bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–03–12
37 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
  2. Fumarate induces vesicular release of mtDNA to drive innate immunity.
  3. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
  4. Mitochondrial molecule controls inflammation.
  5. Primary cilia sense glutamine availability and respond via asparagine synthetase.
  6. Determinants and outcomes of mitochondrial dynamics.
  7. Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
  8. ASS1-mediated reductive carboxylation of cytosolic glutamine confers ferroptosis resistance in cancer cells.
  9. Organ-specific fuel rewiring in acute and chronic hypoxia redistributes glucose and fatty acid metabolism.
  10. Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
  11. Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function.
  12. Protection from alcohol intoxication: Must be FGF21 to enter.
  13. Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans.
  14. EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation.
  15. Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes.
  16. L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.
  17. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.
  18. NUDT22 promotes cancer growth through pyrimidine salvage.
  19. Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.
  20. The autophagy-NAD axis in longevity and disease.
  21. Characterization of Dendritic Cell Metabolism by Flow Cytometry.
  22. How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
  23. Unanticipated metabolic plasticity in response to chronic hypoxia.
  24. Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.
  25. cGAS-STING signalling in cancer: striking a balance with chromosomal instability.
  26. MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint.
  27. Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
  28. FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system.
  29. Co-opting signalling molecules enables logic-gated control of CAR T cells.
  30. A protein bridge to death between the ER and mitochondria.
  31. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
  32. Droplet-based forward genetic screening of astrocyte-microglia cross-talk.
  33. Nutrient priming of the pre-metastatic niche.
  34. Bench-to-Bedside Studies of Arginine Deprivation in Cancer.
  35. The role of lysosomes in metabolic and autoimmune diseases.
  36. Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors.
  37. Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence.
  1. Elife. 2023 Mar 08. pii: e78654. [Epub ahead of print]12
    Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.
    Madeleine L Hart, Evan Quon, Anna-Lena B G Vigil, Ian A Engstrom, Oliver J Newsom, Kristian Davidsen, Pia Hoellerbauer, Samantha M Carlisle, Lucas B Sullivan.
      The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD+ to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss of function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.
    Keywords:  biochemistry; cancer biology; chemical biology; human
    DOI:  https://doi.org/10.7554/eLife.78654
  2. Nature. 2023 Mar 08.
    Fumarate induces vesicular release of mtDNA to drive innate immunity.
    Vincent Zecchini, Vincent Paupe, Irene Herranz-Montoya, Joëlle Janssen, Inge M N Wortel, Jordan L Morris, Ashley Ferguson, Suvagata Roy Chowdury, Marc Segarra-Mondejar, Ana S H Costa, Gonçalo C Pereira, Laura Tronci, Timothy Young, Efterpi Nikitopoulou, Ming Yang, Dóra Bihary, Federico Caicci, Shun Nagashima, Alyson Speed, Kalliopi Bokea, Zara Baig, Shamith Samarajiwa, Maxine Tran, Thomas Mitchell, Mark Johnson, Julien Prudent, Christian Frezza.
      Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma1. Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate2. However, although the long-term consequences of FH loss have been described, the acute response has not so far been investigated. Here we generated an inducible mouse model to study the chronology of FH loss in the kidney. We show that loss of FH leads to early alterations of mitochondrial morphology and the release of mitochondrial DNA (mtDNA) into the cytosol, where it triggers the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway and stimulates an inflammatory response that is also partially dependent on retinoic-acid-inducible gene I (RIG-I). Mechanistically, we show that this phenotype is mediated by fumarate and occurs selectively through mitochondrial-derived vesicles in a manner that depends on sorting nexin 9 (SNX9). These results reveal that increased levels of intracellular fumarate induce a remodelling of the mitochondrial network and the generation of mitochondrial-derived vesicles, which allows the release of mtDNAin the cytosol and subsequent activation of the innate immune response.
    DOI:  https://doi.org/10.1038/s41586-023-05770-w
  3. Nature. 2023 Mar 08.
    Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
    Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill.
      Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
    DOI:  https://doi.org/10.1038/s41586-023-05720-6
  4. Nature. 2023 Mar 08.
    Mitochondrial molecule controls inflammation.
    Taylor A Poor, Navdeep S Chandel.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  5. Nat Metab. 2023 Mar 06.
    Primary cilia sense glutamine availability and respond via asparagine synthetase.
    Maria Elena Steidl, Elisa A Nigro, Anne Kallehauge Nielsen, Roberto Pagliarini, Laura Cassina, Matteo Lampis, Christine Podrini, Marco Chiaravalli, Valeria Mannella, Gianfranco Distefano, Ming Yang, Mariam Aslanyan, Giovanna Musco, Ronald Roepman, Christian Frezza, Alessandra Boletta.
      Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
    DOI:  https://doi.org/10.1038/s42255-023-00754-6
  6. Mol Cell. 2023 Feb 28. pii: S1097-2765(23)00115-6. [Epub ahead of print]
    Determinants and outcomes of mitochondrial dynamics.
    Rubén Quintana-Cabrera, Luca Scorrano.
      Mitochondria are not only central organelles in metabolism and energy conversion but are also platforms for cellular signaling cascades. Classically, the shape and ultrastructure of mitochondria were depicted as static. The discovery of morphological transitions during cell death and of conserved genes controlling mitochondrial fusion and fission contributed to establishing the concept that mitochondrial morphology and ultrastructure are dynamically regulated by mitochondria-shaping proteins. These finely tuned, dynamic changes in mitochondrial shape can in turn control mitochondrial function, and their alterations in human diseases suggest that this space can be explored for drug discovery. Here, we review the basic tenets and molecular mechanisms of mitochondrial morphology and ultrastructure, describing how they can coordinately define mitochondrial function.
    Keywords:  cristae; cristae remodeling; fusion fission; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.012
  7. Elife. 2023 Mar 06. pii: e85494. [Epub ahead of print]12
    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.
    Chelsea U Kidwell, Joseph R Casalini, Soorya Pradeep, Sandra D Scherer, Daniel Greiner, Defne Bayik, Dionysios C Watson, Gregory S Olson, Justin D Lathia, Jarrod S Johnson, Jared Rutter, Alana L Welm, Thomas A Zangle, Minna Roh-Johnson.
      Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.
    Keywords:  cancer biology; cell biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.85494
  8. Cancer Res. 2023 Mar 09. pii: CAN-22-1999. [Epub ahead of print]
    ASS1-mediated reductive carboxylation of cytosolic glutamine confers ferroptosis resistance in cancer cells.
    Qiangsheng Hu, Jie Dai, Zheng Zhang, Huansha Yu, Jing Zhang, Xinsheng Zhu, Yi Qin, Lele Zhang, Peng Zhang.
      Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anti-cancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non-small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative TCA cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1-SREBP1-SCD5 axis to promote de novo monounsaturated fatty acid synthesis by utilizing acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared to either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1999
  9. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00043-8. [Epub ahead of print]35(3): 504-516.e5
    Organ-specific fuel rewiring in acute and chronic hypoxia redistributes glucose and fatty acid metabolism.
    Ayush D Midha, Yuyin Zhou, Bruno B Queliconi, Alec M Barrios, Augustinus G Haribowo, Brandon T L Chew, Cyril O Y Fong, Joseph E Blecha, Henry VanBrocklin, Youngho Seo, Isha H Jain.
      Oxygen deprivation can be detrimental. However, chronic hypoxia is also associated with decreased incidence of metabolic syndrome and cardiovascular disease in high-altitude populations. Previously, hypoxic fuel rewiring has primarily been studied in immortalized cells. Here, we describe how systemic hypoxia rewires fuel metabolism to optimize whole-body adaptation. Acclimatization to hypoxia coincided with dramatically lower blood glucose and adiposity. Using in vivo fuel uptake and flux measurements, we found that organs partitioned fuels differently during hypoxia adaption. Acutely, most organs increased glucose uptake and suppressed aerobic glucose oxidation, consistent with previous in vitro investigations. In contrast, brown adipose tissue and skeletal muscle became "glucose savers," suppressing glucose uptake by 3-5-fold. Interestingly, chronic hypoxia produced distinct patterns: the heart relied increasingly on glucose oxidation, and unexpectedly, the brain, kidney, and liver increased fatty acid uptake and oxidation. Hypoxia-induced metabolic plasticity carries therapeutic implications for chronic metabolic diseases and acute hypoxic injuries.
    Keywords:  PET scan; TCA cycle; fatty acid metabolism; fuel rewiring; fuel uptake; glucose metabolism; hypoxia; isotope tracing; organ-specific metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.007
  10. Commun Biol. 2023 Mar 10. 6(1): 255
    Setd2 inactivation sensitizes lung adenocarcinoma to inhibitors of oxidative respiration and mTORC1 signaling.
    David M Walter, Amy C Gladstein, Katherine R Doerig, Ramakrishnan Natesan, Saravana G Baskaran, A Andrea Gudiel, Keren M Adler, Jonuelle O Acosta, Douglas C Wallace, Irfan A Asangani, David M Feldser.
      SETD2 is a tumor suppressor that is frequently inactivated in several cancer types. The mechanisms through which SETD2 inactivation promotes cancer are unclear, and whether targetable vulnerabilities exist in these tumors is unknown. Here we identify heightened mTORC1-associated gene expression programs and functionally higher levels of oxidative metabolism and protein synthesis as prominent consequences of Setd2 inactivation in KRAS-driven mouse models of lung adenocarcinoma. Blocking oxidative respiration and mTORC1 signaling abrogates the high rates of tumor cell proliferation and tumor growth specifically in SETD2-deficient tumors. Our data nominate SETD2 deficiency as a functional marker of sensitivity to clinically actionable therapeutics targeting oxidative respiration and mTORC1 signaling.
    DOI:  https://doi.org/10.1038/s42003-023-04618-3
  11. Am J Physiol Cell Physiol. 2023 Mar 06.
    Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function.
    Giulia Avellino, Ruhi Deshmukh, Stephanie N Rogers, D Stephen Charnock-Jones, Gordon C S Smith, Saverio Tardito, Irving L M H Aye.
      Human trophoblast cultures provide powerful tools to model key processes of placental development. In vitro trophoblast studies to date have relied on commercial media which contains non-physiological levels of nutrients, and the impact of these conditions on trophoblast metabolism and function is unknown. Here we show that the physiological medium (Plasmaxä) with nutrient and metabolite concentrations recapitulating human plasma improves human trophoblast stem cell (hTSC) proliferation and differentiation compared to standard medium (DMEM-F12). hTSCs cultured in Plasmax-based medium also show altered glycolytic and mitochondrial metabolism, as well as reduced S-adenosylmethionine/S-adenosyl-homosysteine ratio compared to DMEM-F12-based medium. These findings demonstrate the importance of the nutritional environment for phenotyping cultured human trophoblasts.
    Keywords:  culture medium; placenta; stem cells
    DOI:  https://doi.org/10.1152/ajpcell.00581.2022
  12. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00046-3. [Epub ahead of print]35(3): 377-379
    Protection from alcohol intoxication: Must be FGF21 to enter.
    Martin Jastroch, Susanne Keipert, Matthias H Tschöp.
      Fibroblast growth factor 21 (FGF21) is generally known as a stress-induced metabolic regulator with enormous therapeutic potential to treat metabolic diseases, but a more specific role of FGF21 concerns physiological handling of alcohol in mammals. In this issue of Cell Metabolism, Choi et al. demonstrate that FGF21 mediates the recovery from alcohol intoxication by directly activating noradrenergic neurons in mice, thus advancing our knowledge on FGF21 biology and further diversifying its therapeutic potential.
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.010
  13. Cell Rep. 2023 Mar 09. pii: S2211-1247(23)00229-2. [Epub ahead of print]42(3): 112218
    Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans.
    Tumpa Dutta, Nidhi Kapoor, Meril Mathew, Suban S Chakraborty, Nathan P Ward, Nicolas Prieto-Farigua, Aimee Falzone, James P DeLany, Steven R Smith, Paul M Coen, Gina M DeNicola, Stephen J Gardell.
      Metabolic routing of nicotinamide (NAM) to NAD+ or 1-methylnicotinamide (MeNAM) has impacts on human health and aging. NAM is imported by cells or liberated from NAD+. The fate of 2H4-NAM in cultured cells, mice, and humans was determined by stable isotope tracing. 2H4-NAM is an NAD+ precursor via the salvage pathway in cultured A549 cells and human PBMCs and in A549 cell xenografts and PBMCs from 2H4-NAM-dosed mice and humans, respectively. 2H4-NAM is a MeNAM precursor in A549 cell cultures and xenografts, but not isolated PBMCs. NAM released from NAD+ is a poor MeNAM precursor. Additional A549 cell tracer studies yielded further mechanistic insight. NAMPT activators promote NAD+ synthesis and consumption. Surprisingly, NAM liberated from NAD+ in NAMPT activator-treated A549 cells is also routed toward MeNAM production. Metabolic fate mapping of the dual NAM sources across the translational spectrum (cells, mice, humans) illuminates a key regulatory node governing NAD+ and MeNAM synthesis.
    Keywords:  1-methylnicotinamide; CP: Metabolism; NAD; NAMPT; NAMPT activator; metabolite tracing; nicotinamide; salvage pathway
    DOI:  https://doi.org/10.1016/j.celrep.2023.112218
  14. PLoS Biol. 2023 Mar;21(3): e3002034
    EGR1 drives cell proliferation by directly stimulating TFEB transcription in response to starvation.
    Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Susanna Ambrosio, Rossella De Cegli, Margherita Mutarelli, Lorenzo Vaccaro, Micheal J Ziller, Davide Cacchiarelli, Diego L Medina, Andrea Ballabio.
      The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the proliferation of 2D and 3D cultures of cells displaying constitutive activation of TFEB, including those from a patient with Birt-Hogg-Dubé (BHD) syndrome, a TFEB-driven inherited cancer condition. Overall, we uncover an additional layer of TFEB regulation consisting in modulating its transcription via EGR1 and propose that interfering with the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
    DOI:  https://doi.org/10.1371/journal.pbio.3002034
  15. Mol Cell. 2023 Mar 06. pii: S1097-2765(23)00116-8. [Epub ahead of print]
    Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes.
    Alan H Baik, Augustinus G Haribowo, Xuewen Chen, Bruno B Queliconi, Alec M Barrios, Ankur Garg, Mazharul Maishan, Alexandre R Campos, Michael A Matthay, Isha H Jain.
      Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.
    Keywords:  DNA damage; Fe-S clusters; hyperoxia; lung injury; mitochondria; oxygen; purine synthesis; redox; translation fidelity
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.013
  16. Oncogene. 2023 Mar 06.
    L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.
    Sho Tabata, Yasushi Kojima, Takeharu Sakamoto, Kaori Igarashi, Ko Umetsu, Takamasa Ishikawa, Akiyoshi Hirayama, Rie Kajino-Sakamoto, Naoya Sakamoto, Ken-Ichi Yasumoto, Keiichi Okano, Yasuyuki Suzuki, Shinichi Yachida, Masahiro Aoki, Tomoyoshi Soga.
      Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.
    DOI:  https://doi.org/10.1038/s41388-023-02632-7
  17. Cell Metab. 2023 Mar 06. pii: S1550-4131(23)00049-9. [Epub ahead of print]
    Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.
    Carina B Nava Lauson, Silvia Tiberti, Paola A Corsetto, Federica Conte, Punit Tyagi, Markus Machwirth, Stefan Ebert, Alessia Loffreda, Lukas Scheller, Dalia Sheta, Zeinab Mokhtari, Timo Peters, Ayush T Raman, Francesco Greco, Angela M Rizzo, Andreas Beilhack, Giovanni Signore, Nicola Tumino, Paola Vacca, Liam A McDonnell, Andrea Raimondi, Philip D Greenberg, Johannes B Huppa, Simone Cardaci, Ignazio Caruana, Simona Rodighiero, Luigi Nezi, Teresa Manzo.
      The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.
    Keywords:  CD8 T cells; adoptive T cell therapy; linoleic acid; lipid metabolism; metabolic fitness
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.013
  18. Oncogene. 2023 Mar 04.
    NUDT22 promotes cancer growth through pyrimidine salvage.
    Melanie Walter, Florian Mayr, Bishoy M F Hanna, Victoria Cookson, Oliver Mortusewicz, Thomas Helleday, Patrick Herr.
      The NUDIX hydrolase NUDT22 converts UDP-glucose into glucose-1-phosphate and the pyrimidine nucleotide uridine monophosphate but a biological significance for this biochemical reaction has not yet been established. Glucose-1-phosphate is an important metabolite for energy and biomass production through glycolysis and nucleotides required for DNA replication are produced through energetically expensive de novo or energy-efficient salvage pathways. Here, we describe p53-regulated pyrimidine salvage through NUDT22-dependent hydrolysis of UDP-glucose to maintain cancer cell growth and to prevent replication stress. NUDT22 expression is consistently elevated in cancer tissues and high NUDT22 expression correlates with worse survival outcomes in patients indicating an increased dependency of cancer cells to NUDT22. Furthermore, we show that NUDT22 transcription is induced after inhibition of glycolysis, MYC-mediated oncogenic stress, and DNA damage directly through p53. NUDT22-deficient cancer cells suffer from growth retardation, S-phase delay, and slower DNA replication fork speed. Uridine supplementation rescues replication fork progression and alleviates replication stress and DNA damage. Conversely, NUDT22 deficiency sensitizes cells to de novo pyrimidine synthesis inhibition in vitro and reduces cancer growth in vivo. In conclusion, NUDT22 maintains pyrimidine supply in cancer cells and depletion of NUDT22 leads to genome instability. Targeting NUDT22 therefore has high potential for therapeutic applications in cancer therapy.
    DOI:  https://doi.org/10.1038/s41388-023-02643-4
  19. Geroscience. 2023 Mar 06.
    Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction.
    Brandon J Berry, Evan Mjelde, Fatima Carreno, Kathryn Gilham, Emily J Hanson, Emily Na, Matt Kaeberlein.
      Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψm) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψm is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψm during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψm declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψm blocked the longevity and health benefits of DR. Genetic perturbation of Δψm and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψm is a critical factor for health and longevity in response to DR.
    Keywords:  Aging; Bioenergetics; Calorie restriction; Fasting; Metabolism; Mitochondrial uncoupling
    DOI:  https://doi.org/10.1007/s11357-023-00766-w
  20. Trends Cell Biol. 2023 Mar 04. pii: S0962-8924(23)00023-5. [Epub ahead of print]
    The autophagy-NAD axis in longevity and disease.
    Niall Wilson, Tetsushi Kataura, Miriam E Korsgen, Congxin Sun, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is an intracellular degradation pathway that recycles subcellular components to maintain metabolic homeostasis. NAD is an essential metabolite that participates in energy metabolism and serves as a substrate for a series of NAD+-consuming enzymes (NADases), including PARPs and SIRTs. Declining levels of autophagic activity and NAD represent features of cellular ageing, and consequently enhancing either significantly extends health/lifespan in animals and normalises metabolic activity in cells. Mechanistically, it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress. In this review we highlight the mechanisms underlying this bidirectional relationship between NAD and autophagy, and the potential therapeutic targets it provides for combatting age-related disease and promoting longevity.
    Keywords:  PARP; Parkinson's disease; ageing; mitophagy; neurodegeneration; nicotinamide; sirtuins
    DOI:  https://doi.org/10.1016/j.tcb.2023.02.004
  21. Methods Mol Biol. 2023 ;2618 219-237
    Characterization of Dendritic Cell Metabolism by Flow Cytometry.
    Eline C Brombacher, Thiago A Patente, Marjolein Quik, Bart Everts.
      In response to different stimuli, dendritic cells (DCs) undergo metabolic reprogramming to support their function. Here we describe how fluorescent dyes and antibody-based approaches can be used to assess various metabolic parameters of DCs including glycolysis, lipid metabolism, mitochondrial activity, and the activity of important sensors and regulators of cellular metabolism, mTOR and AMPK. These assays can be performed using standard flow cytometry and will allow for the determination of metabolic properties of DC populations at single-cell level and to characterize metabolic heterogeneity within them.
    Keywords:  Dendritic cells; Flow cytometry; Glucose; Lipids; Metabolism; Mitochondria; ROS
    DOI:  https://doi.org/10.1007/978-1-0716-2938-3_16
  22. Cancers (Basel). 2023 Feb 23. pii: 1417. [Epub ahead of print]15(5):
    How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.
    Zoé Daverio, Aneta Balcerczyk, Gilles J P Rautureau, Baptiste Panthu.
      Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.
    Keywords:  Warburg effect; glucose deprivation; lactic acidosis; metabolic symbiosis; tumour heterogeneity
    DOI:  https://doi.org/10.3390/cancers15051417
  23. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00047-5. [Epub ahead of print]35(3): 381-383
    Unanticipated metabolic plasticity in response to chronic hypoxia.
    Ioanna Papandreou, Martin Benej, Nicholas C Denko.
      In this issue of Cell Metabolism, Midha et al. investigate the metabolic changes in mice after exposure to reduced oxygen tension for an acute or chronic duration. Their organ-specific findings may help explain physiological observations in humans living at high altitude but raise additional questions concerning pathological hypoxia after vascular damage or in cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.011
  24. Science. 2023 Mar 10. 379(6636): 996-1003
    Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.
    Kevin G Hicks, Ahmad A Cluntun, Heidi L Schubert, Sean R Hackett, Jordan A Berg, Paul G Leonard, Mariana A Ajalla Aleixo, Youjia Zhou, Alex J Bott, Sonia R Salvatore, Fei Chang, Aubrie Blevins, Paige Barta, Samantha Tilley, Aaron Leifer, Andrea Guzman, Ajak Arok, Sarah Fogarty, Jacob M Winter, Hee-Chul Ahn, Karen N Allen, Samuel Block, Iara A Cardoso, Jianping Ding, Ingrid Dreveny, William C Gasper, Quinn Ho, Atsushi Matsuura, Michael J Palladino, Sabin Prajapati, Pengkai Sun, Kai Tittmann, Dean R Tolan, Judith Unterlass, Andrew P VanDemark, Matthew G Vander Heiden, Bradley A Webb, Cai-Hong Yun, Pengkai Zhao, Bei Wang, Francisco J Schopfer, Christopher P Hill, Maria Cristina Nonato, Florian L Muller, James E Cox, Jared Rutter.
      Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.
    DOI:  https://doi.org/10.1126/science.abm3452
  25. Biochem Soc Trans. 2023 Mar 06. pii: BST20220838. [Epub ahead of print]
    cGAS-STING signalling in cancer: striking a balance with chromosomal instability.
    Bruno Beernaert, Eileen E Parkes.
      Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are detected by the nucleic acid sensor cGAS, leading to the production of the second messenger 2'3'-cGAMP and activation of the critical hub of innate immune signalling STING. Activation of this immune pathway should instigate the influx and activation of immune cells, resulting in the eradication of cancer cells. That this does not universally occur in the context of CIN remains an unanswered paradox in cancer. Instead, CIN-high cancers are notably adept at immune evasion and are highly metastatic with typically poor outcomes. In this review, we discuss the diverse facets of the cGAS-STING signalling pathway, including emerging roles in homeostatic processes and their intersection with genome stability regulation, its role as a driver of chronic pro-tumour inflammation, and crosstalk with the tumour microenvironment, which may collectively underlie its apparent maintenance in cancers. A better understanding of the mechanisms whereby this immune surveillance pathway is commandeered by chromosomally unstable cancers is critical to the identification of new vulnerabilities for therapeutic exploitation.
    Keywords:  DNA synthesis and repair; cGAS-STING; chromosomal instability; immunosurveillance; innate immunity
    DOI:  https://doi.org/10.1042/BST20220838
  26. Proc Natl Acad Sci U S A. 2023 Mar 14. 120(11): e2215376120
    MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint.
    Benjamin A H Smith, Anja Deutzmann, Kristina M Correa, Corleone S Delaveris, Renumathy Dhanasekaran, Christopher G Dove, Delaney K Sullivan, Simon Wisnovsky, Jessica C Stark, John V Pluvinage, Srividya Swaminathan, Nicholas M Riley, Anand Rajan, Ravindra Majeti, Dean W Felsher, Carolyn R Bertozzi.
      The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.
    Keywords:  MYC; Siglec; glycosylation; oncogene
    DOI:  https://doi.org/10.1073/pnas.2215376120
  27. Blood. 2023 Mar 08. pii: blood.2022018711. [Epub ahead of print]
    Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression.
    Aisha Jibril, Charlotte Hellmich, Edyta Wojtowicz, Katherine Hampton, Rebecca S Maynard, Ravindu De Silva, Dominic J Fowler-Shorten, Jayna J Mistry, Jamie A Moore, Kristian M Bowles, Stuart A Rushworth.
      Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites and DNA and have various context specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognised via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma and cancer patients, however the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in-vivo models, we describe the role of MM cell derived mtDAMPs in the pro-tumoral BM microenvironment, and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of MM patients compared to healthy controls. Using the MM1S cells engrafted into NSG mice we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the STING pathway and inhibition of this pathway reduces MM tumor-burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signalling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the pro-tumoral BM microenvironment.
    DOI:  https://doi.org/10.1182/blood.2022018711
  28. Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00041-4. [Epub ahead of print]35(3): 429-437.e5
    FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system.
    Mihwa Choi, Marc Schneeberger, Wei Fan, Abhijit Bugde, Laurent Gautron, Kevin Vale, Robert E Hammer, Yuan Zhang, Jeffrey M Friedman, David J Mangelsdorf, Steven A Kliewer.
      Animals that consume fermenting fruit and nectar are at risk of exposure to ethanol and the detrimental effects of inebriation. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in murine and human liver, stimulates arousal from intoxication without changing ethanol catabolism. Mice lacking FGF21 take longer than wild-type littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduces the time needed for mice to recover from ethanol-induced unconsciousness and ataxia. FGF21 did not counteract sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediates its anti-intoxicant effects by directly activating noradrenergic neurons in the locus coeruleus region, which regulates arousal and alertness. These results suggest that this FGF21 liver-brain pathway evolved to protect against ethanol-induced intoxication and that it might be targeted pharmaceutically for treating acute alcohol poisoning.
    Keywords:  FGF21; alcohol; amethystic; anti-intoxicant; hormone; inebriation; liver; locus coeruleus; noradrenergic
    DOI:  https://doi.org/10.1016/j.cmet.2023.02.005
  29. Nature. 2023 Mar 08.
    Co-opting signalling molecules enables logic-gated control of CAR T cells.
    Aidan M Tousley, Maria Caterina Rotiroti, Louai Labanieh, Lea Wenting Rysavy, Won-Ju Kim, Caleb Lareau, Elena Sotillo, Evan W Weber, Skyler P Rietberg, Guillermo Nicolas Dalton, Yajie Yin, Dorota Klysz, Peng Xu, Eva L de la Serna, Alexander R Dunn, Ansuman T Satpathy, Crystal L Mackall, Robbie G Majzner.
      Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells1,2. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity3-5; however, a truly safe and effective logic-gated CAR has remained elusive6. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for signal propagation. We exploited the cooperative role of LAT and SLP-76 to engineer logic-gated intracellular network (LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and prevention of on-target, off-tumour toxicity. LINK CAR will expand the range of molecules that can be targeted with CAR T cells, and will enable these powerful therapeutic agents to be used for solid tumours and diverse diseases such as autoimmunity7 and fibrosis8. In addition, this work shows that the internal signalling machinery of cells can be repurposed into surface receptors, which could open new avenues for cellular engineering.
    DOI:  https://doi.org/10.1038/s41586-023-05778-2
  30. J Biol Chem. 2023 Mar 03. pii: S0021-9258(23)00223-5. [Epub ahead of print] 104581
    A protein bridge to death between the ER and mitochondria.
    Jialing Lin.
      Commitment to apoptotic cell death occurs at the mitochondria, and is regulated by BCL-2 family proteins localized to this organelle. However, BIK, a resident protein of the endoplasmic reticulum inhibits mitochondrial BCL-2 proteins to promote apoptosis. In a recent paper in the JBC, Osterlund et al. investigated this conundrum. Surprisingly, they discovered that these endoplasmic reticulum and mitochondrial proteins moved toward each other and met at the contact site between the two organelles, thereby forming a 'bridge to death'.
    DOI:  https://doi.org/10.1016/j.jbc.2023.104581
  31. Nat Aging. 2023 Feb;3(2): 157-161
    Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan.
    Brandon J Berry, Anežka Vodičková, Annika Müller-Eigner, Chen Meng, Christina Ludwig, Matt Kaeberlein, Shahaf Peleg, Andrew P Wojtovich.
      Mitochondrial dysfunction plays a central role in aging but the exact biological causes are still being determined. Here, we show that optogenetically increasing mitochondrial membrane potential during adulthood using a light-activated proton pump improves age-associated phenotypes and extends lifespan in C. elegans. Our findings provide direct causal evidence that rescuing the age-related decline in mitochondrial membrane potential is sufficient to slow the rate of aging and extend healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-022-00340-7
  32. Science. 2023 Mar 10. 379(6636): 1023-1030
    Droplet-based forward genetic screening of astrocyte-microglia cross-talk.
    Michael A Wheeler, Iain C Clark, Hong-Gyun Lee, Zhaorong Li, Mathias Linnerbauer, Joseph M Rone, Manon Blain, Camilo Faust Akl, Gavin Piester, Federico Giovannoni, Marc Charabati, Joon-Hyuk Lee, Yoon-Chul Kye, Joshua Choi, Liliana M Sanmarco, Lena Srun, Elizabeth N Chung, Lucas E Flausino, Brian M Andersen, Veit Rothhammer, Hiroshi Yano, Tomer Illouz, Stephanie E J Zandee, Carolin Daniel, David Artis, Marco Prinz, Adam R Abate, Vijay K Kuchroo, Jack P Antel, Alexandre Prat, Francisco J Quintana.
      Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.
    DOI:  https://doi.org/10.1126/science.abq4822
  33. Nat Rev Cancer. 2023 Mar 09.
    Nutrient priming of the pre-metastatic niche.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-023-00559-5
  34. Molecules. 2023 Feb 24. pii: 2150. [Epub ahead of print]28(5):
    Bench-to-Bedside Studies of Arginine Deprivation in Cancer.
    George C Field, Iuliia Pavlyk, Peter W Szlosarek.
      Arginine is a semi-essential amino acid which becomes wholly essential in many cancers commonly due to the functional loss of Argininosuccinate Synthetase 1 (ASS1). As arginine is vital for a plethora of cellular processes, its deprivation provides a rationale strategy for combatting arginine-dependent cancers. Here we have focused on pegylated arginine deiminase (ADI-PEG20, pegargiminase)-mediated arginine deprivation therapy from preclinical through to clinical investigation, from monotherapy to combinations with other anticancer therapeutics. The translation of ADI-PEG20 from the first in vitro studies to the first positive phase 3 trial of arginine depletion in cancer is highlighted. Finally, this review discusses how the identification of biomarkers that may denote enhanced sensitivity to ADI-PEG20 beyond ASS1 may be realized in future clinical practice, thus personalising arginine deprivation therapy for patients with cancer.
    Keywords:  ADI-PEG20; arginine; arginine deprivation; argininosuccinate synthetase 1; biomarkers; cancer; combination therapy; monotherapy
    DOI:  https://doi.org/10.3390/molecules28052150
  35. Nat Rev Nephrol. 2023 Mar 09.
    The role of lysosomes in metabolic and autoimmune diseases.
    Frédéric Gros, Sylviane Muller.
      Lysosomes are catabolic organelles that contribute to the degradation of intracellular constituents through autophagy and of extracellular components through endocytosis, phagocytosis and macropinocytosis. They also have roles in secretory mechanisms, the generation of extracellular vesicles and certain cell death pathways. These functions make lysosomes central organelles in cell homeostasis, metabolic regulation and responses to environment changes including nutrient stresses, endoplasmic reticulum stress and defects in proteostasis. Lysosomes also have important roles in inflammation, antigen presentation and the maintenance of long-lived immune cells. Their functions are tightly regulated by transcriptional modulation via TFEB and TFE3, as well as by major signalling pathways that lead to activation of mTORC1 and mTORC2, lysosome motility and fusion with other compartments. Lysosome dysfunction and alterations in autophagy processes have been identified in a wide variety of diseases, including autoimmune, metabolic and kidney diseases. Deregulation of autophagy can contribute to inflammation, and lysosomal defects in immune cells and/or kidney cells have been reported in inflammatory and autoimmune pathologies with kidney involvement. Defects in lysosomal activity have also been identified in several pathologies with disturbances in proteostasis, including autoimmune and metabolic diseases such as Parkinson disease, diabetes mellitus and lysosomal storage diseases. Targeting lysosomes is therefore a potential therapeutic strategy to regulate inflammation and metabolism in a variety of pathologies.
    DOI:  https://doi.org/10.1038/s41581-023-00692-2
  36. Nat Genet. 2023 Mar 09.
    Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors.
    Luis Zapata, Giulio Caravagna, Marc J Williams, Eszter Lakatos, Khalid AbdulJabbar, Benjamin Werner, Diego Chowell, Chela James, Lucie Gourmet, Salvatore Milite, Ahmet Acar, Nadeem Riaz, Timothy A Chan, Trevor A Graham, Andrea Sottoriva.
      In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.
    DOI:  https://doi.org/10.1038/s41588-023-01313-1
  37. Nat Commun. 2023 Mar 10. 14(1): 1323
    Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence.
    Yinsheng Wu, Lixu Tang, Han Huang, Qi Yu, Bicheng Hu, Gang Wang, Feng Ge, Tailang Yin, Shanshan Li, Xilan Yu.
      Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to reduction of intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates ageing in mice. Our findings reveal that enhancing serine biosynthesis could become a therapy to promote healthy ageing.
    DOI:  https://doi.org/10.1038/s41467-023-37094-8
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