bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒10‒20
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
  2. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
  3. Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock.
  4. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  5. CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
  6. Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
  7. Molecular mechanisms of mitochondrial dynamics.
  8. Hydrogen sulfide: A whiff of trouble for cancer cell survival.
  9. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
  10. Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex.
  11. Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.
  12. Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
  13. A TBK1-independent primordial function of STING in lysosomal biogenesis.
  14. Quantification of nutrient fluxes during acute exercise in mice.
  15. A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms.
  16. Mitophagy as a guardian against cellular aging.
  17. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
  18. Selective utilization of glucose metabolism guides mammalian gastrulation.
  19. Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.
  20. Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis.
  21. Itaconate modulates mitochondria for antiviral IFN-β.
  22. Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
  23. Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma.
  24. Visualizing VDAC1 in live cells using a tetracysteine tag.
  25. Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.
  26. Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex.
  27. Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.
  28. Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
  29. Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
  30. Direct targeting of mitochondria by cisplatin leads to cytotoxicity in zebrafish lateral-line hair cells.
  31. Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport.
  32. Catabolism of extracellular glutathione supplies amino acids to support tumor growth.
  33. USP7 protects TFEB from proteasome-mediated degradation.
  34. Peroxisomal import stress activates integrated stress response and inhibits ribosome biogenesis.
  35. Somatic mitochondrial DNA mutations are a source of heterogeneity among primary leukemic cells.
  36. Cholesterol sensing and metabolic adaptation in tissue immunity.
  37. Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.
  38. m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.
  39. Lighting up arginine metabolism reveals its functional diversity in physiology and pathology.
  40. Unraveling the roles and mechanisms of mitochondrial translation in normal and malignant hematopoiesis.
  41. A rising star involved in tumour immunity: Lactylation.
  42. Quantifying constraint in the human mitochondrial genome.
  43. Epigenetic clocks and programmatic aging.
  44. Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
  45. Ubiquitin ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes.
  46. KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.
  47. Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells.
  48. Autophagy, aging, and age-related neurodegeneration.
  49. Structural basis of respiratory complex adaptation to cold temperatures.
  50. Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
  51. Integrating priorities at the intersection of cancer and neuroscience.
  52. Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5.
  53. Glucose has a surprise role in directing cell fate and migration.
  54. Ex vivo imaging reveals the spatiotemporal control of ovulation.
  55. Analysis of Somatic Mutations in Senescent Cells Using Single-Cell Whole-Genome Sequencing.
  56. A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
  57. Vitamin B6 Pathway Maintains Glioblastoma Cell Survival in 3D Spheroid Cultures.
  58. Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer.
  59. Loss of STING impairs lactogenic differentiation.
  1. Nat Metab. 2024 Oct 15.
    Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
    Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.
      Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.
    DOI:  https://doi.org/10.1038/s42255-024-01145-1
  2. Nat Metab. 2024 Oct 14.
    Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
    Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.
      Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
    DOI:  https://doi.org/10.1038/s42255-024-01143-3
  3. Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01216-6. [Epub ahead of print]43(10): 114865
    Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock.
    Jiameng Sun, Yiming Zhang, Joshua A Adams, Cassandra B Higgins, Shannon C Kelly, Hao Zhang, Kevin Y Cho, Ulysses G Johnson, Benjamin M Swarts, Shun-Ichi Wada, Gary J Patti, Leah P Shriver, Brian N Finck, Erik D Herzog, Brian J DeBosch.
      Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus. In vivo isotopic tracing and indirect calorimetry demonstrate that hepatocyte Per1-deficient mice fail to transit from oxidation of glucose to fat, which is completely reversible by exogenous FGF21 or by inhibiting pyruvate dehydrogenase. Strikingly, disturbing other core circadian genes does not perturb Per1 induction during fasting. We thus describe Per1 as an important mechanism by which hepatocytes integrate internal circadian rhythm and external nutrition signals to facilitate proper fuel utilization.
    Keywords:  CP: Metabolism; circadian clock; fasting; glucose oxidation; liver metabolism; metabolite tracing; single-nucleus multiome sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2024.114865
  4. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  5. Immunity. 2024 Oct 09. pii: S1074-7613(24)00457-6. [Epub ahead of print]
    CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
    Jana L Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil Kc, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P Connelly, Shondra M Pruett-Miller, Miguel Reina-Campos, Ananda W Goldrath, Yasmine Belkaid, Hongbo Chi.
      Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.
    Keywords:  CD8 T cell; adaptive immunity; dietary intervention; immunometabolism; lysosome; mitochondria; tissue-resident memory
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.013
  6. bioRxiv. 2024 Oct 08. pii: 2024.10.07.617073. [Epub ahead of print]
    Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, Marisa J Lang, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Ji Eon Kim, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, James Carrington, Jonathan Leon Catrow, Quentinn Pearce, Mi-Young Jeong, Alex J Bott, Álvaro J Narbona-Pérez, Claire E Stanley, Qing Li, David R Eberhardt, Jeffrey T Morgan, Tarun Yadav, Chloe E Wells, Dinesh K A Ramadurai, Wojciech I Swiatek, Dipayan Chaudhuri, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Steven A Baker, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.
    DOI:  https://doi.org/10.1101/2024.10.07.617073
  7. Nat Rev Mol Cell Biol. 2024 Oct 17.
    Molecular mechanisms of mitochondrial dynamics.
    Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.
      Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.
    DOI:  https://doi.org/10.1038/s41580-024-00785-1
  8. Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00783-4. [Epub ahead of print]84(20): 3865-3867
    Hydrogen sulfide: A whiff of trouble for cancer cell survival.
    Jung Seung Nam, Maya S Dixon, Iok In Christine Chio.
      Hydrogen sulfide (H2S) can regulate biological processes by post-translational persulfidation of proteins at select cysteine residues. In this issue of Molecular Cell, Zheng et al.1 identify the enzyme SAHH as an H2S substrate, which upon persulfidation disrupts homocysteine metabolism and sensitizes lung cancer cells to ferroptosis.
    DOI:  https://doi.org/10.1016/j.molcel.2024.09.027
  9. Nat Commun. 2024 Oct 17. 15(1): 8983
    Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.
    Nneka E Mbah, Amy L Myers, Peter Sajjakulnukit, Chan Chung, Joyce K Thompson, Hanna S Hong, Heather Giza, Derek Dang, Zeribe C Nwosu, Mengrou Shan, Stefan R Sweha, Daniella D Maydan, Brandon Chen, Li Zhang, Brian Magnuson, Zirui Zhu, Megan Radyk, Brooke Lavoie, Viveka Nand Yadav, Imhoi Koo, Andrew D Patterson, Daniel R Wahl, Luigi Franchi, Sameer Agnihotri, Carl J Koschmann, Sriram Venneti, Costas A Lyssiotis.
      H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
    DOI:  https://doi.org/10.1038/s41467-024-52973-4
  10. bioRxiv. 2024 Oct 01. pii: 2024.10.01.616059. [Epub ahead of print]
    Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex.
    Bibek R Karki, Austin C Macmillan, Sara Vicente-Muñoz, Kenneth D Greis, Lindsey E Romick, J Tom Cunningham.
      The phosphoribosyl pyrophosphate synthetase (PRPS) enzyme conducts a chokepoint reaction connecting central carbon metabolism and nucleotide production pathways, making it essential for life 1,2 . Here, we show that the presence of multiple PRPS-encoding genes is a hallmark trait of eukaryotes, and we trace the evolutionary origins and define the individual functions of each of the five mammalian PRPS homologs - three isozymes (one testis-restricted) 3,4 and two non-enzymatic associated proteins (APs) 5,6 - which we demonstrate operate together as a large molecular weight complex capable of attaining a heterogeneous array of functional multimeric configurations. Employing a repertoire of isogenic fibroblast clones in all viable individual or combinatorial assembly states, we define preferential interactions between subunits, and we show that cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity. We demonstrate how numerous evolutionary innovations in the duplicated genes have created specialized roles for individual complex members and identify translational control mechanisms that enable fine-tuned regulation of PRPS assembly and activity, which provide clues into the positive and negative selective pressures that facilitate metabolic flexibility and tissue specialization in advanced lifeforms. Collectively, our study demonstrates how evolution has transformed a single PRPS gene into a multimeric complex endowed with functional and regulatory features that govern cellular biochemistry.
    DOI:  https://doi.org/10.1101/2024.10.01.616059
  11. Dev Cell. 2024 Oct 15. pii: S1534-5807(24)00538-0. [Epub ahead of print]
    Outer mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis.
    Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Claudia Christiane Bippes, Albert Neutzner, Liron Boyman, Mariusz Karbowski.
      We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. In human immortalized cells, MARCH5 knockout leads to the accumulation of immature peroxisomes, reduced fatty-acid-induced peroxisomal biogenesis, and abnormal peroxisome biogenesis in MARCH5/Pex14 and MARCH5/Pex3 dko cells. Upon fatty-acid-induced peroxisomal biogenesis, MARCH5 redistributes to peroxisomes, and ubiquitination activity-deficient mutants of MARCH5 accumulate on peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Similarly, depletion of peroxisome biogenesis factor Pex14 leads to the accumulation of MARCH5- and Tom20-positive pre-peroxisomes, whereas no peroxisomes are detected in MARCH5/Pex14 dko cells. Inconsistent with MARCH5 merely acting as a quality factor, mitochondrial decline is not evident in tested models. Furthermore, reduced expression of peroxisomal proteins is detected in MARCH5-/- cells, whereas some of these proteins are stabilized in peroxisome biogenesis deficiency models lacking MARCH5 expression. Thus, MARCH5 is central for mitochondria-dependent peroxisome biogenesis.
    Keywords:  MARCH5; Pex14; Pex3; Ub E3 ligase; biogenesis; metabolic adaptation; mitochondria; mitochondria-derived pre-peroxisomes; peroxisomes
    DOI:  https://doi.org/10.1016/j.devcel.2024.09.010
  12. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00103-5. [Epub ahead of print]389 67-103
    Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells.
    Sanjay Pandey, Vandana Anang, Michelle M Schumacher.
      Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).
    Keywords:  AMPK; CAR-T; Fatty acid oxidation; Glycolysis; HIF1α; MTOR; Metabolism; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial metabolism; OXPHOS; T cell exhaustion; T cell metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.07.003
  13. Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00703-2. [Epub ahead of print]84(20): 3979-3996.e9
    A TBK1-independent primordial function of STING in lysosomal biogenesis.
    Bo Lv, William A Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan.
      Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.
    Keywords:  STING; STING channel; TBK1; TFE3; TFEB; autophagy; cGAS; chronic STING signaling; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.026
  14. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
    Quantification of nutrient fluxes during acute exercise in mice.
    Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  15. Cell Death Dis. 2024 Oct 14. 15(10): 746
    A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms.
    Joy Armistead, Sebastian Höpfl, Pierre Goldhausen, Andrea Müller-Hartmann, Evelin Fahle, Julia Hatzold, Rainer Franzen, Susanne Brodesser, Nicole E Radde, Matthias Hammerschmidt.
      Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1afr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.
    DOI:  https://doi.org/10.1038/s41419-024-07134-2
  16. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  17. EMBO J. 2024 Oct 17.
    Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
    Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima.
      During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.
    Keywords:  Autophagy; Liquid–Liquid Phase Separation; Mitophagy; Optineurin; Wetting
    DOI:  https://doi.org/10.1038/s44318-024-00272-5
  18. Nature. 2024 Oct 16.
    Selective utilization of glucose metabolism guides mammalian gastrulation.
    Dominica Cao, Jenna Bergmann, Liangwen Zhong, Anupama Hemalatha, Chaitanya Dingare, Tyler Jensen, Andy L Cox, Valentina Greco, Benjamin Steventon, Berna Sozen.
      The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens alone generate spatially and temporally distinct expression patterns. However, metabolism has also emerged as a critical developmental regulator1-10, independent of its functions in energy production and growth. The mechanistic role of nutrient utilization in instructing cellular programmes to shape the in vivo developing mammalian embryo remains unknown. Here we reveal two spatially resolved, cell-type- and stage-specific waves of glucose metabolism during mammalian gastrulation by using single-cell-resolution quantitative imaging of developing mouse embryos, stem cell models and embryo-derived tissue explants. We identify that the first spatiotemporal wave of glucose metabolism occurs through the hexosamine biosynthetic pathway to drive fate acquisition in the epiblast, and the second wave uses glycolysis to guide mesoderm migration and lateral expansion. Furthermore, we demonstrate that glucose exerts its influence on these developmental processes through cellular signalling pathways, with distinct mechanisms connecting glucose with the ERK activity in each wave. Our findings underscore that-in synergy with genetic mechanisms and morphogenic gradients-compartmentalized cellular metabolism is integral in guiding cell fate and specialized functions during development. This study challenges the view of the generic and housekeeping nature of cellular metabolism, offering valuable insights into its roles in various developmental contexts.
    DOI:  https://doi.org/10.1038/s41586-024-08044-1
  19. Proc Natl Acad Sci U S A. 2024 Oct 22. 121(43): e2410830121
    Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution.
    Yoshiharu Muto, Yasuhiro Yoshimura, Haojia Wu, Monica Chang-Panesso, Nicolas Ledru, Owen M Woodward, Patricia Outeda, Tao Cheng, Moe R Mahjoub, Terry J Watnick, Benjamin D Humphreys.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
    Keywords:  PKD1; mouse model; multiomics; polycystic kidney disease; single cell analysis
    DOI:  https://doi.org/10.1073/pnas.2410830121
  20. Sci Adv. 2024 Oct 18. 10(42): eadp6164
    Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis.
    Sanket More, Julie Bonnereau, David Wouters, Xander Spotbeen, Panagiotis Karras, Francesca Rizzollo, Theo Killian, Tom Venken, Stefan Naulaerts, Ellen Vervoort, Maarten Ganne, David Nittner, Jelle Verhoeven, Oliver Bechter, Francesca Bosisio, Diether Lambrechts, Alejandro Sifrim, Brent R Stockwell, Johannes V Swinnen, Jean Christophe Marine, Patrizia Agostinis.
      A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (APOE) as the top lipid-metabolism gene segregating the melanoma MITFhigh/AXLlow proliferative/ferroptosis-resistant from MITFlow/AXLhigh invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITFhigh/AXLlow cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that APOEhigh expression in patients with melanoma is associated with resistance to ferroptosis, regardless of APOE germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and APOEhigh expression as a potential biomarker for poor ferroptosis response in melanoma.
    DOI:  https://doi.org/10.1126/sciadv.adp6164
  21. Nat Metab. 2024 Oct 15.
    Itaconate modulates mitochondria for antiviral IFN-β.
    Thekla Cordes, Karsten Hiller.
      
    DOI:  https://doi.org/10.1038/s42255-024-01146-0
  22. Cells. 2024 Oct 09. pii: 1671. [Epub ahead of print]13(19):
    Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
    Lukas F J Althoff, Markus M Kramer, Benjamin Bührer, Denise Gaspar, Gerald Radziwill.
      Mitochondria provide cells with energy and regulate the cellular metabolism. Almost all mitochondrial proteins are nuclear-encoded, translated on ribosomes in the cytoplasm, and subsequently transferred to the different subcellular compartments of mitochondria. Here, we developed OptoMitoImport, an optogenetic tool to control the import of proteins into the mitochondrial matrix via the presequence pathway on demand. OptoMitoImport is based on a two-step process: first, light-induced cleavage by a TEV protease cuts off a plasma membrane-anchored fusion construct in close proximity to a mitochondrial targeting sequence; second, the mitochondrial targeting sequence preceding the protein of interest recruits to the outer mitochondrial membrane and imports the protein fused to it into mitochondria. Upon reaching the mitochondrial matrix, the matrix processing peptidase cuts off the mitochondrial targeting sequence and releases the protein of interest. OptoMitoImport is available as a two-plasmid system as well as a P2A peptide or IRES sequence-based bicistronic system. Fluorescence studies demonstrate the release of the plasma membrane-anchored protein of interest through light-induced TEV protease cleavage and its localization to mitochondria. Cell fractionation experiments confirm the presence of the peptidase-cleaved protein of interest in the mitochondrial fraction. The processed product is protected from proteinase K treatment. Depletion of the membrane potential across the inner mitochondria membrane prevents the mitochondrial protein import, indicating an import of the protein of interest by the presequence pathway. These data demonstrate the functionality of OptoMitoImport as a generic system with which to control the post-translational mitochondrial import of proteins via the presequence pathway.
    Keywords:  CRY2; LOV domain; MTS; TEV; matrix peptidases; mitochondrial import; optogenetics
    DOI:  https://doi.org/10.3390/cells13191671
  23. Mol Cell. 2024 Oct 14. pii: S1097-2765(24)00782-2. [Epub ahead of print]
    Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma.
    Sadaaki Nishimura, Juan F Linares, Antoine L'Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R Roberts, Maria T Diaz-Meco, Jorge Moscat.
      Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.
    Keywords:  CD8(+) T cells; NBR1; STING; TRIM32; hepatic stellate cells; hepatocellular carcinoma; interferon; microenvironment; p62
    DOI:  https://doi.org/10.1016/j.molcel.2024.09.026
  24. PLoS One. 2024 ;19(10): e0311107
    Visualizing VDAC1 in live cells using a tetracysteine tag.
    Johannes Pilic, Furkan E Oflaz, Benjamin Gottschalk, Yusuf C Erdogan, Wolfgang F Graier, Roland Malli.
      The voltage-dependent anion channel 1 (VDAC1) is a crucial gatekeeper in the outer mitochondrial membrane, controlling metabolic and energy homeostasis. The available methodological approaches fell short of accurate visualization of VDAC1 in living cells. To permit precise VDAC1 imaging, we utilized the tetracysteine (TC)-tag and visualized VDAC1 dynamics in living cells. TC-tagged VDAC1 had a cluster-like distribution on mitochondria. The labeling of TC-tagged VDAC1 was validated with immunofluorescence. The majority of VDAC1-TC-clusters were localized at endoplasmic reticulum (ER)-mitochondria contact sites. Notably, VDAC1 colocalized with BCL-2 Antagonist/Killer (BAK)-clusters upon apoptotic stimulation. Using this new tool, we were able to observe VDAC1-TC at mitochondrial fission sites. These findings highlight the suitability of the TC-tag for live-cell imaging of VDAC1, shedding light on the roles of VDAC1 in cellular processes.
    DOI:  https://doi.org/10.1371/journal.pone.0311107
  25. Nat Commun. 2024 Oct 17. 15(1): 8980
    Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.
    Maiko Matsui, Lauren E Lynch, Isabella Distefano, Allison Galante, Aravind R Gade, Hong-Gang Wang, Nicolas Gómez-Banoy, Patrick Towers, Daniel S Sinden, Eric Q Wei, Adam S Barnett, Kenneth Johnson, Renan Lima, Alfonso Rubio-Navarro, Ang K Li, Steven O Marx, Timothy E McGraw, Paul S Thornton, Katherine W Timothy, James C Lo, Geoffrey S Pitt.
      The canonical G406R mutation that increases Ca2+ influx through the CACNA1C-encoded CaV1.2 Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca2+ influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of CaV1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS.
    DOI:  https://doi.org/10.1038/s41467-024-52885-3
  26. Cell. 2024 Oct 03. pii: S0092-8674(24)01068-7. [Epub ahead of print]
    Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex.
    Owen T Tuck, Benjamin A Adler, Emily G Armbruster, Arushi Lahiri, Jason J Hu, Julia Zhou, Joe Pogliano, Jennifer A Doudna.
      Hachiman is a broad-spectrum antiphage defense system of unknown function. We show here that Hachiman is a heterodimeric nuclease-helicase complex, HamAB. HamA, previously a protein of unknown function, is the effector nuclease. HamB is the sensor helicase. HamB constrains HamA activity during surveillance of intact double-stranded DNA (dsDNA). When the HamAB complex detects DNA damage, HamB helicase activity activates HamA, unleashing nuclease activity. Hachiman activation degrades all DNA in the cell, creating "phantom" cells devoid of both phage and host DNA. We demonstrate Hachiman activation in the absence of phage by treatment with DNA-damaging agents, suggesting that Hachiman responds to aberrant DNA states. Phylogenetic similarities between the Hachiman helicase and enzymes from eukaryotes and archaea suggest deep functional symmetries with other important helicases across domains of life.
    Keywords:  cryo-EM; genome integrity; helicase; immunity; phage defense
    DOI:  https://doi.org/10.1016/j.cell.2024.09.020
  27. bioRxiv. 2024 Oct 10. pii: 2024.10.10.617517. [Epub ahead of print]
    Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.
    Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley J Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, cardiolipin (CL) was downregulated across four mouse models of MASLD. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous MASH with elevated mitochondrial electron leak. Loss of CL interfered with the ability of coenzyme Q (CoQ) to transfer electrons, promoting leak primarily at sites II F and III Q0 . Data from human liver biopsies revealed a highly robust correlation between mitochondrial CL and CoQ, co-downregulated with MASH. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.
    DOI:  https://doi.org/10.1101/2024.10.10.617517
  28. J Clin Invest. 2024 Oct 15. pii: e169722. [Epub ahead of print]
    Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
    Andrew LaPoint, Jason M Singer, Daniel Ferguson, Trevor M Shew, M Katie Renkemeyer, Hector H Palacios, Rachael L Field, Sireeesha Yerrathota, Roshan Kumari, Mahalakshmi Shankaran, Gordon I Smith, Jun Yoshino, Mai He, Gary J Patti, Marc K Hellerstein, Samuel Klein, E Matthew Morris, Jonathan R Brestoff, Brian N Finck, Andrew Lutkewitte.
      Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.
    Keywords:  Diabetes; Hepatology; Insulin signaling; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169722
  29. EMBO Rep. 2024 Oct 16.
    Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
    Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Kristina Morris, Cameron Baker, Lauren M Hablitz, Matthew N McCall, Minsoo Kim, Brian J Altman.
      Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.
    Keywords:  Circadian Rhythms; Immuno-oncology; Immunology; Macrophage; Tumor Microenvironment
    DOI:  https://doi.org/10.1038/s44319-024-00288-2
  30. iScience. 2024 Oct 18. 27(10): 110975
    Direct targeting of mitochondria by cisplatin leads to cytotoxicity in zebrafish lateral-line hair cells.
    David S Lee, Angela Schrader, Jiaoxia Zou, Wee Han Ang, Mark E Warchol, Lavinia Sheets.
      Cisplatin is a chemotherapy drug that causes permanent hearing loss by injuring cochlear hair cells. Hair cell mitochondria have emerged as potential mediators of hair cell cytotoxicity. Using in vivo live imaging of hair cells in the zebrafish lateral-line organ expressing a genetically encoded indicator of cumulative mitochondrial activity, we first demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conducted time-lapse imaging to understand dynamic changes in mitochondrial homeostasis and observe elevated mitochondrial and cytosolic calcium that surge prior to hair cell death. Furthermore, using a localized probe that fluoresces in the presence of cisplatin, we show that cisplatin directly accumulates in hair cell mitochondria, and this accumulation occurs before mitochondrial dysregulation and apoptosis. Our findings provide evidence that cisplatin directly targets hair cell mitochondria and support that the mitochondria are integral to cisplatin cytotoxicity in hair cells.
    Keywords:  biological sciences; cancer systems biology; natural sciences; pharmacology; systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110975
  31. Mol Metab. 2024 Oct 15. pii: S2212-8778(24)00178-9. [Epub ahead of print] 102047
    Distinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport.
    Sotiria Tavoulari, Denis Lacabanne, Gonçalo C Pereira, Chancievan Thangaratnarajah, Martin S King, Jiuya He, Roy Chowdhury, Lisa Tilokani, Shane M Palmer, Julien Prudent, John E Walker, Edmund R S Kunji.
      OBJECTIVE: Citrin, the mitochondrial aspartate/glutamate carrier isoform 2, is structurally and mechanistically the most complex SLC25 family member, because it consists of three-domains and forms a homodimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.METHODS: We have employed structural modelling and functional reconstitution of purified proteins in proteoliposomes to assess the transport activity and calcium regulation of wild-type citrin and pathogenic variants associated with citrin deficiency. We have also developed a double knock-out of citrin and aralar (AGC1), the two paralogs of the mitochondrial aspartate/glutamate carrier, in HAP1 cells to perform mitochondrial imaging and to investigate mitochondrial localisation.
    RESULTS: Using 33 pathogenic variants of citrin we clarify determinants of sub-cellular localization and transport mechanism. We identify crucial elements of the carrier domain that are required for transport, including those involved in substrate binding, network formation and dynamics. We show that the N-terminal domain is not involved in calcium regulation of transport, as previously thought, but when mutated causes a mitochondrial import defect.
    CONCLUSIONS: Our work introduces a new role for the N-terminal domain of citrin and demonstrates that dysfunction of the different domains contributes to distinct pathogenic mechanisms in citrin deficiency.
    Keywords:  SLC25; calcium regulation; citrin deficiency; transport; urea cycle disorders
    DOI:  https://doi.org/10.1016/j.molmet.2024.102047
  32. bioRxiv. 2024 Oct 11. pii: 2024.10.10.617667. [Epub ahead of print]
    Catabolism of extracellular glutathione supplies amino acids to support tumor growth.
    Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Bradley Smith, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Fatemeh Alimohammadi, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.
      Restricting amino acids from tumors is an emerging therapeutic strategy with significant promise. While typically considered an intracellular antioxidant with tumor-promoting capabilities, glutathione (GSH) is a tripeptide of cysteine, glutamate, and glycine that can be catabolized, yielding amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here, we find that GSH catabolism promotes tumor growth. We show that depletion of intracellular GSH does not perturb tumor growth, and extracellular GSH is highly abundant in the tumor microenvironment, highlighting the potential importance of GSH outside of tumors. We find supplementation with GSH can rescue cancer cell survival and growth in cystine-deficient conditions, and this rescue is dependent on the catabolic activity of γ-glutamyltransferases (GGTs). Finally, pharmacologic targeting of GGTs' activity prevents the breakdown of circulating GSH, lowers tumor cysteine levels, and slows tumor growth. Our findings indicate a non-canonical role for GSH in supporting tumors by acting as a reservoir of amino acids. Depriving tumors of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Further, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
    DOI:  https://doi.org/10.1101/2024.10.10.617667
  33. Cell Rep. 2024 Oct 15. pii: S2211-1247(24)01223-3. [Epub ahead of print]43(11): 114872
    USP7 protects TFEB from proteasome-mediated degradation.
    Swati Keshri, Mariella Vicinanza, Michael Takla, David C Rubinsztein.
      The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with ubiquitin-specific protease 7 (USP7) emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
    Keywords:  CP: Cell biology; CP: Molecular biology; TFEB; USP7; autophagy; lysosomal biogenesis; post-translational modifications; proteasomal degradation; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2024.114872
  34. PNAS Nexus. 2024 Oct;3(10): pgae429
    Peroxisomal import stress activates integrated stress response and inhibits ribosome biogenesis.
    Jinoh Kim, Kerui Huang, Pham Thuy Tien Vo, Ting Miao, Jacinta Correia, Ankur Kumar, Mirre J P Simons, Hua Bai.
      Impaired organelle-specific protein import triggers a variety of cellular stress responses, including adaptive pathways to balance protein homeostasis. Most of the previous studies focus on the cellular stress response triggered by misfolded proteins or defective protein import in the endoplasmic reticulum or mitochondria. However, little is known about the cellular stress response to impaired protein import in the peroxisome, an understudied organelle that has recently emerged as a key signaling hub for cellular and metabolic homeostasis. To uncover evolutionarily conserved cellular responses upon defective peroxisomal import, we carried out a comparative transcriptomic analysis on fruit flies with tissue-specific peroxin knockdown and human HEK293 cells expressing dominant-negative PEX5C11A. Our RNA-seq results reveal that defective peroxisomal import upregulates integrated stress response (ISR) and downregulates ribosome biogenesis in both flies and human cells. Functional analyses confirm that impaired peroxisomal import induces eIF2α phosphorylation and ATF4 expression. Loss of ATF4 exaggerates cellular damage upon peroxisomal import defects, suggesting that ATF4 activation serves as a cellular cytoprotective mechanism upon peroxisomal import stress. Intriguingly, we show that peroxisomal import stress decreases the expression of rRNA processing genes and inhibits early pre-rRNA processing, which leads to the accumulation of 47S precursor rRNA and reduction of downstream rRNA intermediates. Taken together, we identify ISR activation and ribosome biogenesis inhibition as conserved adaptive stress responses to defective peroxisomal import and uncover a novel link between peroxisomal dysfunction and rRNA processing.
    Keywords:  PEX5; early rRNA processing; integrated stress response; peroxisomal import stress; ribosome biogenesis
    DOI:  https://doi.org/10.1093/pnasnexus/pgae429
  35. medRxiv. 2024 Sep 27. pii: 2024.09.26.24314381. [Epub ahead of print]
    Somatic mitochondrial DNA mutations are a source of heterogeneity among primary leukemic cells.
    Kelly McCastlain, Catherine Welsh, Yonghui Ni, Liang Ding, Melissa Franco, Robert Autry, Besian Sejdiu, Ti-Cheng Chang, Wenan Chen, Huiyun Wu, Qingfei Pan, Veronica Gonzalez-Pena, Patrick Schreiner, Sasi Arunachalam, Joung Joo, Benshang Li, Shuhong Shen, Samuel Brady, Jinghui Zhang, Charles Gawad, William Evans, M Madan Babu, Konstantin Khrapko, Gang Wu, Jiyang Yu, Stanley Pounds, Mondira Kundu.
      Somatic mitochondrial DNA (mtDNA) mutations are prevalent in tumors, yet defining their biological significance remains challenging due to the intricate interplay between selective pressure, heteroplasmy, and cell state. Utilizing bulk whole-genome sequencing data from matched tumor and normal samples from two cohorts of pediatric cancer patients, we uncover differences in the accumulation of synonymous and nonsynonymous mtDNA mutations in pediatric leukemias, indicating distinct selective pressures. By integrating single-cell sequencing (SCS) with mathematical modeling and network-based systems biology approaches, we identify a correlation between the extent of cell-state changes associated with tumor-enriched mtDNA mutations and the selective pressures shaping their distribution among individual leukemic cells. Our findings also reveal an association between specific heteroplasmic mtDNA mutations and cellular responses that may contribute to functional heterogeneity among leukemic cells and influence their fitness. This study highlights the potential of SCS strategies for distinguishing between pathogenic and passenger somatic mtDNA mutations in cancer.
    DOI:  https://doi.org/10.1101/2024.09.26.24314381
  36. Trends Immunol. 2024 Oct 17. pii: S1471-4906(24)00221-7. [Epub ahead of print]
    Cholesterol sensing and metabolic adaptation in tissue immunity.
    Eric V Dang, Andrea Reboldi.
      Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states.
    Keywords:  adaptive immunity; innate immunity; lung; mevalonate–cholesterol pathway; oxysterols; small intestine
    DOI:  https://doi.org/10.1016/j.it.2024.09.013
  37. Aging (Albany NY). 2024 Oct 16. 16
    Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity.
    Yu-Xuan Lyu, Qiang Fu, Dominika Wilczok, Kejun Ying, Aaron King, Adam Antebi, Aleksandar Vojta, Alexandra Stolzing, Alexey Moskalev, Anastasia Georgievskaya, Andrea B Maier, Andrea Olsen, Anja Groth, Anna Katharina Simon, Anne Brunet, Aisyah Jamil, Anton Kulaga, Asif Bhatti, Benjamin Yaden, Bente Klarlund Pedersen, Björn Schumacher, Boris Djordjevic, Brian Kennedy, Chieh Chen, Christine Yuan Huang, Christoph U Correll, Coleen T Murphy, Collin Y Ewald, Danica Chen, Dario Riccardo Valenzano, Dariusz Sołdacki, David Erritzoe, David Meyer, David A Sinclair, Eduardo Nunes Chini, Emma C Teeling, Eric Morgen, Eric Verdin, Erik Vernet, Estefano Pinilla, Evandro F Fang, Evelyne Bischof, Evi M Mercken, Fabian Finger, Folkert Kuipers, Frank W Pun, Gabor Gyülveszi, Gabriele Civiletto, Garri Zmudze, Gil Blander, Harold A Pincus, Joshua McClure, James L Kirkland, James Peyer, Jamie N Justice, Jan Vijg, Jennifer R Gruhn, Jerry McLaughlin, Joan Mannick, João Passos, Joseph A Baur, Joe Betts-LaCroix, John M Sedivy, John R Speakman, Jordan Shlain, Julia von Maltzahn, Katrin I Andreasson, Kelsey Moody, Konstantinos Palikaras, Kristen Fortney, Laura J Niedernhofer, Lene Juel Rasmussen, Liesbeth M Veenhoff, Lisa Melton, Luigi Ferrucci, Marco Quarta, Maria Koval, Maria Marinova, Mark Hamalainen, Maximilian Unfried, Michael S Ringel, Milos Filipovic, Mourad Topors, Natalia Mitin, Nawal Roy, Nika Pintar, Nir Barzilai, Paolo Binetti, Parminder Singh, Paul Kohlhaas, Paul D Robbins, Paul Rubin, Peter O Fedichev, Petrina Kamya, Pura Muñoz-Canoves, Rafael de Cabo, Richard G A Faragher, Rob Konrad, Roberto Ripa, Robin Mansukhani, Sabrina Büttner, Sara A Wickström, Sebastian Brunemeier, Sergey Jakimov, Shan Luo, Sharon Rosenzweig-Lipson, Shih-Yin Tsai, Stefanie Dimmeler, Thomas A Rando, Tim R Peterson, Tina Woods, Tony Wyss-Coray, Toren Finkel, Tzipora Strauss, Vadim N Gladyshev, Valter D Longo, Varun B Dwaraka, Vera Gorbunova, Victoria A Acosta-Rodríguez, Vincenzo Sorrentino, Vittorio Sebastiano, Wenbin Li, Yousin Suh, Alex Zhavoronkov, Morten Scheibye-Knudsen, Daniela Bakula.
      The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.
    Keywords:  artificial intelligence; biotechnology; healthy longevity
    DOI:  https://doi.org/10.18632/aging.206135
  38. Adv Sci (Weinh). 2024 Oct 18. e2404033
    m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.
    Wenqin Luo, Zhehao Xu, Fan Li, Lifeng Ding, Ruyue Wang, Yudong Lin, Xudong Mao, Xianjiong Chen, Yang Li, Zeyi Lu, Haiyun Xie, Huan Wang, Ziwei Zhu, Yi Lu, Luying Guo, Xiaojing Yu, Liqun Xia, Housheng Hansen He, Gonghui Li.
      N6-methyl-2'-O-methyladenosine (m6Am), occurring adjacent to the 7-methylguanosine (m7G) cap structure and catalyzed by the newly identified writer PCIF1 (phosphorylated CTD interacting factor 1), has been implicated in the pathogenesis of various diseases. However, its involvement in renal cell carcinoma (RCC) remains unexplored. Here, significant upregulation of PCIF1 and m6Am levels in RCC tissues are identified, unveiling their oncogenic roles both in vitro and in vivo. Mechanically, employing m6Am-Exo-Seq, LPP3 (phospholipid phosphatase 3) mRNA is identified as a key downstream target whose translation is enhanced by m6Am modification. Furthermore, LPP3 is revealed as a key regulator of phosphatidic acid metabolism, critical for preventing its accumulation in mitochondria and facilitating mitochondrial fission. Consequently, Inhibition of the PCIF1/LPP3 axis significantly altered mitochondrial morphology and reduced RCC tumor progression. In addition, depletion of PCIF1 sensitizes RCC to sunitinib treatment. This study highlights the intricate interplay between m6Am modification, phosphatidic acid metabolism, and mitochondrial dynamics, offering a promising therapeutic avenue for RCC.
    Keywords:  N6,2′‐O‐dimethyladenosine; PCIF1; mitochondrial dynamics; phosphatidic acid metabolism; renal cell carcinoma
    DOI:  https://doi.org/10.1002/advs.202404033
  39. Cell Metab. 2024 Oct 14. pii: S1550-4131(24)00375-9. [Epub ahead of print]
    Lighting up arginine metabolism reveals its functional diversity in physiology and pathology.
    Rui Li, Yan Li, Kun Jiang, Lijuan Zhang, Ting Li, Aihua Zhao, Zhuo Zhang, Yale Xia, Kun Ge, Yaqiong Chen, Chengnuo Wang, Weitao Tang, Shuning Liu, Xiaoxi Lin, Yuqin Song, Jie Mei, Chun Xiao, Aoxue Wang, Yejun Zou, Xie Li, Xianjun Chen, Zhenyu Ju, Wei Jia, Joseph Loscalzo, Yu Sun, Wei Fang, Yi Yang, Yuzheng Zhao.
      Arginine is one of the most metabolically versatile amino acids and plays pivotal roles in diverse biological and pathological processes; however, sensitive tracking of arginine dynamics in situ remains technically challenging. Here, we engineer high-performance fluorescent biosensors, denoted sensitive to arginine (STAR), to illuminate arginine metabolism in cells, mice, and clinical samples. Utilizing STAR, we demonstrate the effects of different amino acids in regulating intra- and extracellular arginine levels. STAR enabled live-cell monitoring of arginine fluctuations during macrophage activation, phagocytosis, efferocytosis, and senescence and revealed cellular senescence depending on arginine availability. Moreover, a simple and fast assay based on STAR revealed that serum arginine levels tended to increase with age, and the elevated serum arginine level is a potential indicator for discriminating the progression and severity of vitiligo. Collectively, our study provides important insights into the metabolic and functional roles of arginine, as well as its potential in diagnostic and therapeutic applications.
    Keywords:  arginine exchange landscape; arginine metabolism; highly responsive arginine sensors; point-of-care clinical screening; real-time monitoring
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.011
  40. J Hematol Oncol. 2024 Oct 12. 17(1): 95
    Unraveling the roles and mechanisms of mitochondrial translation in normal and malignant hematopoiesis.
    Lianxuan Liu, Mi Shao, Yue Huang, Pengxu Qian, He Huang.
      Due to spatial and genomic independence, mitochondria possess a translational mechanism distinct from that of cytoplasmic translation. Several regulators participate in the modulation of mitochondrial translation. Mitochondrial translation is coordinated with cytoplasmic translation through stress responses. Importantly, the inhibition of mitochondrial translation leads to the inhibition of cytoplasmic translation and metabolic disruption. Therefore, defects in mitochondrial translation are closely related to the functions of hematopoietic cells and various immune cells. Finally, the inhibition of mitochondrial translation is a potential therapeutic target for treating multiple hematologic malignancies. Collectively, more in-depth insights into mitochondrial translation not only facilitate our understanding of its functions in hematopoiesis, but also provide a basis for the discovery of new treatments for hematological malignancies and the modulation of immune cell function.
    Keywords:  HSC; Hematologic malignancy; Hematopoiesis; Immune cell; Mitochondrial translation; T cell
    DOI:  https://doi.org/10.1186/s13045-024-01615-9
  41. J Cell Mol Med. 2024 Oct;28(20): e70146
    A rising star involved in tumour immunity: Lactylation.
    Xu Zhang, Changming Liang, Chengwei Wu, Senlin Wan, Lishuai Xu, Song Wang, Jiawei Wang, Xiaoxu Huang, Li Xu.
      In recent years, continuous exploration worldwide has revealed that some metabolites produced during cellular and tissue metabolism can act as signalling molecules to exert different effects on the human body. These metabolites may act as cofactors for proteases or as post-translational modifications linked to proteins. Lactate, a traditional metabolite, is found at high levels in the tumour microenvironment (TME). Many studies have shown that lactate influences tumorigenesis and development via different mechanisms, not only through the metabolic reprogramming of tumours but also through its significant impact on tumour immunity. Previously, tumour cells were reported to use glucose and glutamine to fuel lactate metabolism; however, lactate serves not only as an energy source for tumour cells but also as a precursor substance needed for the post-translational modification of proteins. Recent studies identified a novel form of epigenetic modification, lactate-mediated histone lysine lactylation (Kla) and demonstrated that histone lactylation directly stimulates chromatin after gene transcription; consequently, lactylation has become a popular research topic in recent years. This article focuses on the research progress and application prospects of lactylation in the context of tumour immunity.
    Keywords:  immunosuppression; lactate; lactylation; tumour
    DOI:  https://doi.org/10.1111/jcmm.70146
  42. Nature. 2024 Oct 16.
    Quantifying constraint in the human mitochondrial genome.
    Nicole J Lake, Kaiyue Ma, Wei Liu, Stephanie L Battle, Kristen M Laricchia, Grace Tiao, Daniela Puiu, Kenneth K Ng, Justin Cohen, Alison G Compton, Shannon Cowie, John Christodoulou, David R Thorburn, Hongyu Zhao, Dan E Arking, Shamil R Sunyaev, Monkol Lek.
      Mitochondrial DNA (mtDNA) has an important yet often overlooked role in health and disease. Constraint models quantify the removal of deleterious variation from the population by selection and represent powerful tools for identifying genetic variation that underlies human phenotypes1-4. However, nuclear constraint models are not applicable to mtDNA, owing to its distinct features. Here we describe the development of a mitochondrial genome constraint model and its application to the Genome Aggregation Database (gnomAD), a large-scale population dataset that reports mtDNA variation across 56,434 human participants5. Specifically, we analyse constraint by comparing the observed variation in gnomAD to that expected under neutrality, which was calculated using a mtDNA mutational model and observed maximum heteroplasmy-level data. Our results highlight strong depletion of expected variation, which suggests that many deleterious mtDNA variants remain undetected. To aid their discovery, we compute constraint metrics for every mitochondrial protein, tRNA and rRNA gene, which revealed a range of intolerance to variation. We further characterize the most constrained regions within genes through regional constraint and identify the most constrained sites within the entire mitochondrial genome through local constraint, which showed enrichment of pathogenic variation. Constraint also clustered in three-dimensional structures, which provided insight into functionally important domains and their disease relevance. Notably, we identify constraint at often overlooked sites, including in rRNA and noncoding regions. Last, we demonstrate that these metrics can improve the discovery of deleterious variation that underlies rare and common phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08048-x
  43. Ageing Res Rev. 2024 Oct 14. pii: S1568-1637(24)00364-7. [Epub ahead of print] 102546
    Epigenetic clocks and programmatic aging.
    David Gems, Roop Singh Virk, João Pedro de Magalhães.
      The last decade has seen remarkable progress in the characterization of methylation clocks that can serve as indicators of biological age in humans and many other mammalian species. While the biological processes of aging that underlie these clocks have remained unclear, several clues have pointed to a link to developmental mechanisms. These include the presence in the vicinity of clock CpG sites of genes that specify development, including those of the Hox (homeobox) and polycomb classes. Here we discuss how recent advances in programmatic theories of aging provide a framework within which methylation clocks can be understood as part of a developmental process of aging. This includes how such clocks evolve, how developmental mechanisms cause aging, and how they give rise to late-life disease. The combination of ideas from evolutionary biology, biogerontology and developmental biology open a path to a new discipline, that of developmental gerontology (devo-gero). Drawing on the properties of methylation clocks, we offer several new hypotheses that exemplify devo-gero thinking. We suggest that polycomb controls a trade-off between earlier developmental fidelity and later developmental plasticity. We also propose the existence of an evolutionarily-conserved developmental sequence spanning ontogenesis, adult development and aging, that both constrains and determines the evolution of aging.
    Keywords:  aging; development; epigenetics; hyperfunction; methylation clocks; programmatic theory
    DOI:  https://doi.org/10.1016/j.arr.2024.102546
  44. Nat Cancer. 2024 Oct 16.
    Two distinct epithelial-to-mesenchymal transition programs control invasion and inflammation in segregated tumor cell populations.
    Khalil Kass Youssef, Nitin Narwade, Aida Arcas, Angel Marquez-Galera, Raúl Jiménez-Castaño, Cristina Lopez-Blau, Hassan Fazilaty, David García-Gutierrez, Amparo Cano, Joan Galcerán, Gema Moreno-Bueno, Jose P Lopez-Atalaya, M Angela Nieto.
      Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination.
    DOI:  https://doi.org/10.1038/s43018-024-00839-5
  45. Dev Cell. 2024 Oct 14. pii: S1534-5807(24)00600-2. [Epub ahead of print]
    Ubiquitin ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes.
    Jun Zheng, Jing Chen, Zhihe Cao, Kaichen Wu, Jinhui Wang, Yusong Guo, Min Zhuang.
      Peroxisome biogenesis involves two pathways: growth and division from pre-existing mature peroxisomes and de novo biogenesis from the endoplasmic reticulum, with a contribution from mitochondria, particularly in human peroxisome-deficient cells. However, the essential components that control peroxisome de novo biogenesis are largely unknown. Dual organelle localized ubiquitin ligase MARCH5 functions on peroxisomes to control pexophagy. Here, we show that mitochondria-localized MARCH5 is essential for the formation of vesicles in the de novo biogenesis of peroxisomes from mitochondria in human cell lines. Loss of MARCH5 specifically impedes the budding of PEX3-containing vesicles from mitochondria, thereby blocking the formation of pre-peroxisomes. Overall, our study highlights the function of MARCH5 for mitochondria-derived pre-peroxisomes, emphasizing MARCH5 as one regulator to maintain peroxisome homeostasis.
    Keywords:  MARCH5; MDVs; PEX3; de nono biogenesis; mitochondria-derived vesicles; peroxisome
    DOI:  https://doi.org/10.1016/j.devcel.2024.09.029
  46. Cancer Res. 2024 Oct 16.
    KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.
    Sigrid K Fey, Arafath K Najumudeen, Dale M Watt, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Rosalin J Simpson, Kathy McLay, Rosanna Upstill-Goddard, David Chang, William Clark, Colin Nixon, Joanna L Birch, Simon T Barry, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.
      Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2709
  47. FASEB Bioadv. 2024 Sep;6(9): 327-336
    Mouse developmental defects, but not paraganglioma tumorigenesis, upon conditional Complex II loss in early Sox10+ cells.
    Elizabeth P Lewis, Fatimah Al Khazal, Brandon Wilbanks, Naomi M Gades, Patricia Ortega-Sáenz, José López-Barneo, Igor Adameyko, L James Maher.
      In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest-derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10-driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle-deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development.
    Keywords:  Sox10; familial paraganglioma; gait defect; melanocyte; mouse; neural crest; pheochromocytoma; succinate dehydrogenase
    DOI:  https://doi.org/10.1096/fba.2024-00056
  48. Neuron. 2024 Oct 08. pii: S0896-6273(24)00663-9. [Epub ahead of print]
    Autophagy, aging, and age-related neurodegeneration.
    Jennifer E Palmer, Niall Wilson, Sung Min Son, Pawel Obrocki, Lidia Wrobel, Matea Rob, Michael Takla, Viktor I Korolchuk, David C Rubinsztein.
      Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; autophagy; frontotemporal dementia; motor neuron disease; neurodegeneration; senescence
    DOI:  https://doi.org/10.1016/j.neuron.2024.09.015
  49. Cell. 2024 Oct 03. pii: S0092-8674(24)01087-0. [Epub ahead of print]
    Structural basis of respiratory complex adaptation to cold temperatures.
    Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A Paulo, Steven P Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver.
      In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.
    Keywords:  CIII(2) rotation; brown adipose tissue; cellular adaptation; electron transport chain; membrane lipid remodeling; respiratory complexes
    DOI:  https://doi.org/10.1016/j.cell.2024.09.029
  50. J Clin Invest. 2024 Oct 01. pii: e177242. [Epub ahead of print]
    Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
    Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb.
      Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
    Keywords:  Asthma; Immunology; Pulmonology; Sex hormones; T cells
    DOI:  https://doi.org/10.1172/JCI177242
  51. Cancer Cell. 2024 Oct 15. pii: S1535-6108(24)00362-3. [Epub ahead of print]
    Integrating priorities at the intersection of cancer and neuroscience.
    William L Hwang, Ella N Perrault, Alexander Birbrair, Brandi J Mattson, David H Gutmann, Donald J Mabbott, Edna Cukierman, Elizabeth A Repasky, Erica K Sloan, Hui Zong, Ihsan Ekin Demir, Jami L Saloman, Jeremy C Borniger, Jian Hu, Jorg Dietrich, Joshua J Breunig, Kaan Çifcibaşı, Khalil Ali Ahmad Kasm, Manuel Valiente, Max Wintermark, Munjal M Acharya, Nicole N Scheff, Nisha J D'Silva, Paola D Vermeer, Richard J Wong, Sebastien Talbot, Shawn L Hervey-Jumper, Timothy C Wang, Yi Ye, Yuan Pan, Yuri L Bunimovich, Moran Amit.
      Cancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward.
    DOI:  https://doi.org/10.1016/j.ccell.2024.09.014
  52. Cell Death Differ. 2024 Oct 15.
    Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5.
    Sebastian Rühl, Zhenrui Li, Shagun Srivastava, Luigi Mari, Clifford S Guy, Mao Yang, Tudor Moldoveanu, Douglas R Green.
      BCL-2 family proteins regulate apoptosis by initiating mitochondrial outer membrane permeabilization (MOMP). Activation of the MOMP effectors BAX and BAK is controlled by the interplay of anti-apoptotic BCL-2 proteins (e.g., MCL-1) and pro-apoptotic BH3-only proteins (e.g., BIM). Using a genome-wide CRISPR-dCas9 transactivation screen we identified BNIP5 as an inhibitor of BAK-, but not BAX-induced apoptosis. BNIP5 blocked BAK activation in different cell types and in response to various cytotoxic therapies. The BH3 domain of BNIP5 was both necessary and sufficient to block BAK activation. Mechanistically, the BH3 domain of BNIP5 acts as a selective BAK activator, but a poor de-repressor of complexes between BAK and pro-survival BCL-2 family proteins. By promoting the binding of activated BAK to MCL-1 or BCL-xL, BNIP5 inhibits apoptosis when BAX is absent. Based on our observations, BNIP5 can act functionally as an anti-apoptotic BH3-only protein.
    DOI:  https://doi.org/10.1038/s41418-024-01386-3
  53. Nature. 2024 Oct 16.
    Glucose has a surprise role in directing cell fate and migration.
    Christian Schröter.
      
    Keywords:  Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03284-7
  54. Nat Cell Biol. 2024 Oct 16.
    Ex vivo imaging reveals the spatiotemporal control of ovulation.
    Christopher Thomas, Tabea Lilian Marx, Sarah Mae Penir, Melina Schuh.
      During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction.
    DOI:  https://doi.org/10.1038/s41556-024-01524-6
  55. Aging Biol. 2023 ;pii: 20230005. [Epub ahead of print]1(1):
    Analysis of Somatic Mutations in Senescent Cells Using Single-Cell Whole-Genome Sequencing.
    Lei Zhang, Marco De Cecco, Moonsook Lee, Xiaoxiao Hao, Alexander Y Maslov, Cristina Montagna, Judith Campisi, Xiao Dong, John M Sedivy, Jan Vijg.
      Somatic mutations accumulate in multiple organs and tissues during aging and are a known cause of cancer. Cellular senescence is a possible cause of functional decline in aging, yet also acts as an anticancer mechanism in vivo. Here, we compared somatic mutation burden between early passage and deeply senescent human fibroblasts using single-cell whole-genome sequencing. The results show that single-nucleotide variants (SNVs) and small insertions and deletions (INDELs) are increased in senescent cells by about twofold but have the same mutational signature as early passage cells. The increase in SNVs and INDELs can be explained by increased replication errors due to the increased number of cell divisions senescent cells are likely to have undergone. By contrast, a stark increase of aneuploidies was observed in deeply senescent cells, with about half of all senescent cells affected but none of the early passage cells analyzed. These results indicate that large chromosomal events rather than small base substitutions or insertions and deletions could be mechanistically linked to cellular senescence.
    DOI:  https://doi.org/10.59368/agingbio.20230005
  56. Nature. 2024 Oct 16.
    A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
    Nusayhah Hudaa Gopee, Elena Winheim, Bayanne Olabi, Chloe Admane, April Rose Foster, Ni Huang, Rachel A Botting, Fereshteh Torabi, Dinithi Sumanaweera, Anh Phuong Le, Jin Kim, Luca Verger, Emily Stephenson, Diana Adão, Clarisse Ganier, Kelly Y Gim, Sara A Serdy, CiCi Deakin, Issac Goh, Lloyd Steele, Karl Annusver, Mohi-Uddin Miah, Win Min Tun, Pejvak Moghimi, Kwasi Amoako Kwakwa, Tong Li, Daniela Basurto Lozada, Ben Rumney, Catherine L Tudor, Kenny Roberts, Nana-Jane Chipampe, Keval Sidhpura, Justin Englebert, Laura Jardine, Gary Reynolds, Antony Rose, Vicky Rowe, Sophie Pritchard, Ilaria Mulas, James Fletcher, Dorin-Mirel Popescu, Elizabeth Poyner, Anna Dubois, Alyson Guy, Andrew Filby, Steven Lisgo, Roger A Barker, Ian A Glass, Jong-Eun Park, Roser Vento-Tormo, Marina Tsvetomilova Nikolova, Peng He, John E G Lawrence, Josh Moore, Stephane Ballereau, Christine B Hale, Vijaya Shanmugiah, David Horsfall, Neil Rajan, John A McGrath, Edel A O'Toole, Barbara Treutlein, Omer Bayraktar, Maria Kasper, Fränze Progatzky, Pavel Mazin, Jiyoon Lee, Laure Gambardella, Karl R Koehler, Sarah A Teichmann, Muzlifah Haniffa.
      Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.
    DOI:  https://doi.org/10.1038/s41586-024-08002-x
  57. Int J Mol Sci. 2024 Sep 27. pii: 10428. [Epub ahead of print]25(19):
    Vitamin B6 Pathway Maintains Glioblastoma Cell Survival in 3D Spheroid Cultures.
    Najla Yussuf Moosa, Sara Abdullah Azeem, John K Lodge, William Cheung, Shafiq Uddin Ahmed.
      Glioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs.
    Keywords:  3D culture; glioblastoma; metabolic pathways; metabolomics; vitamin B6
    DOI:  https://doi.org/10.3390/ijms251910428
  58. EMBO J. 2024 Oct 17.
    Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer.
    Kanu Wahi, Natasha Freidman, Qian Wang, Michelle Devadason, Lake-Ee Quek, Angel Pang, Larissa Lloyd, Mark Larance, Fabio Zanini, Kate Harvey, Sandra O'Toole, Yi Fang Guan, Jeff Holst.
      Triple-negative breast cancer (TNBC) metabolism and cell growth uniquely rely on glutamine uptake by the transporter ASCT2. Despite previous data reporting cell growth inhibition after ASCT2 knockdown, we here show that ASCT2 CRISPR knockout is tolerated by TNBC cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady-state levels were increased in ASCT2 knockout compared to control cells. Proteomics analysis revealed upregulation of macropinocytosis, reduction in glutamine efflux and increased glutamine synthesis in ASCT2 knockout cells. Deletion of ASCT2 in the TNBC cell line HCC1806 induced a strong increase in macropinocytosis across five ASCT2 knockout clones, compared to a modest increase in ASCT2 knockdown. In contrast, ASCT2 knockout impaired cell proliferation in the non-macropinocytic HCC1569 breast cancer cells. These data identify macropinocytosis as a critical secondary glutamine acquisition pathway in TNBC and a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, providing a rationale for targeting of more downstream glutamine metabolism components.
    Keywords:  ASCT2; Glutamine Metabolism; Macropinocytosis; Metabolomics; Triple-Negative Breast Cancer
    DOI:  https://doi.org/10.1038/s44318-024-00271-6
  59. Development. 2024 Oct 01. pii: dev202998. [Epub ahead of print]151(19):
    Loss of STING impairs lactogenic differentiation.
    Ramiah R Vickers, Garhett L Wyatt, Lilia Sanchez, Jordyn J VanPortfliet, A Phillip West, Weston W Porter.
      Heightened energetic and nutrient demand during lactogenic differentiation of the mammary gland elicits upregulation of various stress responses to support cellular homeostasis. Here, we identify the stimulator of interferon genes (STING) as an immune supporter of the functional development of mouse mammary epithelial cells (MECs). An in vitro model of MEC differentiation revealed that STING is activated in a cGAS-independent manner to produce both type I interferons and proinflammatory cytokines in response to the accumulation of mitochondrial reactive oxygen species. Induction of STING activity was found to be dependent on the breast tumor suppressor gene single-minded 2 (SIM2). Using mouse models of lactation, we discovered that loss of STING activity results in early involution of #3 mammary glands, severely impairing lactational performance. Our data suggest that STING is required for successful functional differentiation of the mammary gland and bestows a differential lactogenic phenotype between #3 mammary glands and the traditionally explored inguinal 4|9 pair. These findings affirm unique development of mammary gland pairs that is essential to consider in future investigations into normal development and breast cancer initiation.
    Keywords:  Breast cancer; Inflammation; Lactation; Mammary gland development; Mouse; STING
    DOI:  https://doi.org/10.1242/dev.202998
This page is being maintained by Thomas Krichel. It was last updated on 2024‒10‒20 at 5:00.