bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020‒11‒15
fourteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity.
  2. An Endoplasmic Reticulum ATPase Safeguards Endoplasmic Reticulum Identity by Removing Ectopically Localized Mitochondrial Proteins.
  3. A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.
  4. Assembly of the peripheral stalk of ATP synthase in human mitochondria.
  5. Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling.
  6. Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics.
  7. Macrophage mitochondrial MFN2 (mitofusin 2) links immune stress and immune response through reactive oxygen species (ROS) production.
  8. Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.
  9. MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.
  10. Determinants of Tissue-Specific Metabolic Adaptation of T Cells.
  11. Inter-organelle membrane contact sites: implications for lipid metabolism.
  12. Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.
  13. Insight into the Interactome of Intramitochondrial PKA Using Biotinylation-Proximity Labeling.
  14. Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import.
  1. Nat Commun. 2020 11 11. 11(1): 5711
    MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity.
    Yuki Hanada, Naotada Ishihara, Lixiang Wang, Hidenori Otera, Takaya Ishihara, Takumi Koshiba, Katsuyoshi Mihara, Yoshihiro Ogawa, Masatoshi Nomura.
      Mitochondria are multifunctional organelles that produce energy and are critical for various signaling pathways. Mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein essential for the anti-RNA viral immune response, which is regulated by mitochondrial dynamics and energetics; however, the molecular link between mitochondrial metabolism and immunity is unclear. Here we show in cultured mammalian cells that MAVS is activated by mitochondrial fission factor (Mff), which senses mitochondrial energy status. Mff mediates the formation of active MAVS clusters on mitochondria, independent of mitochondrial fission and dynamin-related protein 1. Under mitochondrial dysfunction, Mff is phosphorylated by the cellular energy sensor AMP-activated protein kinase (AMPK), leading to the disorganization of MAVS clusters and repression of the acute antiviral response. Mff also contributes to immune tolerance during chronic infection by disrupting the mitochondrial MAVS clusters. Taken together, Mff has a critical function in MAVS-mediated innate immunity, by sensing mitochondrial energy metabolism via AMPK signaling.
    DOI:  https://doi.org/10.1038/s41467-020-19287-7
  2. Cell Rep. 2020 Nov 10. pii: S2211-1247(20)31352-8. [Epub ahead of print]33(6): 108363
    An Endoplasmic Reticulum ATPase Safeguards Endoplasmic Reticulum Identity by Removing Ectopically Localized Mitochondrial Proteins.
    Qing Qin, Ting Zhao, Wei Zou, Kang Shen, Xiangming Wang.
      Stringent targeting of membrane proteins to corresponding organelles is essential for organelle identity and functions. In addition to molecular pathways that target proteins to appropriate organelles, surveillance mechanisms clear mistargeted proteins from undesired destinations. Although Msp1 functions on the mitochondrial membrane to remove mistargeted proteins, the surveillance mechanism for the endoplasmic reticulum (ER) is not well understood. Here, we show that a conserved P5A-type ATPase CATP-8, which localizes to ER, removes ectopic mitochondrial tail-anchored (TA) and signal-anchored (SA) proteins from the ER. In catp-8 mutant, mitochondria fission protein FIS-1 mislocalizes to the ER membrane. Together with another mitochondria fission protein MFF-2, FIS-1 causes ER fragmentation in a Dynamin-related protein (DRP-1)-dependent manner. In addition, CATP-8 is essential for dendrite development. catp-8 mutant dramatically reduces the level of the dendrite guidance receptor DMA-1, leading to diminished dendritic arbors. Hence, P5A ATPase safeguards ER morphology and functions by preventing mitochondrial proteins mislocalization.
    DOI:  https://doi.org/10.1016/j.celrep.2020.108363
  3. PLoS Genet. 2020 Nov;16(11): e1009129
    A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics.
    Daniel C Maddison, Mónica Alfonso-Núñez, Aisha M Swaih, Carlo Breda, Susanna Campesan, Natalie Allcock, Anna Straatman-Iwanowska, Charalambos P Kyriacou, Flaviano Giorgini.
      The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson's disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.
    DOI:  https://doi.org/10.1371/journal.pgen.1009129
  4. Proc Natl Acad Sci U S A. 2020 Nov 09. pii: 202017987. [Epub ahead of print]
    Assembly of the peripheral stalk of ATP synthase in human mitochondria.
    Jiuya He, Joe Carroll, Shujing Ding, Ian M Fearnley, Martin G Montgomery, John E Walker.
      The adenosine triphosphate (ATP) synthase in human mitochondria is a membrane bound assembly of 29 proteins of 18 kinds organized into F1-catalytic, peripheral stalk (PS), and c8-rotor ring modules. All but two membrane components are encoded in nuclear genes, synthesized on cytoplasmic ribosomes, imported into the mitochondrial matrix, and assembled into the complex with the mitochondrial gene products ATP6 and ATP8. Intermediate vestigial ATPase complexes formed by disruption of nuclear genes for individual subunits provide a description of how the various domains are introduced into the enzyme. From this approach, it is evident that three alternative pathways operate to introduce the PS module (including associated membrane subunits e, f, and g). In one pathway, the PS is built up by addition to the core subunit b of membrane subunits e and g together, followed by membrane subunit f. Then this b-e-g-f complex is bound to the preformed F1-c8 module by subunits OSCP and F6 The final component of the PS, subunit d, is added subsequently to form a key intermediate that accepts the two mitochondrially encoded subunits. In another route to this key intermediate, first e and g together and then f are added to a preformed F1-c8-OSCP-F6-b-d complex. A third route involves the addition of the c8-ring module to the complete F1-PS complex. The key intermediate then accepts the two mitochondrially encoded subunits, stabilized by the addition of subunit j, leading to an ATP synthase complex that is coupled to the proton motive force and capable of making ATP.
    Keywords:  ATP synthase; assembly; human mitochondria; peripheral stalk
    DOI:  https://doi.org/10.1073/pnas.2017987117
  5. Aging Cell. 2020 Nov 09. e13268
    Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling.
    Mustafa N Okur, Evandro F Fang, Elayne M Fivenson, Vinod Tiwari, Deborah L Croteau, Vilhelm A Bohr.
      Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD+ precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD+ restoration.
    Keywords:  AMPK; Cockayne syndrome; NAD+; accelerated ageing; aging; mitochondrial maintenance; mitophagy
    DOI:  https://doi.org/10.1111/acel.13268
  6. EMBO Rep. 2020 Nov 12. e49019
    Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics.
    Diana Molino, Irene Pila-Castellanos, Henri-Baptiste Marjault, Nivea Dias Amoedo, Katja Kopp, Leila Rochin, Ola Karmi, Yang-Sung Sohn, Laetitia Lines, Ahmed Hamaï, Stéphane Joly, Pauline Radreau, Jacky Vonderscher, Patrice Codogno, Francesca Giordano, Peter Machin, Rodrigue Rossignol, Eric Meldrum, Damien Arnoult, Alessia Ruggieri, Rachel Nechushtai, Benoit de Chassey, Etienne Morel.
      Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER-mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research.
    Keywords:  NEET proteins; contact sites; mitochondria; morphodynamics; virus
    DOI:  https://doi.org/10.15252/embr.201949019
  7. Autophagy. 2020 Nov 10. 1-3
    Macrophage mitochondrial MFN2 (mitofusin 2) links immune stress and immune response through reactive oxygen species (ROS) production.
    Jorge Lloberas, Juan P Muñoz, María Isabel Hernández-Álvarez, Pere-Joan Cardona, Antonio Zorzano, Antonio Celada.
      MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired response in a model of non-septic inflammation in mice, as well as a failure in protection from Listeria, Mycobacterium tuberculosis or LPS endotoxemia. These results reveal an unexpected role of MFN2 to ROS production in macrophages affecting natural and acquired immunity and the immune response.
    Keywords:  Autophagy; ROS; bactericidal activity; cytokine; inflammation; macrophages; phagocytosis
    DOI:  https://doi.org/10.1080/15548627.2020.1839191
  8. Nat Chem Biol. 2020 Nov 09.
    Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.
    Hiroki Kobayashi, Hideyuki Hatakeyama, Haruna Nishimura, Mutsumi Yokota, Sadafumi Suzuki, Yuri Tomabechi, Mikako Shirouzu, Hiroyuki Osada, Masakazu Mimaki, Yu-Ichi Goto, Minoru Yoshida.
      Mitochondrial DNA (mtDNA) mutations are the major cause of mitochondrial diseases. Cells harboring disease-related mtDNA mutations exhibit various phenotypic abnormalities, such as reduced respiration and elevated lactic acid production. Induced pluripotent stem cell (iPSC) lines derived from patients with mitochondrial disease, with high proportions of mutated mtDNA, exhibit defects in maturation into neurons or cardiomyocytes. In this study, we have discovered a small-molecule compound, which we name tryptolinamide (TLAM), that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived iPSCs. We found that TLAM inhibits phosphofructokinase-1 (PFK1), which in turn activates AMPK-mediated fatty-acid oxidation to promote oxidative phosphorylation, and redirects carbon flow from glycolysis toward the pentose phosphate pathway to reinforce anti-oxidative potential. Finally, we found that TLAM rescued the defect in neuronal differentiation of iPSCs carrying a high ratio of mutant mtDNA, suggesting that PFK1 represents a potential therapeutic target for mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41589-020-00676-4
  9. Nucleic Acids Res. 2020 Nov 11. pii: gkaa1011. [Epub ahead of print]
    MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.
    Sneha Rath, Rohit Sharma, Rahul Gupta, Tslil Ast, Connie Chan, Timothy J Durham, Russell P Goodman, Zenon Grabarek, Mary E Haas, Wendy H W Hung, Pallavi R Joshi, Alexis A Jourdain, Sharon H Kim, Anna V Kotrys, Stephanie S Lam, Jason G McCoy, Joshua D Meisel, Maria Miranda, Apekshya Panda, Anupam Patgiri, Robert Rogers, Shayan Sadre, Hardik Shah, Owen S Skinner, Tsz-Leung To, Melissa A Walker, Hong Wang, Patrick S Ward, Jordan Wengrod, Chen-Ching Yuan, Sarah E Calvo, Vamsi K Mootha.
      The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.
    DOI:  https://doi.org/10.1093/nar/gkaa1011
  10. Cell Metab. 2020 Nov 06. pii: S1550-4131(20)30546-5. [Epub ahead of print]
    Determinants of Tissue-Specific Metabolic Adaptation of T Cells.
    Siva Karthik Varanasi, Sushmitha Vijaya Kumar, Barry T Rouse.
      Metabolic reprogramming is a hallmark of T cell activation and function. As our understanding of T cell metabolism increases, so does our appreciation of its inherent complexity. The metabolic heterogeneity of T cells that reside in different locations, such as lymphoid and non-lymphoid tissues, presents a challenge to developing therapies that exploit metabolic vulnerabilities. The roots of metabolic heterogeneity are only beginning to be understood. Here, we propose four factors that contribute to the adaptation of T cells to their dynamic tissue environment: (1) functional status of T cells, (2) local factors unique to the tissue niche, (3) type of inflammation, and (4) time spent in a specific tissue. We review emerging concepts about tissue-specific metabolic reprogramming in T cells with particular attention to explain how such metabolic properties are used as an adaptation mechanism. Adaptation of immune cells to the local microenvironment is critical for their persistence and function. Here, Varanasi et al. review the role and types of metabolic adaptation acquired by T cells in tissues and how these adaptations might differ between tissue type, disease state, and functionality of a T cell.
    Keywords:  CD4 T cells; CD8 T cells; T cells; autoimmunity; cancer; fatty acids; hypoxia; immunology; infection; inflammation; metabolism; mitochondria; regulatory T cells
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.013
  11. Biol Direct. 2020 Nov 11. 15(1): 24
    Inter-organelle membrane contact sites: implications for lipid metabolism.
    Jean E Vance.
      This article supplements a recent Perspective by Scorrano et al. in Nature Communications [10 [ (1)]:1287] in which the properties and functions of inter-organelle membrane contact sites were summarized. It is now clear that inter-organelle membrane contact sites are widespread in eukaryotic cells and that diverse pairs of organelles can be linked via unique protein tethers. An appropriate definition of what constitutes an inter-organelle membrane contact site was proposed in the Perspective. In addition, the various experimental approaches that are frequently used to study these organelle associations, as well as the advantages and disadvantages of each of these methods, were considered. The nature of the tethers that link the pairs of organelles at the contact sites was discussed in detail and some biological functions that have been ascribed to specific membrane contact sites were highlighted. Nevertheless, the functions of most types of organelle contact sites remain unclear. In the current article I have considered some of the points raised in the Perspective but have omitted detailed information on the roles of membrane contact sites in biological functions such as apoptosis, autophagy, calcium homeostasis and mitochondrial fusion. Instead, I have provided some background on the initial discovery of mitochondria-endoplasmic reticulum membrane contact sites, and have focussed on the known roles of membrane contact sites in inter-organelle lipid transport. In addition, potential roles for membrane contact sites in human diseases are briefly discussed.
    Keywords:  Cholesterol transport; Endoplasmic reticulum; Membrane contact sites; Mitochondria; Mitochondria-associated membranes (MAM); Phospholipid transport; Plasma membrane
    DOI:  https://doi.org/10.1186/s13062-020-00279-y
  12. Cell Rep. 2020 Nov 10. pii: S2211-1247(20)31364-4. [Epub ahead of print]33(6): 108375
    Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.
    Phillip J White, Amanda L Lapworth, Robert W McGarrah, Lydia Coulter Kwee, Scott B Crown, Olga Ilkayeva, Jie An, Matthew W Carson, Bridgette A Christopher, James R Ball, Michael N Davies, Lilja Kjalarsdottir, Tabitha George, Michael J Muehlbauer, James R Bain, Robert D Stevens, Timothy R Koves, Deborah M Muoio, Joseph T Brozinick, Ruth E Gimeno, M Julia Brosnan, Timothy P Rolph, William E Kraus, Svati H Shah, Christopher B Newgard.
      Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitrogen handling were strongly associated with glycine in correlation analyses. Stable isotope labeling in Zucker fatty rats (ZFRs) shows that glycine acts as a carbon donor for the pyruvate-alanine cycle in a BCAA-regulated manner. Inhibition of the BCAA transaminase (BCAT) enzymes depletes plasma pools of alanine and raises glycine levels. In high-fat-fed ZFRs, dietary glycine supplementation raises urinary acyl-glycine content and lowers circulating triglycerides but also results in accumulation of long-chain acyl-coenzyme As (acyl-CoAs), lower 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in muscle, and no improvement in glucose tolerance. Collectively, these studies frame a mechanism for explaining obesity-related glycine depletion and also provide insight into the impact of glycine supplementation on systemic glucose, lipid, and amino acid metabolism.
    Keywords:  amino acids; metabolism; obesity; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2020.108375
  13. Int J Mol Sci. 2020 Nov 05. pii: E8283. [Epub ahead of print]21(21):
    Insight into the Interactome of Intramitochondrial PKA Using Biotinylation-Proximity Labeling.
    Yasmine Ould Amer, Etienne Hebert-Chatelain.
      Mitochondria are fully integrated in cell signaling. Reversible phosphorylation is involved in adjusting mitochondrial physiology to the cellular needs. Protein kinase A (PKA) phosphorylates several substrates present at the external surface of mitochondria to maintain cellular homeostasis. However, few targets of PKA located inside the organelle are known. The aim of this work was to characterize the impact and the interactome of PKA located inside mitochondria. Our results show that the overexpression of intramitochondrial PKA decreases cellular respiration and increases superoxide levels. Using proximity-dependent biotinylation, followed by LC-MS/MS analysis and in silico phospho-site prediction, we identified 21 mitochondrial proteins potentially targeted by PKA. We confirmed the interaction of PKA with TIM44 using coimmunoprecipitation and observed that TIM44-S80 is a key residue for the interaction between the protein and the kinase. These findings provide insights into the interactome of intramitochondrial PKA and suggest new potential mechanisms in the regulation of mitochondrial functions.
    Keywords:  BioID2; TIM44; mitochondria; protein kinase A; proteomics; serine/threonine phosphoprediction
    DOI:  https://doi.org/10.3390/ijms21218283
  14. Int J Mol Sci. 2020 Nov 06. pii: E8327. [Epub ahead of print]21(21):
    Skeletal Phenotypes Due to Abnormalities in Mitochondrial Protein Homeostasis and Import.
    Tian Zhao, Caitlin Goedhart, Gerald Pfeffer, Steven C Greenway, Matthew Lines, Aneal Khan, A Micheil Innes, Timothy E Shutt.
      Mitochondrial disease represents a collection of rare genetic disorders caused by mitochondrial dysfunction. These disorders can be quite complex and heterogeneous, and it is recognized that mitochondrial disease can affect any tissue at any age. The reasons for this variability are not well understood. In this review, we develop and expand a subset of mitochondrial diseases including predominantly skeletal phenotypes. Understanding how impairment ofdiverse mitochondrial functions leads to a skeletal phenotype will help diagnose and treat patients with mitochondrial disease and provide additional insight into the growing list of human pathologies associated with mitochondrial dysfunction. The underlying disease genes encode factors involved in various aspects of mitochondrial protein homeostasis, including proteases and chaperones, mitochondrial protein import machinery, mediators of inner mitochondrial membrane lipid homeostasis, and aminoacylation of mitochondrial tRNAs required for translation. We further discuss a complex of frequently associated phenotypes (short stature, cataracts, and cardiomyopathy) potentially explained by alterations to steroidogenesis, a process regulated by mitochondria. Together, these observations provide novel insight into the consequences of impaired mitochondrial protein homeostasis.
    Keywords:  mitochondrial disease; protein homeostasis; protein import; skeletal abnormality
    DOI:  https://doi.org/10.3390/ijms21218327
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