mitophagy; SMYD3; TCA cycle
    DOI:  https://doi.org/10.1016/j.intimp.2023.111329
  28. Nat Commun. 2023 Dec 13. 14(1): 8260
    Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology.
    Thomas Hu, Mayar Allam, Shuangyi Cai, Walter Henderson, Brian Yueh, Aybuke Garipcan, Anton V Ievlev, Maryam Afkarian, Semir Beyaz, Ahmet F Coskun.
      Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet's ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.
    DOI:  https://doi.org/10.1038/s41467-023-43917-5
  29. Nat Commun. 2023 Dec 12. 14(1): 8251
    Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis.
    Balkrishna Chaube, Kathryn M Citrin, Mahnaz Sahraei, Abhishek K Singh, Diego Saenz de Urturi, Wen Ding, Richard W Pierce, Raaisa Raaisa, Rebecca Cardone, Richard Kibbey, Carlos Fernández-Hernando, Yajaira Suárez.
      Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iΔEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.
    DOI:  https://doi.org/10.1038/s41467-023-43900-0
  30. Curr Opin Biotechnol. 2023 Dec 06. pii: S0958-1669(23)00137-4. [Epub ahead of print]85 103027
    Boundary flux analysis: an emerging strategy for investigating metabolic pathway activity in large cohorts.
    Ian A Lewis.
      Many biological phenotypes are rooted in metabolic pathway activity rather than the concentrations of individual metabolites. Despite this, most metabolomics studies only capture steady-state metabolism - not metabolic flux. Although sophisticated metabolic flux analysis strategies have been developed, these methods are technically challenging and difficult to implement in large-cohort studies. Recently, a new boundary flux analysis (BFA) approach has emerged that captures large-scale metabolic flux phenotypes by quantifying changes in metabolite levels in the media of cultured cells. This approach is advantageous because it is relatively easy to implement yet captures complex metabolic flux phenotypes. We describe the opportunities and challenges of BFA and illustrate how it can be harnessed to investigate a wide transect of biological phenomena.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103027
  31. Nat Commun. 2023 Dec 12. 14(1): 8248
    The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
    Lindsay McGregor, Samira Acajjaoui, Ambroise Desfosses, Melissa Saïdi, Maria Bacia-Verloop, Jennifer J Schwarz, Pauline Juyoux, Jill von Velsen, Matthew W Bowler, Andrew A McCarthy, Eaazhisai Kandiah, Irina Gutsche, Montserrat Soler-Lopez.
      The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer's disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.
    DOI:  https://doi.org/10.1038/s41467-023-43865-0
  32. Int J Mol Sci. 2023 Nov 24. pii: 16724. [Epub ahead of print]24(23):
    Mitochondrial Cation Signalling in the Control of Inflammatory Processes.
    Pampa Pain, Francesca Spinelli, Gaia Gherardi.
      Mitochondria are the bioenergetic organelles responsible for the maintenance of cellular homeostasis and have also been found to be associated with inflammation. They are necessary to induce and maintain innate and adaptive immune cell responses, acting as signalling platforms and mediators in effector responses. These organelles are also known to play a pivotal role in cation homeostasis as well, which regulates the inflammatory responses through the modulation of these cation channels. In particular, this review focuses on mitochondrial Ca2+ and K+ fluxes in the regulation of inflammatory response. Nevertheless, this review aims to understand the interplay of these inflammation inducers and pathophysiological conditions. In detail, we discuss some examples of chronic inflammation such as lung, bowel, and metabolic inflammatory diseases caused by a persistent activation of the innate immune response due to a dysregulation of mitochondrial cation homeostasis.
    Keywords:  inflammation; mitochondrial Ca2+ uptake; mitochondrial K+ flux
    DOI:  https://doi.org/10.3390/ijms242316724
  33. Biochim Biophys Acta Rev Cancer. 2023 Dec 05. pii: S0304-419X(23)00187-7. [Epub ahead of print] 189038
    A metabolic perspective on nitric oxide function in melanoma.
    John Jimenez, Parul Dubey, Bethany Carter, John Koomen, Joseph Markowitz.
      Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.
    Keywords:  Melanoma; Metabolism; Nitration; Nitric oxide; S-nitrosylation; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189038
  34. Mitochondrion. 2023 Dec 11. pii: S1567-7249(23)00105-8. [Epub ahead of print] 101825
    CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
    Rajdeep Das, Sebabrata Maity, Palamou Das, Izaz Monir Kamal, Saikat Chakrabarti, Oishee Chakrabarti.
      Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.
    DOI:  https://doi.org/10.1016/j.mito.2023.101825
  35. Nat Genet. 2023 Dec;55(12): 2019
    A single-nucleus pan-cancer epigenetic and transcriptomic landscape.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-023-01616-3
  36. Elife. 2023 12 11. pii: RP87510. [Epub ahead of print]12
    A positive feedback loop between ZEB2 and ACSL4 regulates lipid metabolism to promote breast cancer metastasis.
    Jiamin Lin, Pingping Zhang, Wei Liu, Guorong Liu, Juan Zhang, Min Yan, Yuyou Duan, Na Yang.
      Lipid metabolism plays a critical role in cancer metastasis. However, the mechanisms through which metastatic genes regulate lipid metabolism remain unclear. Here, we describe a new oncogenic-metabolic feedback loop between the epithelial-mesenchymal transition transcription factor ZEB2 and the key lipid enzyme ACSL4 (long-chain acyl-CoA synthetase 4), resulting in enhanced cellular lipid storage and fatty acid oxidation (FAO) to drive breast cancer metastasis. Functionally, depletion of ZEB2 or ACSL4 significantly reduced lipid droplets (LDs) abundance and cell migration. ACSL4 overexpression rescued the invasive capabilities of the ZEB2 knockdown cells, suggesting that ACSL4 is crucial for ZEB2-mediated metastasis. Mechanistically, ZEB2-activated ACSL4 expression by directly binding to the ACSL4 promoter. ACSL4 binds to and stabilizes ZEB2 by reducing ZEB2 ubiquitination. Notably, ACSL4 not only promotes the intracellular lipogenesis and LDs accumulation but also enhances FAO and adenosine triphosphate production by upregulating the FAO rate-limiting enzyme CPT1A (carnitine palmitoyltransferase 1 isoform A). Finally, we demonstrated that ACSL4 knockdown significantly reduced metastatic lung nodes in vivo. In conclusion, we reveal a novel positive regulatory loop between ZEB2 and ACSL4, which promotes LDs storage to meet the energy needs of breast cancer metastasis, and identify the ZEB2-ACSL4 signaling axis as an attractive therapeutic target for overcoming breast cancer metastasis.
    Keywords:  cancer biology; ACSL4; lipid metabolism; lipid droplets; cancer metastasis; EMT; ZEB2
    DOI:  https://doi.org/10.7554/eLife.87510
  37. Nat Rev Cancer. 2023 Dec 07.
    Targeting cancer cell dormancy.
    Judith Agudo, Julio A Aguirre-Ghiso, Mickie Bhatia, Lewis A Chodosh, Ana Luísa Correia, Christoph A Klein.
      
    DOI:  https://doi.org/10.1038/s41568-023-00642-x
  38. World J Gastrointest Oncol. 2023 Nov 15. 15(11): 1852-1863
    Glutamine addiction and therapeutic strategies in pancreatic cancer.
    Lin-Lin Ren, Tao Mao, Pin Meng, Li Zhang, Hong-Yun Wei, Zi-Bin Tian.
      Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.
    Keywords:  Cancer treatment; Glutamine metabolism; Pancreatic cancer; Therapeutic strategies
    DOI:  https://doi.org/10.4251/wjgo.v15.i11.1852
  39. Nature. 2023 Dec 13.
    Control of lipolysis by a population of oxytocinergic sympathetic neurons.
    Erwei Li, Luhong Wang, Daqing Wang, Jingyi Chi, Zeran Lin, Gordon I Smith, Samuel Klein, Paul Cohen, Evan D Rosen.
      Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of β-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.
    DOI:  https://doi.org/10.1038/s41586-023-06830-x
  40. Inflamm Res. 2023 Dec 09.
    Serine metabolism in macrophage polarization.
    Xinqiong Huang, Xue Yang, Li Xiang, Yuping Chen.
      OBJECTIVE: Emerging studies have revealed that macrophages possess different dependences on the uptake, synthesis, and metabolism of serine for their activation and functionalization, necessitating our insight into how serine availability and utilization impact macrophage activation and inflammatory responses.METHODS: This article summarizes the reports published domestically and internationally about the serine uptake, synthesis, and metabolic flux by the macrophages polarizing with distinct stimuli and under different pathologic conditions, and particularly analyzes how altered serine metabolism rewires the metabolic behaviors of polarizing macrophages and their genetic and epigenetic reprogramming.
    RESULTS: Macrophages dynamically change serine metabolism to orchestrate their anabolism, redox balance, mitochondrial function, epigenetics, and post-translation modification, and thus match the distinct needs for both classical and alternative activation.
    CONCLUSION: Serine metabolism coordinates multiple metabolic pathways to tailor macrophage polarization and their responses to different pathogenic attacks and thus holds the potential as therapeutic target for types of acute and chronic inflammatory diseases.
    Keywords:  Inflammation; Innate immunity; Macrophage polarization; Serine metabolism
    DOI:  https://doi.org/10.1007/s00011-023-01815-y
  41. J Clin Invest. 2023 Dec 07. pii: e172256. [Epub ahead of print]
    Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
    Fan He, Angelo B A Laranjeira, Tim Kong, Shuyang Lin, Katrina J Ashworth, Alice Liu, Nina M Lasky, Daniel Ac Fisher, Maggie J Cox, Mary C Fulbright, Lilian A Antunes Heck, LaYow C Yu, Molly Brakhane, Bei Gao, Stephen M Sykes, Angelo D'Alessandro, Jorge A Di Paola, Stephen T Oh.
      Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR and oxidative phosphorylation (OXPHOS) in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation, accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid (TCA) cycle, but lower alpha-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F mice with α-KG significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte and platelet counts. Finally, α-KG incubation significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling, contributing to platelet hyperreactivity in MPN patients.
    Keywords:  Hematology; Platelets
    DOI:  https://doi.org/10.1172/JCI172256
  42. Nat Genet. 2023 Dec 08.
    CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity.
    Marco Varrone, Daniele Tavernari, Albert Santamaria-Martínez, Logan A Walsh, Giovanni Ciriello.
      Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophil and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.
    DOI:  https://doi.org/10.1038/s41588-023-01588-4
  43. Mol Cancer Res. 2023 Dec 12.
    Mitochondria transfer by platelet-derived microparticles regulates breast cancer bioenergetic states and malignant features.
    Vanessa Veilleux, Nicolas Pichaud, Luc H Boudreau, Gilles A Robichaud.
      An increasing number of studies show that platelets as well as platelet-derived microparticles (PMPs) play significant roles in cancer malignancy and disease progression. Particularly, PMPs have the capacity to interact and internalize within target cells resulting in the transfer of their bioactive cargo, which can modulate the signaling and activation processes of recipient cells. We recently identified a new subpopulation of these vesicles (termed mitoMPs), which contain functional mitochondria. Given the predominant role of mitochondria in cancer cell metabolism and disease progression, we set out to investigate the impact of mitoMPs on breast cancer metabolic reprograming and phenotypic processes leading to malignancy. Interestingly, we observed that recipient cell permeability to PMP internalization varied among the breast cancer cell types evaluated in our study. Specifically, cells permissive to mitoMPs acquire mitochondrial-dependent functions, which stimulate increased cellular oxygen consumption rates and intracellular ATP production. In addition, cancer cells co-incubated with PMPs display enhanced malignant features in terms of migration and invasion. Most importantly, the cancer aggressive processes and notable metabolic plasticity induced by PMPs were highly dependent on the functional status of the mitoMP-packaged mitochondria. These findings characterize a new mechanism by which breast cancer cells acquire foreign mitochondria resulting in the gain of metabolic processes and malignant features. A better understanding of these mechanisms may provide therapeutic opportunities through PMP blockade to deprive cancer cells from resources vital in disease progression. Implications: We show that the transfer of foreign mitochondria by microparticles modulates recipient cancer cell metabolic plasticity, leading to greater malignant processes.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0329
  44. NPJ Syst Biol Appl. 2023 Dec 12. 9(1): 61
    Mesenchymal ovarian cancer cells promote CD8+ T cell exhaustion through the LGALS3-LAG3 axis.
    Edward Yakubovich, David P Cook, Galaxia M Rodriguez, Barbara C Vanderhyden.
      Cancer cells often metastasize by undergoing an epithelial-mesenchymal transition (EMT). Although abundance of CD8+ T-cells in the tumor microenvironment correlates with improved survival, mesenchymal cancer cells acquire greater resistance to antitumor immunity in some cancers. We hypothesized the EMT modulates the immune response to ovarian cancer. Here we show that cancer cells from infiltrated/inflamed tumors possess more mesenchymal cells, than excluded and desert tumors. We also noted high expression of LGALS3 is associated with EMT in vivo, a finding validated with in vitro EMT models. Dissecting the cellular communications among populations in the tumor revealed that mesenchymal cancer cells in infiltrated tumors communicate through LGALS3 to LAG3 receptor expressed by CD8+ T cells. We found CD8+ T cells express high levels of LAG3, a marker of T cell exhaustion. The results indicate that EMT in ovarian cancer cells promotes interactions between cancer cells and T cells through the LGALS3 - LAG3 axis, which could increase T cell exhaustion in infiltrated tumors, dampening antitumor immunity.
    DOI:  https://doi.org/10.1038/s41540-023-00322-4
  45. Curr Opin Cell Biol. 2023 Dec 13. pii: S0955-0674(23)00142-4. [Epub ahead of print]86 102293
    Organelle morphology and positioning orchestrate physiological and disease-associated processes.
    Katerina Jerabkova-Roda, Rituraj Marwaha, Tamal Das, Jacky G Goetz.
      In cells, organelles are distributed nonrandomly to regulate cells' physiological and disease-associated processes. Based on their morphology, position within the cell, and contacts with other organelles, they exert different biological functions. Endo-lysosomes are critical cell metabolism and nutrient-sensing regulators modulating cell growth and cellular adaptation in response to nutrient availability. Their spatial distribution is intimately linked to their function. In this review, we will discuss the role of endolysosomes under physiological conditions and in the context of cancer progression, with a special focus on their morphology, the molecular mechanisms determining their subcellular position, and the contacts they form with other organelles. We aim to highlight the relationship between cell architecture and cell function and its impact on maintaining organismal homeostasis.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102293
  46. Cancer Discov. 2023 Dec 08. OF1
    Trans-vaccenic Acid Reprograms CD8+ T Cells and Enhances Antitumor Immunity.
      Trans-vaccenic acid (TVA) enhances antitumor immunity by promoting CD8+ T-cell accumulation and function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-192
  47. Science. 2023 Dec 08. 382(6675): eadf3208
    ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging.
    Goda Snieckute, Laura Ryder, Anna Constance Vind, Zhenzhen Wu, Frederic Schrøder Arendrup, Mark Stoneley, Sébastien Chamois, Ana Martinez-Val, Marion Leleu, René Dreos, Alexander Russell, David Michael Gay, Aitana Victoria Genzor, Beatrice So-Yun Choi, Astrid Linde Basse, Frederike Sass, Morten Dall, Lucile Chantal Marie Dollet, Melanie Blasius, Anne E Willis, Anders H Lund, Jonas T Treebak, Jesper Velgaard Olsen, Steen Seier Poulsen, Mary Elizabeth Pownall, Benjamin Anderschou Holbech Jensen, Christoffer Clemmensen, Zach Gerhart-Hines, David Gatfield, Simon Bekker-Jensen.
      The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.
    DOI:  https://doi.org/10.1126/science.adf3208
  48. Cancer Cell. 2023 Dec 01. pii: S1535-6108(23)00399-9. [Epub ahead of print]
    B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling.
    Amulya Sreekumar, Michelle Lu, Biswa Choudhury, Tien-Chi Pan, Dhruv K Pant, Matthew R Lawrence-Paul, Christopher J Sterner, George K Belka, Takashi Toriumi, Brian A Benz, Matias Escobar-Aguirre, Francesco E Marino, Jeffrey D Esko, Lewis A Chodosh.
      Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.
    Keywords:  6-O-sulfation; B3GALT6; FGFR2; HS6ST1; breast cancer; dormancy; glycans; glycosaminoglycans; heparan sulfate; proteoglycans
    DOI:  https://doi.org/10.1016/j.ccell.2023.11.008
  49. bioRxiv. 2023 Dec 01. pii: 2023.12.01.569475. [Epub ahead of print]
    A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.
    Surbhi Verma, Mrinmoy Das, Raman D Sharma, Vikas Yadav, Shweta Thakur, Priya Sharma, Mardiana Marzuki, Shihui Foo, Giulia M Piperno, Mehak Z Khan, Babu Mathew, Meenu Bajpai, Jaswinder Singh Maras, Shanshan Howland, Sovan Sarkar, Federica Benvenuti, Amit Singh, Vinay Nandicoori, Amit Singhal, Dhiraj Kumar.
      Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis ( Mtb ) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb -phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion ( p62 KD ) blocks mitophagy flux without impacting mitochondrial quality. In p62 KD cells, Mtb growth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20 + mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62 KD cells, TOM20 + -MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62 KD cells, TOM20 + -MDVs get extensively targeted to Mtb -phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb . Triggering MQC collapse in p62 KD cells further diminishes Mtb survival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.
    DOI:  https://doi.org/10.1101/2023.12.01.569475
  50. Nat Commun. 2023 Dec 09. 14(1): 8154
    Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion.
    Xuemei Gu, Haoran Wei, Caixia Suo, Shengqi Shen, Chuxu Zhu, Liang Chen, Kai Yan, Zhikun Li, Zhenhua Bian, Pinggen Zhang, Mengqiu Yuan, Yingxuan Yu, Jinzhi Du, Huafeng Zhang, Linchong Sun, Ping Gao.
      Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.
    DOI:  https://doi.org/10.1038/s41467-023-43988-4
  51. Commun Biol. 2023 Dec 08. 6(1): 1240
    Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
    Raquel Fernando, Anastasia V Shindyapina, Mario Ost, Didac Santesmasses, Yan Hu, Alexander Tyshkovskiy, Sun Hee Yim, Jürgen Weiss, Vadim N Gladyshev, Tilman Grune, José Pedro Castro.
      Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
    DOI:  https://doi.org/10.1038/s42003-023-05595-3
  52. Cell Rep. 2023 Dec 04. pii: S2211-1247(23)01547-4. [Epub ahead of print]42(12): 113535
    Epinephrine inhibits PI3Kα via the Hippo kinases.
    Ting-Yu Lin, Shakti Ramsamooj, Tiffany Perrier, Katarina Liberatore, Louise Lantier, Neil Vasan, Kannan Karukurichi, Seo-Kyoung Hwang, Edward A Kesicki, Edward R Kastenhuber, Thorsten Wiederhold, Tomer M Yaron, Emily M Huntsman, Mengmeng Zhu, Yilun Ma, Marcia N Paddock, Guoan Zhang, Benjamin D Hopkins, Owen McGuinness, Robert E Schwartz, Baran A Ersoy, Lewis C Cantley, Jared L Johnson, Marcus D Goncalves.
      The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.
    Keywords:  CP: Metabolism; CP: Molecular biology; Hippo kinases; PI3K signaling; epinephrine signaling; glucose metabolism; glycogen metabolism; insulin sensitivity; liver
    DOI:  https://doi.org/10.1016/j.celrep.2023.113535
  53. Nat Commun. 2023 Dec 12. 14(1): 8237
    An integrated workflow for quantitative analysis of the newly synthesized proteome.
    Toman Borteçen, Torsten Müller, Jeroen Krijgsveld.
      The analysis of proteins that are newly synthesized upon a cellular perturbation can provide detailed insight into the proteomic response that is elicited by specific cues. This can be investigated by pulse-labeling of cells with clickable and stable-isotope-coded amino acids for the enrichment and mass spectrometric characterization of newly synthesized proteins (NSPs), however convoluted protocols prohibit their routine application. Here we report the optimization of multiple steps in sample preparation, mass spectrometry and data analysis, and we integrate them into a semi-automated workflow for the quantitative analysis of the newly synthesized proteome (QuaNPA). Reduced input requirements and data-independent acquisition (DIA) enable the analysis of triple-SILAC-labeled NSP samples, with enhanced throughput while featuring high quantitative accuracy. We apply QuaNPA to investigate the time-resolved cellular response to interferon-gamma (IFNg), observing rapid induction of targets 2 h after IFNg treatment. QuaNPA provides a powerful approach for large-scale investigation of NSPs to gain insight into complex cellular processes.
    DOI:  https://doi.org/10.1038/s41467-023-43919-3
  54. Nat Commun. 2023 Dec 08. 14(1): 8125
    A class of secreted mammalian peptides with potential to expand cell-cell communication.
    Amanda L Wiggenhorn, Hind Z Abuzaid, Laetitia Coassolo, Veronica L Li, Julia T Tanzo, Wei Wei, Xuchao Lyu, Katrin J Svensson, Jonathan Z Long.
      Peptide hormones and neuropeptides are signaling molecules that control diverse aspects of mammalian homeostasis and physiology. Here we provide evidence for the endogenous presence of a sequence diverse class of blood-borne peptides that we call "capped peptides." Capped peptides are fragments of secreted proteins and defined by the presence of two post-translational modifications - N-terminal pyroglutamylation and C-terminal amidation - which function as chemical "caps" of the intervening sequence. Capped peptides share many regulatory characteristics in common with that of other signaling peptides, including dynamic physiologic regulation. One capped peptide, CAP-TAC1, is a tachykinin neuropeptide-like molecule and a nanomolar agonist of mammalian tachykinin receptors. A second capped peptide, CAP-GDF15, is a 12-mer peptide cleaved from the prepropeptide region of full-length GDF15 that, like the canonical GDF15 hormone, also reduces food intake and body weight. Capped peptides are a potentially large class of signaling molecules with potential to broadly regulate cell-cell communication in mammalian physiology.
    DOI:  https://doi.org/10.1038/s41467-023-43857-0
  55. Nat Commun. 2023 Dec 09. 14(1): 8151
    Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity.
    Jinjie Duan, Wenhui Dong, Guangyan Wang, Wenjing Xiu, Guangyin Pu, Jingwen Xu, Chenji Ye, Xu Zhang, Yi Zhu, Chunjiong Wang.
      Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-023-44026-z
  56. J Clin Invest. 2023 Dec 12. pii: e173034. [Epub ahead of print]
    Itaconate suppresses atherosclerosis by activating a Nrf2-dependent anti-inflammatory response in macrophages in mice.
    Jianrui Song, Yanling Zhang, Ryan A Frieler, Anthony Andren, Sherri C Wood, Daniel J Tyrrell, Peter Sajjakulnukit, Jane C Deng, Costas A Lyssiotis, Richard M Mortensen, Morgan Salmon, Daniel R Goldstein.
      Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as "immune-responsive gene 1"/IRG1) are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-ocytyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, Nuclear factor erythroid-2 Related Factor 2 (Nrf2) was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
    Keywords:  Atherosclerosis; Cardiology; Cardiovascular disease; Inflammation; Macrophages
    DOI:  https://doi.org/10.1172/JCI173034
  57. Biochim Biophys Acta Mol Cell Res. 2023 Dec 11. pii: S0167-4889(23)00221-5. [Epub ahead of print] 119648
    The protease Lon prolongs insect lifespan by responding to reactive oxygen species and degrading mitochondrial transcription factor A.
    Xiao-Long Su, Zhi-Ren Su, Wei-Hua Xu.
      Diapause is a widespread adaptation of insects that enables them to survive during unfavorable seasons and is characterized by suppressed metabolism and increased lifespan. Previous works have demonstrated that high levels of reactive oxygen species (ROS) and hypoxia-inducible factor-1α (HIF-1α) in the pupal brain of the moth Helicoverpa armigera induce diapause and extend lifespan by downregulating mitochondrial transcription factor A (TFAM). However, the molecular mechanisms of ROS-HIF-1α regulating metabolic activity to extend lifespan are still poorly understood. Here, we show that the mitochondrial abundance in diapause-type pupal brains is markedly lower than that in their nondiapause-type pupae, suggesting that ROS-HIF-1α signaling negatively regulates the number of mitochondria. The protease Lon, a major mitochondrial matrix protease, can respond to ROS signals. It is activated by transcription factor HIF-1α, which specifically binds the LON promoter to promote its expression. A high level of LON mediates the degradation of TFAM, which is a crucial factor in regulating mitochondrial abundance and metabolic activity. We believe this is the first report that a previously unrecognized regulatory pathway, ROS-HIF-1α-LON-TFAM, reduces mitochondrial activity to induce diapause, extending insect lifespan.
    Keywords:  Diapause; HIF-1α; LON; ROS; TFAM
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119648
  58. Nat Commun. 2023 Dec 12. 14(1): 8217
    Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.
    Zhengyi Zhen, Yu Chen, Haiyan Wang, Huanyin Tang, Haiping Zhang, Haipeng Liu, Ying Jiang, Zhiyong Mao.
      Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-43001-y
  59. Nucleic Acids Res. 2023 Dec 12. pii: gkad1184. [Epub ahead of print]
    cGAS-STING signalling regulates microglial chemotaxis in genome instability.
    Emily J Talbot, Lisha Joshi, Peter Thornton, Mahya Dezfouli, Kalliopi Tsafou, Michael Perkinton, Svetlana V Khoronenkova.
      Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-β treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system.
    DOI:  https://doi.org/10.1093/nar/gkad1184
  60. Nature. 2023 Dec;624(7991): 237-238
    Are your organs ageing well? The blood holds clues.
    Max Kozlov.
      
    Keywords:  Ageing; Diseases; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-03821-w
  61. Oncogene. 2023 Dec 11.
    ROS production by mitochondria: function or dysfunction?
    Flavio R Palma, Benjamin N Gantner, Marcelo J Sakiyama, Cezar Kayzuka, Sanjeev Shukla, Riccardo Lacchini, Brian Cunniff, Marcelo G Bonini.
      In eukaryotic cells, ATP generation is generally viewed as the primary function of mitochondria under normoxic conditions. Reactive oxygen species (ROS), in contrast, are regarded as the by-products of respiration, and are widely associated with dysfunction and disease. Important signaling functions have been demonstrated for mitochondrial ROS in recent years. Still, their chemical reactivity and capacity to elicit oxidative damage have reinforced the idea that ROS are the products of dysfunctional mitochondria that accumulate during disease. Several studies support a different model, however, by showing that: (1) limited oxygen availability results in mitochondria prioritizing ROS production over ATP, (2) ROS is an essential adaptive mitochondrial signal triggered by various important stressors, and (3) while mitochondria-independent ATP production can be easily engaged by most cells, there is no known replacement for ROS-driven redox signaling. Based on these observations and other evidence reviewed here, we highlight the role of ROS production as a major mitochondrial function involved in cellular adaptation and stress resistance. As such, we propose a rekindled view of ROS production as a primary mitochondrial function as essential to life as ATP production itself.
    DOI:  https://doi.org/10.1038/s41388-023-02907-z
  62. Nat Cardiovasc Res. 2023 Sep;2 835-852
    Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.
    Bianca de Jonckheere, Ferdinand Kollotzek, Patrick Münzer, Vanessa Göb, Melina Fischer, Kristina Mott, Cristina Coman, Nina Nicole Troppmair, Mailin-Christin Manke, Monika Zdanyte, Tobias Harm, Manuel Sigle, Dominik Kopczynski, Andrea Bileck, Christopher Gerner, Nils Hoffmann, David Heinzmann, Alice Assinger, Meinrad Gawaz, David Stegner, Harald Schulze, Oliver Borst, Robert Ahrends.
      During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.
    DOI:  https://doi.org/10.1038/s44161-023-00325-8
  63. Nat Commun. 2023 Dec 08. 14(1): 8115
    Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase.
    Helene Jahn, Ladislav Bartoš, Grace I Dearden, Jeremy S Dittman, Joost C M Holthuis, Robert Vácha, Anant K Menon.
      Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.
    DOI:  https://doi.org/10.1038/s41467-023-43570-y
  64. bioRxiv. 2023 Dec 01. pii: 2023.11.30.568080. [Epub ahead of print]
    Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake.
    Lauren N Woodie, Lily C Melink, Mohit Midha, Alan M de Araújo, Caroline E Geisler, Ahren J Alberto, Brianna M Krusen, Delaine M Zundell, Guillaume de Lartigue, Matthew R Hayes, Mitchell A Lazar.
      Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption.One Sentence Summary: The hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.
    DOI:  https://doi.org/10.1101/2023.11.30.568080
  65. Cancer Immunol Res. 2023 Dec 08. OF1-OF12
    Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function.
    Camille Collier, Kelly Wucherer, Matthew McWhorter, Chelsea Jenkins, Alexandra Bartlett, Rahul Roychoudhuri, Robert Eil.
      T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt-mTOR signaling and effector function. To alleviate K+-mediated T-cell dysfunction, we pursued genetic means to lower intracellular K+. CD8+ T cells robustly and dynamically express the Na+/K+ ATPase, among other K+ transporters. CRISPR-Cas9-mediated disruption of the Atp1a1 locus lowered intracellular K+ and elevated the resting membrane potential (i.e., Vm, Ψ). Despite compromised Ca2+ influx, Atp1a1-deficient T cells harbored tonic hyperactivity in multiple signal transduction cascades, along with a phenotype of exhaustion in mouse and human CD8+ T cells. Provision of exogenous K+ restored intracellular levels in Atp1a1-deficient T cells and prevented damaging levels of reactive oxygen species (ROS), and both antioxidant treatment and exogenous K+ prevented Atp1a1-deficient T-cell exhaustion in vitro. T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will require balancing the beneficial aspects of intracellular K+ with the ROS-dependent nature of T-cell effector function. See related Spotlight by Banuelos and Borges da Silva.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0319
  66. Biotechniques. 2023 Dec 12.
    Is space the final frontier for mitochondrial study?
    Kit Neikirk, Dominique C Stephens, Heather K Beasley, Andrea G Marshall, Jennifer A Gaddy, Steven M Damo, Antentor Hinton.
      Tweetable abstract This perspective considers several avenues for future research on mitochondrial dynamics, stress, and DNA in outer space.
    Keywords:  metabolism; mitochondria; mitochondrial structure; space travel
    DOI:  https://doi.org/10.2144/btn-2023-0071
  67. Sci Adv. 2023 Dec 08. 9(49): eadj4884
    In vivo protein turnover rates in varying oxygen tensions nominate MYBBP1A as a mediator of the hyperoxia response.
    Xuewen Chen, Augustinus G Haribowo, Alan H Baik, Andrea Fossati, Erica Stevenson, Yiwen R Chen, Nabora S Reyes, Tien Peng, Michael A Matthay, Michela Traglia, Alexander R Pico, Daniel F Jarosz, Abigail Buchwalter, Sina Ghaemmaghami, Danielle L Swaney, Isha H Jain.
      Oxygen deprivation and excess are both toxic. Thus, the body's ability to adapt to varying oxygen tensions is critical for survival. While the hypoxia transcriptional response has been well studied, the post-translational effects of oxygen have been underexplored. In this study, we systematically investigate protein turnover rates in mouse heart, lung, and brain under different inhaled oxygen tensions. We find that the lung proteome is the most responsive to varying oxygen tensions. In particular, several extracellular matrix (ECM) proteins are stabilized in the lung under both hypoxia and hyperoxia. Furthermore, we show that complex 1 of the electron transport chain is destabilized in hyperoxia, in accordance with the exacerbation of associated disease models by hyperoxia and rescue by hypoxia. Moreover, we nominate MYBBP1A as a hyperoxia transcriptional regulator, particularly in the context of rRNA homeostasis. Overall, our study highlights the importance of varying oxygen tensions on protein turnover rates and identifies tissue-specific mediators of oxygen-dependent responses.
    DOI:  https://doi.org/10.1126/sciadv.adj4884
  68. Angew Chem Int Ed Engl. 2023 Dec 14. e202318445
    Enzyme-Catalyzed Oxidative Degradation of Ergothioneine.
    Egor Nalivaiko, Camille M Vasseur, Florian P Seebeck.
      Ergothioneine is a sulfur-containing metabolite that is produced by bacteria and fungi, and is absorbed by plants and animals as a micronutrient. Ergothioneine reacts with harmful oxidants including singlet oxygen or hydrogen peroxide, and may therefore protect cells against oxidative stress. In this report we describe two enzymes from actinobacteria that cooperate in the specific oxidative degradation of ergothioneine. The first enzyme is an iron-dependent thiol dioxygenase that produces ergothioneine sulfinic acid. A crystal structure of ergothioneine dioxygenase from Thermocatellispora tengchongensis reveals many similarities with cysteine dioxygenases, suggesting that the two enzymes share a common mechanism. The second enzyme is a metal-dependent ergothioneine sulfinic acid desulfinase that produces Na-trimethylhistidine and SO2. The discovery that certain actinobacteria contain the enzymatic machinery for O2-dependent biosynthesis and O2-dependent degradation of ergothioneine indicates that these organisms may actively manage their ergothioneine content.
    Keywords:  biosynthesis; desulfinase; ergothioneine; thiol dioxygenase
    DOI:  https://doi.org/10.1002/anie.202318445
  69. Cell Rep. 2023 Dec 06. pii: S2211-1247(23)01556-5. [Epub ahead of print]42(12): 113544
    A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.
    Vinita Bharat, Aarooran S Durairaj, Roeland Vanhauwaert, Li Li, Colin M Muir, Sujyoti Chandra, Chulhwan S Kwak, Yann Le Guen, Pawan Nandakishore, Chung-Han Hsieh, Stefano E Rensi, Russ B Altman, Michael D Greicius, Liang Feng, Xinnan Wang.
      Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.
    Keywords:  CP: Neuroscience
    DOI:  https://doi.org/10.1016/j.celrep.2023.113544
  70. Nature. 2023 Dec 13.
    Slide-tags enables single-nucleus barcoding for multimodal spatial genomics.
    Andrew J C Russell, Jackson A Weir, Naeem M Nadaf, Matthew Shabet, Vipin Kumar, Sandeep Kambhampati, Ruth Raichur, Giovanni J Marrero, Sophia Liu, Karol S Balderrama, Charles R Vanderburg, Vignesh Shanmugam, Luyi Tian, J Bryan Iorgulescu, Charles H Yoon, Catherine J Wu, Evan Z Macosko, Fei Chen.
      Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed1-6. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are tagged with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions. These tagged nuclei can then be used as an input into a wide variety of single-nucleus profiling assays. Application of Slide-tags to the mouse hippocampus positioned nuclei at less than 10 μm spatial resolution and delivered whole-transcriptome data that are indistinguishable in quality from ordinary single-nucleus RNA-sequencing data. To demonstrate that Slide-tags can be applied to a wide variety of human tissues, we performed the assay on brain, tonsil and melanoma. We revealed cell-type-specific spatially varying gene expression across cortical layers and spatially contextualized receptor-ligand interactions driving B cell maturation in lymphoid tissue. A major benefit of Slide-tags is that it is easily adaptable to almost any single-cell measurement technology. As a proof of principle, we performed multiomic measurements of open chromatin, RNA and T cell receptor (TCR) sequences in the same cells from metastatic melanoma, identifying transcription factor motifs driving cancer cell state transitions in spatially distinct microenvironments. Slide-tags offers a universal platform for importing the compendium of established single-cell measurements into the spatial genomics repertoire.
    DOI:  https://doi.org/10.1038/s41586-023-06837-4
  71. bioRxiv. 2023 Dec 02. pii: 2023.12.01.569614. [Epub ahead of print]
    Spatial segregation and aging of metabolic processes underlie phenotypic heterogeneity in mycobacteria.
    Celena M Gwin, Kuldeepkumar R Gupta, Yao Lu, Lin Shao, E Hesper Rego.
      Individual cells within clonal populations of mycobacteria vary in size, growth rate, and antibiotic susceptibility. Heterogeneity is, in part, determined by LamA, a protein found exclusively in mycobacteria. LamA localizes to sites of new cell wall synthesis where it recruits proteins important for polar growth and establishing asymmetry. Here, we report that in addition to this function, LamA interacts with complexes involved in oxidative phosphorylation (OXPHOS) at a subcellular location distinct from cell wall synthesis. Importantly, heterogeneity depends on a unique extension of the mycobacterial ATP synthase, and LamA mediates the coupling between ATP production and cell growth in single cells. Strikingly, as single cells age, concentrations of proteins important for oxidative phosphorylation become less abundant, and older cells rely less on oxidative phosphorylation for growth. Together, our data reveal that central metabolism is spatially organized within a single mycobacterium and varies within a genetically identical population of mycobacteria. Designing therapeutic regimens to account for this heterogeneity may help to treat mycobacterial infections faster and more completely.
    DOI:  https://doi.org/10.1101/2023.12.01.569614
  72. Nature. 2023 Dec 08.
    Why we need an academic career path that combines science and art.
    Julie Gould.
      
    Keywords:  Careers; Climate change; Lab life
    DOI:  https://doi.org/10.1038/d41586-023-03394-8
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