bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022–11–13
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
  2. Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
  3. CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
  4. Advancements in Pulsed Stable Isotope-Resolved Metabolomics.
  5. Cancer-derived extracellular succinate: a driver of cancer metastasis.
  6. Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair.
  7. Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution.
  8. Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells.
  9. Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
  10. Probabilistic model checking of cancer metabolism.
  11. REC drives recombination to repair double-strand breaks in animal mtDNA.
  12. Nuclear Interactions: A Spotlight on Nuclear Mitochondrial Membrane Contact Sites.
  13. An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
  14. Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
  15. Chromatin oxygen sensing by histone H3 prolyl hydroxylation.
  16. Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission.
  17. GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.
  18. Mitoferrin, Cellular and Mitochondrial Iron Homeostasis.
  19. Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress.
  20. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.
  21. Isotope-Assisted Metabolic Flux Analysis: A Powerful Technique to Gain New Insights into the Human Metabolome in Health and Disease.
  22. ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.
  23. Mitochondrial dynamics, Leydig cell function, and age-related testosterone deficiency.
  24. Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal.
  25. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
  26. The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
  27. Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.
  28. Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation.
  29. How cells recognize and remove the perforated lysosome.
  30. Rare and common genetic determinants of metabolic individuality and their effects on human health.
  31. Glycolytic flux control by drugging phosphoglycolate phosphatase.
  32. No sugar, just protein please - says the fly.
  33. The human batokine EPDR1 regulates β-cell metabolism and function.
  34. Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.
  35. Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
  36. Regulation of insulin secretion in mouse islets: metabolic amplification by alpha-ketoisocaproate coincides with rapid and sustained increase in acetyl-CoA content.
  37. Reduced mitochondria provide an essential function for the cytosolic methionine cycle.
  38. The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
  39. NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
  40. Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice.
  41. Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate.
  42. Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma.
  43. Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
  44. Regulatory T cells as metabolic sensors.
  45. DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.
  46. Spatial maps of genetically diverse breast cancer cells.
  47. The phenotypic landscape of essential human genes.
  48. SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
  49. Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
  50. Endosymbiotic selective pressure at the origin of eukaryotic cell biology.
  51. A gut-derived hormone suppresses sugar appetite and regulates food choice in Drosophila.
  1. Sci Adv. 2022 Nov 11. 8(45): eabo7956
    AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
    Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.
      Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abo7956
  2. Nat Commun. 2022 Nov 07. 13(1): 6704
    Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.
    Ayesha Sen, Sebastian Kallabis, Felix Gaedke, Christian Jüngst, Julia Boix, Julian Nüchel, Kanjanamas Maliphol, Julia Hofmann, Astrid C Schauss, Marcus Krüger, Rudolf J Wiesner, David Pla-Martín.
      Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.
    DOI:  https://doi.org/10.1038/s41467-022-34205-9
  3. Nat Commun. 2022 Nov 07. 13(1): 6723
    CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
    Phillip M Brailey, Lauren Evans, Juan Carlos López-Rodríguez, Anthony Sinadinos, Victoria Tyrrel, Gavin Kelly, Valerie O'Donnell, Peter Ghazal, Susan John, Patricia Barral.
      Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.
    DOI:  https://doi.org/10.1038/s41467-022-34532-x
  4. Handb Exp Pharmacol. 2022 Nov 11.
    Advancements in Pulsed Stable Isotope-Resolved Metabolomics.
    Martin Forbes, Sabrina Geisberger, Matthias Pietzke, Guido Mastrobuoni, Stefan Kempa.
      The understanding of biochemical processes of metabolism is gained through the measurement of the concentration of intermediates and the rate of metabolite conversion. However, the measurement of metabolite concentrations does not give a full representation of this dynamic system. To understand the kinetics of metabolism, the system must be described and quantified in terms of metabolite flow as a function of time. In order to measure the metabolite flow, or more precisely the metabolic flux through a biological system, substrates of the cell are labelled with stable isotopes. The usage of these substrates by the cell leads to the incorporation of the isotopes into downstream intermediates.The most important metabolic pathways are encompassed in the central carbon metabolism (CCM). According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), the central carbon metabolism "is the most basic aspect of life". It includes all metabolites and enzymatic reactions within: glycolysis and gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), amino acids and nucleotide metabolic pathways. Some molecules are at the crossroad of metabolic pathways, interconnecting diverse metabolic and therefore functional outcomes. Labelling these nodal metabolites and analysing their isotopic composition allows the precise determination of the metabolic flow within the biochemical networks that they are in.Application of stable isotope labelled substrates allows the measurement of metabolic flux through a biochemical pathway. The rapid turnover of metabolites in pathways requires pulse-feeding cells with a labelled substrate. This method allows for the determination of different cell states. For example, the action of a drug from immediate impact until the compensatory response of the metabolic system (cell, organs, organisms). Pulsed labelling is an elegant way to analyse the action of small molecules and drugs and enables the analysis of regulatory metabolic processes in short time scales.
    Keywords:  Cancer metabolism; Isotope-resolved metabolomics; Mass spectrometry methods; Metabolic flux analysis
    DOI:  https://doi.org/10.1007/164_2022_621
  5. J Biomed Sci. 2022 Nov 07. 29(1): 93
    Cancer-derived extracellular succinate: a driver of cancer metastasis.
    Cheng-Chin Kuo, Jing-Yiing Wu, Kenneth K Wu.
      Succinate is a tricarboxylic acid (TCA) cycle intermediate normally confined to the mitochondrial matrix. It is a substrate of succinate dehydrogenase (SDH). Mutation of SDH subunits (SDHD and SDHB) in hereditary tumors such as paraganglioma or reduction of SDHB expression in cancer results in matrix succinate accumulation which is transported to cytoplasma and secreted into the extracellular milieu. Excessive cytosolic succinate is known to stabilize hypoxia inducible factor-1α (HIF-1α) by inhibiting prolyl hydroxylase. Recent reports indicate that cancer-secreted succinate enhances cancer cell migration and promotes cancer metastasis by activating succinate receptor-1 (SUCNR-1)-mediated signaling and transcription pathways. Cancer-derived extracellular succinate enhances cancer cell and macrophage migration through SUCNR-1 → PI-3 K → HIF-1α pathway. Extracellular succinate induces tumor angiogenesis through SUCNR-1-mediated ERK1/2 and STAT3 activation resulting in upregulation of vascular endothelial growth factor (VEGF) expression. Succinate increases SUCNR-1 expression in cancer cells which is considered as a target for developing new anti-metastasis drugs. Furthermore, serum succinate which is elevated in cancer patients may be a theranostic biomarker for selecting patients for SUCNR-1 antagonist therapy.
    Keywords:  Cancer metastasis; G-protein-coupled receptor 91 (GPR91); Hereditary paraganglioma; Succinate; Succinate dehydrogenase; Succinate receptor-1
    DOI:  https://doi.org/10.1186/s12929-022-00878-z
  6. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01479-6. [Epub ahead of print]41(6): 111610
    Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair.
    Shintaro Ide, Kana Ide, Koki Abe, Yoshihiko Kobayashi, Hiroki Kitai, Jennifer McKey, Sarah A Strausser, Lori L O'Brien, Aleksandra Tata, Purushothama Rao Tata, Tomokazu Souma.
      In both humans and mice, repair of acute kidney injury is worse in males than in females. Here, we provide evidence that this sexual dimorphism results from sex differences in ferroptosis, an iron-dependent, lipid-peroxidation-driven regulated cell death. Using genetic and single-cell transcriptomic approaches in mice, we report that female sex confers striking protection against ferroptosis, which was experimentally induced in proximal tubular (PT) cells by deleting glutathione peroxidase 4 (Gpx4). Single-cell transcriptomic analyses further identify the NFE2-related factor 2 (NRF2) antioxidant protective pathway as a female resilience mechanism against ferroptosis. Genetic inhibition and pharmacological activation studies show that NRF2 controls PT cell fate and plasticity by regulating ferroptosis. Importantly, pharmacological NRF2 activation protects male PT cells from ferroptosis and improves cellular plasticity as in females. Our data highlight NRF2 as a potential therapeutic target to prevent failed renal repair after acute kidney injury in both sexes by modulating cellular plasticity.
    Keywords:  CP: Molecular biology; GPX4; NRF2; acute kidney injury; cell fate; cellular plasticity; ferroptosis; glutathione Peroxidase 4; kidney injury and repair; sexual dimorphism; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2022.111610
  7. Nat Commun. 2022 Nov 09. 13(1): 6782
    Reversible Myc hypomorphism identifies a key Myc-dependency in early cancer evolution.
    Nicole M Sodir, Luca Pellegrinet, Roderik M Kortlever, Tania Campos, Yong-Won Kwon, Shinseog Kim, Daniel Garcia, Alessandra Perfetto, Panayiotis Anastasiou, Lamorna Brown Swigart, Mark J Arends, Trevor D Littlewood, Gerard I Evan.
      Germ-line hypomorphism of the pleiotropic transcription factor Myc in mice, either through Myc gene haploinsufficiency or deletion of Myc enhancers, delays onset of various cancers while mice remain viable and exhibit only relatively mild pathologies. Using a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will, we asked whether this resistance to tumour progression is also emplaced when Myc hypomorphism is acutely imposed in adult mice. Indeed, adult Myc hypomorphism profoundly blocked KRasG12D-driven lung and pancreatic cancers, arresting their evolution at the early transition from indolent pre-tumour to invasive cancer. We show that such arrest is due to the incapacity of hypomorphic levels of Myc to drive release of signals that instruct the microenvironmental remodelling necessary to support invasive cancer. The cancer protection afforded by long-term adult imposition of Myc hypomorphism is accompanied by only mild collateral side effects, principally in haematopoiesis, but even these are circumvented if Myc hypomorphism is imposed metronomically whereas potent cancer protection is retained.
    DOI:  https://doi.org/10.1038/s41467-022-34079-x
  8. Nat Commun. 2022 Nov 08. 13(1): 6744
    Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells.
    Yang Sun, Lu Hu, Zhipeng Tao, Gopala K Jarugumilli, Hannah Erb, Alka Singh, Qi Li, Jennifer L Cotton, Patricia Greninger, Regina K Egan, Y Tony Ip, Cyril H Benes, Jianwei Che, Junhao Mao, Xu Wu.
      Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that TEAD palmitoylation inhibitor MGH-CP1 and analogues block cancer cell "stemness", organ overgrowth and tumor initiation in vitro and in vivo. MGH-CP1 sensitivity correlates significantly with YAP-dependency in a large panel of cancer cell lines. However, TEAD inhibition or YAP/TAZ knockdown leads to transient inhibition of cell cycle progression without inducing cell death, undermining their potential therapeutic utilities. We further reveal that TEAD inhibition or YAP/TAZ silencing leads to VGLL3-mediated transcriptional activation of SOX4/PI3K/AKT signaling axis, which contributes to cancer cell survival and confers therapeutic resistance to TEAD inhibitors. Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.
    DOI:  https://doi.org/10.1038/s41467-022-34559-0
  9. Cell. 2022 Nov 02. pii: S0092-8674(22)01318-6. [Epub ahead of print]
    Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
    Haopeng Xiao, Luiz H M Bozi, Yizhi Sun, Christopher L Riley, Vivek M Philip, Mandy Chen, Jiaming Li, Tian Zhang, Evanna L Mills, Margo P Emont, Wenfei Sun, Anita Reddy, Ryan Garrity, Jiani Long, Tobias Becher, Laura Potano Vitas, Dina Laznik-Bogoslavski, Martha Ordonez, Xinyue Liu, Xiong Chen, Yun Wang, Weihai Liu, Nhien Tran, Yitong Liu, Yang Zhang, Aaron M Cypess, Andrew P White, Yuchen He, Rebecca Deng, Heiko Schöder, Joao A Paulo, Mark P Jedrychowski, Alexander S Banks, Yu-Hua Tseng, Paul Cohen, Linus T Tsai, Evan D Rosen, Samuel Klein, Maria Chondronikola, Fiona E McAllister, Nick Van Bruggen, Edward L Huttlin, Bruce M Spiegelman, Gary A Churchill, Steven P Gygi, Edward T Chouchani.
      Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
    DOI:  https://doi.org/10.1016/j.cell.2022.10.003
  10. Sci Rep. 2022 Nov 07. 12(1): 18870
    Probabilistic model checking of cancer metabolism.
    Meir D Friedenberg, Adrian Lita, Mark R Gilbert, Mioara Larion, Orieta Celiku.
      Cancer cell metabolism is often deregulated as a result of adaption to meeting energy and biosynthesis demands of rapid growth or direct mutation of key metabolic enzymes. Better understanding of such deregulation can provide new insights on targetable vulnerabilities, but is complicated by the difficulty in probing cell metabolism at different levels of resolution and under different experimental conditions. We construct computational models of glucose and glutamine metabolism with focus on the effect of IDH1/2-mutations in cancer using a combination of experimental metabolic flux data and patient-derived gene expression data. Our models demonstrate the potential of computational exploration to reveal biologic behavior: they show that an exogenously-mutated IDH1 experimental model utilizes glutamine as an alternative carbon source for lactate production under hypoxia, but does not fully-recapitulate the patient phenotype under normoxia. We also demonstrate the utility of using gene expression data as a proxy for relative differences in metabolic activity. We use the approach of probabilistic model checking and the freely-available Probabilistic Symbolic Model Checker to construct and reason about model behavior.
    DOI:  https://doi.org/10.1038/s41598-022-21846-5
  11. J Cell Biol. 2023 Jan 02. pii: e202201137. [Epub ahead of print]222(1):
    REC drives recombination to repair double-strand breaks in animal mtDNA.
    Anna Klucnika, Peiqiang Mu, Jan Jezek, Matthew McCormack, Ying Di, Charles R Bradshaw, Hansong Ma.
      Mechanisms that safeguard mitochondrial DNA (mtDNA) limit the accumulation of mutations linked to mitochondrial and age-related diseases. Yet, pathways that repair double-strand breaks (DSBs) in animal mitochondria are poorly understood. By performing a candidate screen for mtDNA repair proteins, we identify that REC-an MCM helicase that drives meiotic recombination in the nucleus-also localizes to mitochondria in Drosophila. We show that REC repairs mtDNA DSBs by homologous recombination in somatic and germline tissues. Moreover, REC prevents age-associated mtDNA mutations. We further show that MCM8, the human ortholog of REC, also localizes to mitochondria and limits the accumulation of mtDNA mutations. This study provides mechanistic insight into animal mtDNA recombination and demonstrates its importance in safeguarding mtDNA during ageing and evolution.
    DOI:  https://doi.org/10.1083/jcb.202201137
  12. Contact (Thousand Oaks). 2022 Jan-Dec;5:5 25152564221096217
    Nuclear Interactions: A Spotlight on Nuclear Mitochondrial Membrane Contact Sites.
    Jana Ovciarikova, Shikha Shikha, Lilach Sheiner.
      Membrane contact sites (MCS) are critical for cellular functions of eukaryotes, as they enable communication and exchange between organelles. Research over the last decade unravelled the function and composition of MCS between a variety of organelles including mitochondria, ER, plasma membrane, lysosomes, lipid droplets, peroxisome and endosome, to name a few. In fact, MCS are found between any pair of organelles studied to date, with common functions including lipid exchange, calcium signalling and organelle positioning in the cell. Work in the past year has started addressing the composition and function of nuclear-mitochondrial MCS. Tether components mediating these contacts in yeast have been identified via comprehensive phenotypic screens, which also revealed a possible link between this contact and phosphatidylcholine metabolism. In human cells, and in the protozoan parasites causing malaria, proximity between these organelles is proposed to promote cell survival via a mitochondrial retrograde response. These pioneering studies should inspire the field to explore what cellular processes depend on the exchange between the nucleus and the mitochondrion, given that they play such central roles in cell biology.
    Keywords:  membrane contact sites; mitochondrion (mitochondria); nucleus; parasite
    DOI:  https://doi.org/10.1177/25152564221096217
  13. Nat Commun. 2022 Nov 10. 13(1): 6808
    An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.
    Kaushal Asrani, Juhyung Woo, Adrianna A Mendes, Ethan Schaffer, Thiago Vidotto, Clarence Rachel Villanueva, Kewen Feng, Lia Oliveira, Sanjana Murali, Hans B Liu, Daniela C Salles, Brandon Lam, Pedram Argani, Tamara L Lotan.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
    DOI:  https://doi.org/10.1038/s41467-022-34617-7
  14. Cancers (Basel). 2022 Oct 27. pii: 5268. [Epub ahead of print]14(21):
    Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
    Rishabh Kumar, Anurag Mishra, Priyanka Gautam, Zainab Feroz, Sivakumar Vijayaraghavalu, Eviania M Likos, Girish C Shukla, Munish Kumar.
      Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.
    Keywords:  Warburg effect; amino acid metabolism; cancer metabolism; cancer therapeutics; fatty acid metabolism; glycolysis; microRNA; oncogenes; tumor suppressor genes
    DOI:  https://doi.org/10.3390/cancers14215268
  15. Nat Genet. 2022 Nov;54(11): 1585-1586
    Chromatin oxygen sensing by histone H3 prolyl hydroxylation.
    James A Nathan.
      
    DOI:  https://doi.org/10.1038/s41588-022-01201-0
  16. Front Cell Dev Biol. 2022 ;10 1010232
    Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission.
    Adam Green, Tanvir Hossain, David M Eckmann.
      Mitochondria are cell organelles that play pivotal roles in maintaining cell survival, cellular metabolic homeostasis, and cell death. Mitochondria are highly dynamic entities which undergo fusion and fission, and have been shown to be very motile in vivo in neurons and in vitro in multiple cell lines. Fusion and fission are essential for maintaining mitochondrial homeostasis through control of morphology, content exchange, inheritance of mitochondria, maintenance of mitochondrial DNA, and removal of damaged mitochondria by autophagy. Mitochondrial motility occurs through mechanical and molecular mechanisms which translocate mitochondria to sites of high energy demand. Motility also plays an important role in intracellular signaling. Here, we review key features that mediate mitochondrial dynamics and explore methods to advance the study of mitochondrial motility as well as mitochondrial dynamics-related diseases and mitochondrial-targeted therapeutics.
    Keywords:  disease; fission; fusion; live-cell imaging; mitochondria; mitochondrial DNA; motility; therapeutics
    DOI:  https://doi.org/10.3389/fcell.2022.1010232
  17. Front Oncol. 2022 ;12 988872
    GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.
    Sweta Parik, Juan Fernández-García, Francesca Lodi, Karen De Vlaminck, Marleen Derweduwe, Steven De Vleeschouwer, Raf Sciot, Wietse Geens, Linqian Weng, Francesca Maria Bosisio, Gabriele Bergers, Johnny Duerinck, Frederick De Smet, Diether Lambrechts, Jo A Van Ginderachter, Sarah-Maria Fendt.
      Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.
    Keywords:  FADS2; SCD1; fatty acid metabolism; glioblastoma; lipotoxicity; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fonc.2022.988872
  18. Cells. 2022 Nov 02. pii: 3464. [Epub ahead of print]11(21):
    Mitoferrin, Cellular and Mitochondrial Iron Homeostasis.
    Md Yousuf Ali, Claudia R Oliva, Susanne Flor, Corinne E Griguer.
      Iron is essential for many cellular processes, but cellular iron homeostasis must be maintained to ensure the balance of cellular signaling processes and prevent disease. Iron transport in and out of the cell and cellular organelles is crucial in this regard. The transport of iron into the mitochondria is particularly important, as heme and the majority of iron-sulfur clusters are synthesized in this organelle. Iron is also required for the production of mitochondrial complexes that contain these iron-sulfur clusters and heme. As the principal iron importers in the mitochondria of human cells, the mitoferrins have emerged as critical regulators of cytosolic and mitochondrial iron homeostasis. Here, we review the discovery and structure of the mitoferrins, as well as the significance of these proteins in maintaining cytosolic and mitochondrial iron homeostasis for the prevention of cancer and many other diseases.
    Keywords:  cancer; erythropoiesis; iron; mitochondria; mitoferrin; oxidative stress
    DOI:  https://doi.org/10.3390/cells11213464
  19. Elife. 2022 Nov 08. pii: e82206. [Epub ahead of print]11
    Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress.
    Jingruo Zhang, Manuel A Riquelme, Rui Hua, Francisca M Acosta, Sumin Gu, Jean X Jiang.
      Oxidative stress is a major risk factor that causes osteocyte cell death and bone loss. Prior studies primarily focus on the function of cell surface expressed Cx43 channels. Here, we reported a new role of mitochondrial Cx43 (mtCx43) and hemichannels (HCs) in modulating mitochondria homeostasis and function in bone osteocytes under oxidative stress. In murine long bone osteocyte-Y4 cells, the translocation of Cx43 to mitochondria was increased under H2O2-induced oxidative stress. H2O2 increased the mtCx43 level accompanied by elevated mtCx43 HC activity, determined by dye uptake assay. Cx43 knockdown (KD) by the CRISPR-Cas9 lentivirus system resulted in impairment of mitochondrial function, primarily manifested as decreased ATP production. Cx43 KD had reduced intracellular reactive oxidative species levels and mitochondrial membrane potential. Additionally, live-cell imaging results demonstrated that the proton flux was dependent on mtCx43 HCs because its activity was specifically inhibited by an antibody targeting Cx43 C-terminus. The co-localization and interaction of mtCx43 and ATP synthase subunit F (ATP5J2) were confirmed by Förster resonance energy transfer and a protein pull-down assay. Together, our study suggests that mtCx43 HCs regulate mitochondrial ATP generation by mediating K+, H+, and ATP transfer across the mitochondrial inner membrane and the interaction with mitochondrial ATP synthase, contributing to the maintenance of mitochondrial redox levels in response to oxidative stress.
    Keywords:  ATP synthase; cell biology; connexin 43; mouse; osteocytes; oxidative stress; proton
    DOI:  https://doi.org/10.7554/eLife.82206
  20. Cancer Cell. 2022 Oct 31. pii: S1535-6108(22)00500-1. [Epub ahead of print]
    Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.
    William D Gwynne, Yujin Suk, Stefan Custers, Nicholas Mikolajewicz, Jeremy K Chan, Zsolt Zador, Shawn C Chafe, Kui Zhai, Laura Escudero, Cunjie Zhang, Olga Zaslaver, Chirayu Chokshi, Muhammad Vaseem Shaikh, David Bakhshinyan, Ian Burns, Iqra Chaudhry, Omri Nachmani, Daniel Mobilio, William T Maich, Patricia Mero, Kevin R Brown, Andrew T Quaile, Chitra Venugopal, Jason Moffat, J Rafael Montenegro-Burke, Sheila K Singh.
      MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
    Keywords:  DHODH; brain tumor initiating cells; c-Myc; medulloblastoma; metabolic reprogramming; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.009
  21. Metabolites. 2022 Nov 04. pii: 1066. [Epub ahead of print]12(11):
    Isotope-Assisted Metabolic Flux Analysis: A Powerful Technique to Gain New Insights into the Human Metabolome in Health and Disease.
    Bilal Moiz, Andrew Li, Surya Padmanabhan, Ganesh Sriram, Alisa Morss Clyne.
      Cell metabolism represents the coordinated changes in genes, proteins, and metabolites that occur in health and disease. The metabolic fluxome, which includes both intracellular and extracellular metabolic reaction rates (fluxes), therefore provides a powerful, integrated description of cellular phenotype. However, intracellular fluxes cannot be directly measured. Instead, flux quantification requires sophisticated mathematical and computational analysis of data from isotope labeling experiments. In this review, we describe isotope-assisted metabolic flux analysis (iMFA), a rigorous computational approach to fluxome quantification that integrates metabolic network models and experimental data to generate quantitative metabolic flux maps. We highlight practical considerations for implementing iMFA in mammalian models, as well as iMFA applications in in vitro and in vivo studies of physiology and disease. Finally, we identify promising new frontiers in iMFA which may enable us to fully unlock the potential of iMFA in biomedical research.
    Keywords:  NMR; fluxomics; isotopic non-stationary metabolic flux analysis; mass spectrometry; metabolic engineering; metabolic flux analysis; metabolomics
    DOI:  https://doi.org/10.3390/metabo12111066
  22. Nat Metab. 2022 Nov 07.
    ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.
    Janane F Rahbani, Charlotte Scholtes, Damien M Lagarde, Mohammed F Hussain, Anna Roesler, Christien B Dykstra, Jakub Bunk, Bozena Samborska, Shannon L O'Brien, Emma Tripp, Alain Pacis, Anthony R Angueira, Olivia S Johansen, Jessica Cinkornpumin, Ishtiaque Hossain, Matthew D Lynes, Yang Zhang, Andrew P White, William A Pastor, Maria Chondronikola, Labros Sidossis, Samuel Klein, Anastasia Kralli, Aaron M Cypess, Steen B Pedersen, Niels Jessen, Yu-Hua Tseng, Zachary Gerhart-Hines, Patrick Seale, Davide Calebiro, Vincent Giguère, Lawrence Kazak.
      Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
    DOI:  https://doi.org/10.1038/s42255-022-00667-w
  23. FASEB J. 2022 Dec;36(12): e22637
    Mitochondrial dynamics, Leydig cell function, and age-related testosterone deficiency.
    Samuel Garza, Liting Chen, Melanie Galano, Garett Cheung, Chantal Sottas, Lu Li, Yuchang Li, Barry R Zirkin, Vassilios Papadopoulos.
      The mitochondrial translocator protein (18 kDa; TSPO) is a high-affinity cholesterol-binding protein that is an integral component of the cholesterol trafficking scaffold responsible for determining the rate of cholesterol import into the mitochondria for steroid biosynthesis. Previous studies have shown that TSPO declines in aging Leydig cells (LCs) and that its decline is associated with depressed circulating testosterone levels in aging rats. However, TSPO's role in the mechanistic decline in LC function is not fully understood. To address the role of TSPO depletion in LC function, we first examined mitochondrial quality in Tspo knockout mouse tumor MA-10 nG1 LCs compared to wild-type MA-10 cells. Tspo deletion caused a disruption in mitochondrial function and membrane dynamics. Increasing mitochondrial fusion via treatment with the mitochondrial fusion promoter M1 or by optic atrophy 1 (OPA1) overexpression resulted in the restoration of mitochondrial function and mitochondrial morphology as well as in steroid formation in TSPO-depleted nG1 LCs. LCs isolated from aged rats form less testosterone than LCs isolated from young rats. Treatment of aging LCs with M1 improved mitochondrial function and increased androgen formation, suggesting that aging LC dysfunction may stem from compromised mitochondrial dynamics caused by the age-dependent LC TSPO decline. These results, taken together, suggest that maintaining or enhancing mitochondrial fusion may provide therapeutic strategies to maintain or restore testosterone levels with aging.
    Keywords:  aging; bioenergetics; hypogonadism; mitochondrial fusion; optic atrophy 1; steroidogenesis; testosterone; translocator protein
    DOI:  https://doi.org/10.1096/fj.202201026R
  24. Front Oncol. 2022 ;12 1034397
    Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal.
    Don Benjamin, Michael N Hall.
      Highly glycolytic cancer cells excrete lactate to maintain cellular homeostasis. Inhibiting lactate export by pharmacological targeting of plasma membrane lactate transporters is being pursued as an anti-cancer therapy. Work from many laboratories show that the simultaneous inhibition of lactate export and mitochondrial respiration elicits strong synthetic lethality. The mitochondrial inhibitor, metformin, has been the subject of numerous clinical trials as an anti-cancer agent. We propose that, in future clinical trials, metformin be combined with lactate transport inhibitors to exploit this synergistic interaction.
    Keywords:  MCT4; cancer; lactic acid; metformin; monocarboxylate transporter; syrosingopine
    DOI:  https://doi.org/10.3389/fonc.2022.1034397
  25. Sci Signal. 2022 Nov 08. 15(759): eabj4220
    Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
    Vivien Low, Zhongchi Li, John Blenis.
      The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.
    DOI:  https://doi.org/10.1126/scisignal.abj4220
  26. Immunometabolism (Cobham). 2022 Oct;4(4): e00011
    The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
    Juan F Codocedo, Gary E Landreth.
      Hexokinases (HKs) catalyze the first and irreversible step of glucose metabolism. Its product, glucose-6-phosphate (G-6P) serves as a precursor for catabolic processes like glycolysis for adenosine 5'-triphosphate (ATP) production and anabolic pathways including the pentose phosphate pathway (PPP) for the generation of intermediaries like nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-P. Thus, the cellular fate of glucose is important not only for growth and maintenance, but also to determine different cellular activities. Studies in immune cells have demonstrated an intimate linkage between metabolic pathways and inflammation, however the precise molecular mechanisms that determine the cellular fate of glucose during inflammation or aging are not completely understood. Here we discuss a study by De Jesus et al that describes the role of HK1 cytosolic localization as a critical regulator of glucose flux by shunting glucose into the PPP at the expense of glycolysis, exacerbating the inflammatory response of macrophages. The authors convincingly demonstrate a novel mechanism that is independent of its mitochondrial functions, but involve the association to a protein complex that inhibits glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase. We expand the discussion by comparing previous studies related to the HK2 isoform and how cells have evolved to regulate the mitochondrial association of these two isoforms by non-redundant mechanism.
    Keywords:  glucose; hexokinase
    DOI:  https://doi.org/10.1097/IN9.0000000000000011
  27. Cancer Discov. 2022 Nov 10. pii: CD-21-0218. [Epub ahead of print]
    Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.
    Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe Al Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majeti.
      Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0218
  28. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01501-7. [Epub ahead of print]41(6): 111630
    Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation.
    Poshen B Chen, Patrick C Fiaux, Kai Zhang, Bin Li, Naoki Kubo, Shan Jiang, Rong Hu, Emma Rooholfada, Sihan Wu, Mengchi Wang, Wei Wang, Graham McVicker, Paul S Mischel, Bing Ren.
      A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute to human diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing to identify enhancers required for cell proliferation and fitness in 10 human cancer cell lines. Our results suggest that the cell fitness enhancers, unlike their target genes, display high cell-type specificity of chromatin features. They typically adopt a modular structure, comprised of activating elements enriched for motifs of oncogenic transcription factors, surrounded by repressive elements enriched for motifs recognized by transcription factors with tumor suppressor functions. We further identify cell fitness enhancers that are selectively accessible in clinical tumor samples, and the levels of chromatin accessibility are associated with patient survival. These results reveal functional enhancers across multiple cancer cell lines, characterize their context-dependent chromatin organization, and yield insights into altered transcription programs in cancer cells.
    Keywords:  CP: Cancer; CP: Molecular biology; cell proliferation; functional enhancer; gene regulation; oncogene
    DOI:  https://doi.org/10.1016/j.celrep.2022.111630
  29. Autophagy. 2022 Nov 11. 1-3
    How cells recognize and remove the perforated lysosome.
    Keisuke Tabata, Marika Saeki, Tamotsu Yoshimori, Maho Hamasaki.
      Macroautophagy (hereafter autophagy) is a highly conserved intracellular degradation system to maintain cellular homeostasis by degrading cellular components such as misfolded proteins, nonfunctional organelles, pathogens, and cytosol. Conversely, selective autophagy targets and degrades specific cargo, such as organelles, bacteria, etc. We previously reported that damaged lysosomes are autophagy targets, via a process called lysophagy. However, how cells target damaged lysosomes through autophagy is not known. We performed proteomics analysis followed by siRNA screening to identify genes involved in targeting damaged lysosomes and identified a new E3 ligase complex, involving CUL4A (cullin 4A), as a regulatory complex in lysophagy. We also found that this complex mediates K48-linked poly-ubiquitination on lysosome protein LAMP2 during lysosomal damage; particularly, the lumenal side of LAMP2 is important to recruit the complex to damaged lysosomes. This protein modification is thus critical to initiate the clearance of damaged lysosomes.
    Keywords:  CUL4A; LAMP2; lysophagy; lysosomal membrane damage; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2022.2138686
  30. Nat Med. 2022 Nov 10.
    Rare and common genetic determinants of metabolic individuality and their effects on human health.
    Praveen Surendran, Isobel D Stewart, Victoria P W Au Yeung, Maik Pietzner, Johannes Raffler, Maria A Wörheide, Chen Li, Rebecca F Smith, Laura B L Wittemans, Lorenzo Bomba, Cristina Menni, Jonas Zierer, Niccolò Rossi, Patricia A Sheridan, Nicholas A Watkins, Massimo Mangino, Pirro G Hysi, Emanuele Di Angelantonio, Mario Falchi, Tim D Spector, Nicole Soranzo, Gregory A Michelotti, Wiebke Arlt, Luca A Lotta, Spiros Denaxas, Harry Hemingway, Eric R Gamazon, Joanna M M Howson, Angela M Wood, John Danesh, Nicholas J Wareham, Gabi Kastenmüller, Eric B Fauman, Karsten Suhre, Adam S Butterworth, Claudia Langenberg.
      Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
    DOI:  https://doi.org/10.1038/s41591-022-02046-0
  31. Nat Commun. 2022 Nov 11. 13(1): 6845
    Glycolytic flux control by drugging phosphoglycolate phosphatase.
    Elisabeth Jeanclos, Jan Schlötzer, Kerstin Hadamek, Natalia Yuan-Chen, Mohammad Alwahsh, Robert Hollmann, Stefanie Fratz, Dilan Yesilyurt-Gerhards, Tina Frankenbach, Daria Engelmann, Angelika Keller, Alexandra Kaestner, Werner Schmitz, Martin Neuenschwander, Roland Hergenröder, Christoph Sotriffer, Jens Peter von Kries, Hermann Schindelin, Antje Gohla.
      Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.
    DOI:  https://doi.org/10.1038/s41467-022-34228-2
  32. Nat Metab. 2022 Nov 07.
    No sugar, just protein please - says the fly.
    Afroditi Petsakou, Norbert Perrimon.
      
    DOI:  https://doi.org/10.1038/s42255-022-00665-y
  33. Mol Metab. 2022 Nov 05. pii: S2212-8778(22)00198-3. [Epub ahead of print] 101629
    The human batokine EPDR1 regulates β-cell metabolism and function.
    Luis Rodrigo Cataldo, Qian Gao, Lidia Argemi-Muntadas, Ondrej Hodek, Elaine Cowan, Sergey Hladkou, Sevda Gheibi, Peter Spégel, Rashmi B Prasad, Lena Eliasson, Camilla Scheele, Malin Fex, Hindrik Mulder, Thomas Moritz.
       BACKGROUND AND AIMS: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated.
    MATERIALS AND METHODS: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis.
    RESULTS: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells.
    CONCLUSION: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.
    Keywords:  Beta cells; Insulin secretion; Lactate; Mitochondrial metabolism; TCA cycle; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.molmet.2022.101629
  34. iScience. 2022 Nov 18. 25(11): 105362
    Dissociation of ERMES clusters plays a key role in attenuating the endoplasmic reticulum stress.
    Yuriko Kakimoto-Takeda, Rieko Kojima, Hiroya Shiino, Manatsu Shinmyo, Kazuo Kurokawa, Akihiko Nakano, Toshiya Endo, Yasushi Tamura.
      In yeast, ERMES, which mediates phospholipid transport between the ER and mitochondria, forms a limited number of oligomeric clusters at ER-mitochondria contact sites in a cell. Although the number of the ERMES clusters appears to be regulated to maintain proper inter-organelle phospholipid trafficking, its underlying mechanism and physiological relevance remain poorly understood. Here, we show that mitochondrial dynamics control the number of ERMES clusters. Moreover, we find that ER stress causes dissociation of the ERMES clusters independently of Ire1 and Hac1, canonical ER-stress response pathway components, leading to a delay in the phospholipid transport from the ER to mitochondria. Our biochemical and genetic analyses strongly suggest that the impaired phospholipid transport contributes to phospholipid accumulation in the ER, expanding the ER for ER stress attenuation. We thus propose that the ERMES dissociation constitutes an overlooked pathway of the ER stress response that operates in addition to the canonical Ire1/Hac1-dependent pathway.
    Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105362
  35. Int J Cancer. 2022 Nov 08.
    Target enzymes in serine-glycine-one-carbon metabolic pathway for cancer therapy.
    Wei Sun, Erhu Zhao, Hongjuan Cui.
      Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one-carbon units for nucleotide biosynthesis. In this process, serine-glycine metabolism and the one-carbon cycle play vital roles, which is named serine-glycine-one-carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis, and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate-mediated one-carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use one-carbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors. This article is protected by copyright. All rights reserved.
    Keywords:  cancer therapy; drug resistance; inhibitors; serine-glycine-one-carbon metabolism; target enzymes
    DOI:  https://doi.org/10.1002/ijc.34353
  36. Naunyn Schmiedebergs Arch Pharmacol. 2022 Nov 10.
    Regulation of insulin secretion in mouse islets: metabolic amplification by alpha-ketoisocaproate coincides with rapid and sustained increase in acetyl-CoA content.
    Uwe Panten, Dennis Brüning, Ingo Rustenbeck.
      Glucose and alpha-ketoisocaproate, the keto acid analogue of leucine, stimulate insulin secretion in the absence of other exogenous fuels. Their mitochondrial metabolism in the beta-cell raises the cytosolic ATP/ADP ratio, thereby providing the triggering signal for the exocytosis of the insulin granules. However, additional amplifying signals are required for the full extent of insulin secretion stimulated by these fuels. While it is generally recognized that the amplifying signals are also derived from the mitochondrial metabolism, their exact nature is still unclear. The current study tests the hypothesis that the supply of cytosolic acetyl-CoA is a signal in the amplifying pathway. The contents of acetyl-CoA and acetyl-CoA plus CoA-SH were measured in isolated mouse islets. Insulin secretion was recorded in isolated perifused islets. In islets, the ATP-sensitive K+ channels of which were pharmacologically closed and which were preincubated without exogenous fuel, 10 mmol/L alpha-ketoisocaproate enhanced the acetyl-CoA content after 5 and 20 min incubations and decreased the acetyl-CoA plus CoA-SH within 5 min, but not after 20 min. In islets not exposed to drugs, the preincubation with 3 mmol/L glucose, a non-triggering concentration, elevated the acetyl-CoA content. This content was further increased after 5 min and 20 min incubations with 30 mmol/L glucose, concurrent with a strong increase in insulin secretion. Alpha-ketoisocaproate and glucose increase the supply of acetyl-CoA in the beta-cell cytosol during both phases of insulin secretion. Most likely, this increase provides a signal for the metabolic amplification.
    Keywords:  Acetyl-CoA; Alpha-ketoisocaproate; Beta-cell; Glucose; Insulin secretion; Metabolic amplification
    DOI:  https://doi.org/10.1007/s00210-022-02290-8
  37. Curr Biol. 2022 Nov 02. pii: S0960-9822(22)01673-6. [Epub ahead of print]
    Reduced mitochondria provide an essential function for the cytosolic methionine cycle.
    Justyna Zítek, Zoltán Füssy, Sebastian C Treitli, Priscila Peña-Diaz, Zuzana Vaitová, Daryna Zavadska, Karel Harant, Vladimír Hampl.
      The loss of mitochondria in oxymonad protists has been associated with the redirection of the essential Fe-S cluster assembly to the cytosol. Yet as our knowledge of diverse free-living protists broadens, the list of functions of their mitochondrial-related organelles (MROs) expands. We revealed another such function in the closest oxymonad relative, Paratrimastix pyriformis, after we solved the proteome of its MRO with high accuracy, using localization of organelle proteins by isotope tagging (LOPIT). The newly assigned enzymes connect to the glycine cleavage system (GCS) and produce folate derivatives with one-carbon units and formate. These are likely to be used by the cytosolic methionine cycle involved in S-adenosyl methionine recycling. The data provide consistency with the presence of the GCS in MROs of free-living species and its absence in most endobionts, which typically lose the methionine cycle and, in the case of oxymonads, the mitochondria.
    Keywords:  LOPIT; Paratrimastix; glycine cleavage system; methionine cycle; mitochondrion-related organelle; one-carbon metabolism; proteome; spatial proteomics
    DOI:  https://doi.org/10.1016/j.cub.2022.10.028
  38. EMBO J. 2022 Nov 10. e110833
    The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
    Belén Sanz-Castillo, Begoña Hurtado, Diana Vara-Ciruelos, Aicha El Bakkali, Dario Hermida, Beatriz Salvador-Barbero, Diego Martínez-Alonso, José González-Martínez, Clara Santiveri, Ramón Campos-Olivas, Pilar Ximénez-Embún, Javier Muñoz, Mónica Álvarez-Fernández, Marcos Malumbres.
      The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here, we show that MASTL/Greatwall, a cell cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by the expression of phosphomimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
    Keywords:  AKT; MASTL; cell cycle; glucose homeostasis; mTOR
    DOI:  https://doi.org/10.15252/embj.2022110833
  39. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01494-2. [Epub ahead of print]41(6): 111623
    NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma.
    Gopalakrishnan Ramakrishnan, Parash Parajuli, Pura Singh, Creighton Friend, Eric Hurwitz, Celine Prunier, Mohammed S Razzaque, Keli Xu, Azeddine Atfi.
      A long-standing question in the pancreatic ductal adenocarcinoma (PDAC) field has been whether alternative genetic alterations could substitute for oncogenic KRAS mutations in initiating malignancy. Here, we report that Neurofibromin1 (NF1) inactivation can bypass the requirement of mutant KRAS for PDAC pathogenesis. An in-depth analysis of PDAC databases reveals various genetic alterations in the NF1 locus, including nonsense mutations, which occur predominantly in tumors with wild-type KRAS. Genetic experiments demonstrate that NF1 ablation culminates in acinar-to-ductal metaplasia, an early step in PDAC. Furthermore, NF1 haploinsufficiency results in a dramatic acceleration of KrasG12D-driven PDAC. Finally, we show an association between NF1 and p53 that is orchestrated by PML, and mosaic analysis with double markers demonstrates that concomitant inactivation of NF1 and Trp53 is sufficient to trigger full-blown PDAC. Together, these findings open up an exploratory framework for apprehending the mechanistic paradigms of PDAC with normal KRAS, for which no effective therapy is available.
    Keywords:  CP: Cancer; alternative genetic drivers in pancreatic ductal adenocarcinoma; mosaic analysis with double markers; mutant KRAS; pancreatic ductal adenocarcinoma initiation; tumor-suppressor gene NF1; tumor-suppressor gene PML; tumor-suppressor gene TP53
    DOI:  https://doi.org/10.1016/j.celrep.2022.111623
  40. Am J Physiol Endocrinol Metab. 2022 Nov 09.
    Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice.
    Ferrol I Rome, Gregory L Shobert, William C Voigt, David B Stagg, Patrycja Puchalska, Shawn C Burgess, Peter A Crawford, Curtis C Hughey.
      Acute exercise increases liver gluconeogenesis to supply glucose to working muscle. Concurrently, elevated liver lipid breakdown fuels the high energetic cost of gluconeogenesis. This functional coupling between liver gluconeogenesis and lipid oxidation has been proposed to underlie the ability of regular exercise to enhance liver mitochondrial oxidative metabolism and decrease liver steatosis in individuals with non-alcoholic fatty liver disease. Herein we tested whether repeated bouts of increased hepatic gluconeogenesis are necessary for exercise training to lower liver lipids. Experiments used diet-induced obese mice lacking hepatic phosphoenolpyruvate carboxykinase 1 (KO) to inhibit gluconeogenesis and wild type (WT) littermates. 2H/13C metabolic flux analysis quantified glucose and mitochondrial oxidative fluxes in untrained mice at rest and during acute exercise. Circulating and tissue metabolite levels were determined during sedentary conditions, acute exercise, and refeeding post-exercise. Mice also underwent six weeks of treadmill running protocols to define hepatic and extrahepatic adaptations to exercise training. Untrained KO mice were unable to maintain euglycemia during acute exercise resulting from an inability to increase gluconeogenesis. Liver triacylglycerides were elevated following acute exercise and circulating β-hydroxybutyrate was higher during post-exercise refeeding in untrained KO mice. In contrast, exercise training prevented liver triacylglyceride accumulation in KO mice. This was accompanied by pronounced increases in indices of skeletal muscle mitochondrial oxidative metabolism in KO mice. Together, these results show that hepatic gluconeogenesis is dispensable for exercise training to reduce liver lipids. This may be due to responses in ketone body metabolism and/or metabolic adaptations in skeletal muscle to exercise.
    Keywords:  gluconeogenesis; glycogenolysis; ketone bodies; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00222.2022
  41. Cell Syst. 2022 Oct 30. pii: S2405-4712(22)00430-6. [Epub ahead of print]
    Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate.
    Amy F Peterson, Kayla Ingram, E J Huang, Jeeun Parksong, Connor McKenney, Gabriel S Bever, Sergi Regot.
      The classic network of mitogen-activated protein kinases (MAPKs) is highly interconnected and controls a diverse array of biological processes. In multicellular eukaryotes, the MAPKs ERK, JNK, and p38 control opposing cell behaviors but are often activated simultaneously, raising questions about how input-output specificity is achieved. Here, we use multiplexed MAPK activity biosensors to investigate how cell fate control emerges from the connectivity and dynamics of the MAPK network. Through chemical and genetic perturbation, we systematically explore the outputs and functions of all the MAP3 kinases encoded in the human genome and show that MAP3Ks control cell fate by triggering unique combinations of MAPK activity. We show that these MAPK activity combinations explain the paradoxical dual role of JNK signaling as pro-apoptotic or pro-proliferative kinase. Overall, our integrative analysis indicates that the MAPK network operates as a unit to control cell fate and shifts the focus from MAPKs to MAP3Ks to better understand signaling-mediated control of cell fate.
    Keywords:  MAP kinase network; single-cell signaling dynamics
    DOI:  https://doi.org/10.1016/j.cels.2022.10.003
  42. iScience. 2022 Nov 18. 25(11): 105389
    Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma.
    Joana B Neves, Kirsty Roberts, Janani Sivakumaran Nguyen, Soha El Sheikh, My-Anh Tran-Dang, Catherine Horsfield, Faiz Mumtaz, Peter Campbell, Hans Stauss, Maxine G B Tran, Thomas Mitchell.
      Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.
    Keywords:  Cancer; Cancer systems biology; Genomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105389
  43. Nat Commun. 2022 Nov 09. 13(1): 6779
    Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism.
    Máté Katona, Ádám Bartók, Zuzana Nichtova, György Csordás, Elena Berezhnaya, David Weaver, Arijita Ghosh, Péter Várnai, David I Yule, György Hajnóczky.
      Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when 'parked', mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.
    DOI:  https://doi.org/10.1038/s41467-022-34365-8
  44. Immunity. 2022 Nov 08. pii: S1074-7613(22)00547-7. [Epub ahead of print]55(11): 1981-1992
    Regulatory T cells as metabolic sensors.
    Paola de Candia, Claudio Procaccini, Claudia Russo, Maria Teresa Lepore, Giuseppe Matarese.
      Compelling experimental evidence links immunity and metabolism. In this perspective, we propose forkhead-box-P3 (FoxP3)+CD4+CD25+ regulatory T (Treg) cells as key metabolic sensors controlling the immunological state in response to their intrinsic capacity to perceive nutritional changes. Treg cell high anabolic state in vivo, residency in metabolically crucial districts, and recirculation between lymphoid and non-lymphoid sites enable them to recognize the metabolic cues and adapt their intracellular metabolism and anti-inflammatory function at the paracrine and systemic levels. As privileged regulators at the interface between neuroendocrine and immune systems, the role of Treg cells in maintaining metabolic homeostasis makes these cells promising targets of therapeutic strategies aimed at restoring organismal homeostasis not only in autoimmune but also metabolic disorders.
    Keywords:  Treg cells; autoimmunity; immunometabolism; metabolic disease
    DOI:  https://doi.org/10.1016/j.immuni.2022.10.006
  45. Oncogene. 2022 Nov 07.
    DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.
    Raffaella Spina, Ian Mills, Fahim Ahmad, Chixiang Chen, Heather M Ames, Jeffrey A Winkles, Graeme F Woodworth, Eli E Bar.
      Glioma stem cells (GSCs) promote tumor progression and therapeutic resistance and exhibit remarkable bioenergetic and metabolic plasticity, a phenomenon that has been linked to their ability to escape standard and targeted therapies. However, specific mechanisms that promote therapeutic resistance have been somewhat elusive. We hypothesized that because GSCs proliferate continuously, they may require the salvage and de novo nucleotide synthesis pathways to satisfy their bioenergetic needs. Here, we demonstrate that GSCs lacking EGFR (or EGFRvIII) amplification are exquisitely sensitive to de novo pyrimidine synthesis perturbations, while GSCs that amplify EGFR are utterly resistant. Furthermore, we show that EGFRvIII promotes BAY2402234 resistance in otherwise BAY2402234 responsive GSCs. Remarkably, a novel, orally bioavailable, blood-brain-barrier penetrating, dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 was found to abrogate GSC proliferation, block cell-cycle progression, and induce DNA damage and apoptosis. When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted.
    DOI:  https://doi.org/10.1038/s41388-022-02517-1
  46. Nature. 2022 Nov 09.
    Spatial maps of genetically diverse breast cancer cells.
    Ghamdan Al-Eryani, Alexander Swarbrick.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-022-03560-4
  47. Cell. 2022 Nov 02. pii: S0092-8674(22)01359-9. [Epub ahead of print]
    The phenotypic landscape of essential human genes.
    Luke Funk, Kuan-Chung Su, Jimmy Ly, David Feldman, Avtar Singh, Brittania Moodie, Paul C Blainey, Iain M Cheeseman.
      Understanding the basis for cellular growth, proliferation, and function requires determining the roles of essential genes in diverse cellular processes, including visualizing their contributions to cellular organization and morphology. Here, we combined pooled CRISPR-Cas9-based functional screening of 5,072 fitness-conferring genes in human HeLa cells with microscopy-based imaging of DNA, the DNA damage response, actin, and microtubules. Analysis of >31 million individual cells identified measurable phenotypes for >90% of gene knockouts, implicating gene targets in specific cellular processes. Clustering of phenotypic similarities based on hundreds of quantitative parameters further revealed co-functional genes across diverse cellular activities, providing predictions for gene functions and associations. By conducting pooled live-cell screening of ∼450,000 cell division events for 239 genes, we additionally identified diverse genes with functional contributions to chromosome segregation. Our work establishes a resource detailing the consequences of disrupting core cellular processes that represents the functional landscape of essential human genes.
    Keywords:  CRISPR-Cas9; cell division; essential genes; functional genomics; high-content screening; in situ sequencing; microscopy; mitosis; morphology; optical pooled screening
    DOI:  https://doi.org/10.1016/j.cell.2022.10.017
  48. Proc Natl Acad Sci U S A. 2022 11 16. 119(46): e2215528119
    SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
    Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Patrick F Rodrigues, Raki Sudan, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna.
      Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express <i>Slc7a8</i>, encoding a transporter for arginine and large amino acids. <i>Slc7a8</i> was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of <i>Slc7a8</i> in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, <i>Slc7a8-</i>deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to <i>Slc7a8</i> deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify <i>Slc7a8</i> as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.
    Keywords:  allergy; amino acid; asthma; innate lymphoid cells; transporter
    DOI:  https://doi.org/10.1073/pnas.2215528119
  49. JCI Insight. 2022 Nov 08. pii: e155147. [Epub ahead of print]
    Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress.
    Luca J Delfinis, Catherine A Bellissimo, Shivam Gandhi, Sara N DiBenedetto, Madison C Garibotti, Arshdeep K Thuhan, Stavroula Tsitkanou, Megan E Rosa-Caldwell, Fasih A Rahman, Arthur J Cheng, Michael P Wiggs, Uwe Schlattner, Joe Quadrilatero, Nicholas P Greene, Christopher Gr Perry.
      Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 (C26) cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles vs control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress. Eventual muscle-specific restorations in force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.
    Keywords:  Colorectal cancer; Metabolism; Mitochondria; Oncology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.155147
  50. Elife. 2022 Nov 10. pii: e81033. [Epub ahead of print]11
    Endosymbiotic selective pressure at the origin of eukaryotic cell biology.
    Parth K Raval, Sriram G Garg, Sven B Gould.
      The dichotomy that separates prokaryotic from eukaryotic cells runs deep. The transition from pro- to eukaryote evolution is poorly understood due to a lack of reliable intermediate forms and definitions regarding the nature of the first host that could no longer be considered a prokaryote, the first eukaryotic common ancestor, FECA. The last eukaryotic common ancestor, LECA, was a complex cell that united all traits characterising eukaryotic biology including a mitochondrion. The role of the endosymbiotic organelle in this radical transition towards complex life forms is, however, sometimes questioned. In particular the discovery of the asgard archaea has stimulated discussions regarding the pre-endosymbiotic complexity of FECA. Here we review differences and similarities among models that view eukaryotic traits as isolated coincidental events in asgard archaeal evolution or, on the contrary, as a result of and in response to endosymbiosis. Inspecting eukaryotic traits from the perspective of the endosymbiont uncovers that eukaryotic cell biology can be explained as having evolved as a solution to housing a semi-autonomous organelle and why the addition of another endosymbiont, the plastid, added no extra compartments. Mitochondria provided the selective pressures for the origin (and continued maintenance) of eukaryotic cell complexity. Moreover, they also provided the energetic benefit throughout eukaryogenesis for evolving thousands of gene families unique to eukaryotes. Hence, a synthesis of the current data lets us conclude that traits such as the Golgi apparatus, the nucleus, autophagosomes, and meiosis and sex evolved as a response to the selective pressures an endosymbiont imposes.
    Keywords:  FECA; LECA; cell biology; endomembrane system; endosymbiosis; eukaryogenesis; mitochondria
    DOI:  https://doi.org/10.7554/eLife.81033
  51. Nat Metab. 2022 Nov 07.
    A gut-derived hormone suppresses sugar appetite and regulates food choice in Drosophila.
    Alina Malita, Olga Kubrak, Takashi Koyama, Nadja Ahrentløv, Michael J Texada, Stanislav Nagy, Kenneth V Halberg, Kim Rewitz.
      Animals must adapt their dietary choices to meet their nutritional needs. How these needs are detected and translated into nutrient-specific appetites that drive food-choice behaviours is poorly understood. Here we show that enteroendocrine cells of the adult female Drosophila midgut sense nutrients and in response release neuropeptide F (NPF), which is an ortholog of mammalian neuropeptide Y-family gut-brain hormones. Gut-derived NPF acts on glucagon-like adipokinetic hormone (AKH) signalling to induce sugar satiety and increase consumption of protein-rich food, and on adipose tissue to promote storage of ingested nutrients. Suppression of NPF-mediated gut signalling leads to overconsumption of dietary sugar while simultaneously decreasing intake of protein-rich yeast. Furthermore, gut-derived NPF has a female-specific function in promoting consumption of protein-containing food in mated females. Together, our findings suggest that gut NPF-to-AKH signalling modulates specific appetites and regulates food choice to ensure homeostatic consumption of nutrients, providing insight into the hormonal mechanisms that underlie nutrient-specific hungers.
    DOI:  https://doi.org/10.1038/s42255-022-00672-z
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