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  1. Artikel: Comparative analysis of experimental methods to quantify animal activity in Caenorhabditis elegans models of mitochondrial disease

    Lavorato, Manuela / Mathew, Neal D. / Shah, Nina / Nakamaru-Ogiso, Eiko / Falk, Marni J.

    Journal of visualized experiments. 2021 Apr. 04, , no. 170

    2021  

    Abstract: Caenorhabditis elegans is widely recognized for its central utility as a translational animal model to efficiently interrogate mechanisms and therapies of diverse human diseases. Worms are particularly well-suited for high-throughput genetic and drug ... ...

    Abstract Caenorhabditis elegans is widely recognized for its central utility as a translational animal model to efficiently interrogate mechanisms and therapies of diverse human diseases. Worms are particularly well-suited for high-throughput genetic and drug screens to gain deeper insight into therapeutic targets and therapies by exploiting their fast development cycle, large brood size, short lifespan, microscopic transparency, low maintenance costs, robust suite of genomic tools, mutant repositories, and experimental methodologies to interrogate both in vivo and ex vivo physiology. Worm locomotor activity represents a particularly relevant phenotype that is frequently impaired in mitochondrial disease, which is highly heterogeneous in causes and manifestations but collectively shares an impaired capacity to produce cellular energy. While a suite of different methodologies may be used to interrogate worm behavior, these vary greatly in experimental costs, complexity, and utility for genomic or drug high-throughput screens. Here, the relative throughput, advantages, and limitations of 16 different activity analysis methodologies were compared that quantify nematode locomotion, thrashing, pharyngeal pumping, and/or chemotaxis in single worms or worm populations of C. elegans at different stages, ages, and experimental durations. Detailed protocols were demonstrated for two semi-automated methods to quantify nematode locomotor activity that represent novel applications of available software tools, namely, ZebraLab (a medium-throughput approach) and WormScan (a high-throughput approach). Data from applying these methods demonstrated similar degrees of reduced animal activity occurred at the L4 larval stage, and progressed in day 1 adults, in mitochondrial complex I disease (gas-1(fc21)) mutant worms relative to wild-type (N2 Bristol) C. elegans. This data validates the utility for these novel applications of using the ZebraLab or WormScan software tools to quantify worm locomotor activity efficiently and objectively, with variable capacity to support high-throughput drug screening on worm behavior in preclinical animal models of mitochondrial disease.
    Schlagwörter Caenorhabditis elegans ; animal models ; chemotaxis ; computer software ; drugs ; energy ; genomics ; humans ; larvae ; locomotion ; longevity ; mitochondria ; mutants ; pharynx ; phenotype ; therapeutics
    Sprache Englisch
    Erscheinungsverlauf 2021-0404
    Umfang p. e62244.
    Erscheinungsort Journal of Visualized Experiments
    Dokumenttyp Artikel
    ZDB-ID 2259946-0
    ISSN 1940-087X
    ISSN 1940-087X
    DOI 10.3791/62244
    Datenquelle NAL Katalog (AGRICOLA)

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  2. Artikel ; Online: Comparative Analysis of Experimental Methods to Quantify Animal Activity in Caenorhabditis elegans Models of Mitochondrial Disease.

    Lavorato, Manuela / Mathew, Neal D / Shah, Nina / Nakamaru-Ogiso, Eiko / Falk, Marni J

    Journal of visualized experiments : JoVE

    2021  , Heft 170

    Abstract: Caenorhabditis elegans is widely recognized for its central utility as a translational animal model to efficiently interrogate mechanisms and therapies of diverse human diseases. Worms are particularly well-suited for high-throughput genetic and drug ... ...

    Abstract Caenorhabditis elegans is widely recognized for its central utility as a translational animal model to efficiently interrogate mechanisms and therapies of diverse human diseases. Worms are particularly well-suited for high-throughput genetic and drug screens to gain deeper insight into therapeutic targets and therapies by exploiting their fast development cycle, large brood size, short lifespan, microscopic transparency, low maintenance costs, robust suite of genomic tools, mutant repositories, and experimental methodologies to interrogate both in vivo and ex vivo physiology. Worm locomotor activity represents a particularly relevant phenotype that is frequently impaired in mitochondrial disease, which is highly heterogeneous in causes and manifestations but collectively shares an impaired capacity to produce cellular energy. While a suite of different methodologies may be used to interrogate worm behavior, these vary greatly in experimental costs, complexity, and utility for genomic or drug high-throughput screens. Here, the relative throughput, advantages, and limitations of 16 different activity analysis methodologies were compared that quantify nematode locomotion, thrashing, pharyngeal pumping, and/or chemotaxis in single worms or worm populations of C. elegans at different stages, ages, and experimental durations. Detailed protocols were demonstrated for two semi-automated methods to quantify nematode locomotor activity that represent novel applications of available software tools, namely, ZebraLab (a medium-throughput approach) and WormScan (a high-throughput approach). Data from applying these methods demonstrated similar degrees of reduced animal activity occurred at the L4 larval stage, and progressed in day 1 adults, in mitochondrial complex I disease (gas-1(fc21)) mutant worms relative to wild-type (N2 Bristol) C. elegans. This data validates the utility for these novel applications of using the ZebraLab or WormScan software tools to quantify worm locomotor activity efficiently and objectively, with variable capacity to support high-throughput drug screening on worm behavior in preclinical animal models of mitochondrial disease.
    Mesh-Begriff(e) Animals ; Behavior, Animal ; Caenorhabditis elegans ; Disease Models, Animal ; High-Throughput Screening Assays/methods ; Locomotion ; Mitochondrial Diseases/physiopathology ; Phenotype
    Sprache Englisch
    Erscheinungsdatum 2021-04-04
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
    ZDB-ID 2259946-0
    ISSN 1940-087X ; 1940-087X
    ISSN (online) 1940-087X
    ISSN 1940-087X
    DOI 10.3791/62244
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.

    Lavorato, Manuela / Nakamaru-Ogiso, Eiko / Mathew, Neal D / Herman, Elizabeth / Shah, Nina / Haroon, Suraiya / Xiao, Rui / Seiler, Christoph / Falk, Marni J

    JCI insight

    2022  Band 7, Heft 16

    Abstract: Pathogenic variants in the human F-box and leucine-rich repeat protein 4 (FBXL4) gene result in an autosomal recessive, multisystemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain complex deficiencies with ... ...

    Abstract Pathogenic variants in the human F-box and leucine-rich repeat protein 4 (FBXL4) gene result in an autosomal recessive, multisystemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain complex deficiencies with lactic acidemia. As no FDA-approved effective therapies for this disease exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a PDHc activator, dichloroacetate (DCA), in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts; they showed DCA efficacy in preventing brain death, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1(ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Furthermore, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in humans with FBXL4-/- disease.
    Mesh-Begriff(e) Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Dichloroacetic Acid ; F-Box Proteins/genetics ; F-Box Proteins/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Diseases/drug therapy ; Mitochondrial Diseases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Zebrafish
    Chemische Substanzen F-Box Proteins ; Dichloroacetic Acid (9LSH52S3LQ) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; FbxL4 protein, human (EC 6.3.2.-)
    Sprache Englisch
    Erscheinungsdatum 2022-08-22
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.156346
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: N-acetylcysteine and cysteamine bitartrate prevent azide-induced neuromuscular decompensation by restoring glutathione balance in two novel surf1-/- zebrafish deletion models of Leigh syndrome.

    Haroon, Suraiya / Yoon, Heeyong / Seiler, Christoph / Osei-Frimpong, Bruce / He, Jie / Nair, Rohini M / Mathew, Neal D / Burg, Leonard / Kose, Melis / Venkata, Chavali R M / Anderson, Vernon E / Nakamaru-Ogiso, Eiko / Falk, Marni J

    Human molecular genetics

    2023  Band 32, Heft 12, Seite(n) 1988–2004

    Abstract: SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression and progressive multisystem dysfunction. Here, we describe two novel surf1-/- ...

    Abstract SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression and progressive multisystem dysfunction. Here, we describe two novel surf1-/- zebrafish knockout models generated by CRISPR/Cas9 technology. While gross larval morphology, fertility, and survival into adulthood appeared unaffected, surf1-/- mutants manifested adult-onset ocular anomalies and decreased swimming activity, as well as classical biochemical hallmarks of human SURF1 disease, including reduced complex IV expression and enzymatic activity and increased tissue lactate. surf1-/- larvae also demonstrated oxidative stress and stressor hypersensitivity to the complex IV inhibitor, azide, which exacerbated their complex IV deficiency, reduced supercomplex formation, and induced acute neurodegeneration typical of LS including brain death, impaired neuromuscular responses, reduced swimming activity, and absent heartrate. Remarkably, prophylactic treatment of surf1-/- larvae with either cysteamine bitartrate or N-acetylcysteine, but not other antioxidants, significantly improved animal resiliency to stressor-induced brain death, swimming and neuromuscular dysfunction, and loss of heartbeat. Mechanistic analyses demonstrated cysteamine bitartrate pretreatment did not improve complex IV deficiency, ATP deficiency, or increased tissue lactate but did reduce oxidative stress and restore glutathione balance in surf1-/- animals. Overall, two novel surf1-/- zebrafish models recapitulate the gross neurodegenerative and biochemical hallmarks of LS, including azide stressor hypersensitivity that was associated with glutathione deficiency and ameliorated by cysteamine bitartrate or N-acetylcysteine therapy.
    Mesh-Begriff(e) Animals ; Adult ; Humans ; Leigh Disease/drug therapy ; Leigh Disease/genetics ; Leigh Disease/metabolism ; Cytochrome-c Oxidase Deficiency ; Zebrafish/genetics ; Zebrafish/metabolism ; Acetylcysteine ; Cysteamine/pharmacology ; Azides/metabolism ; Brain Death ; Membrane Proteins/metabolism ; Mitochondrial Proteins/metabolism ; Electron Transport Complex IV/genetics ; Electron Transport Complex IV/metabolism ; Glutathione/metabolism ; Lactates
    Chemische Substanzen Acetylcysteine (WYQ7N0BPYC) ; Cysteamine (5UX2SD1KE2) ; Azides ; Membrane Proteins ; Mitochondrial Proteins ; Electron Transport Complex IV (EC 1.9.3.1) ; Glutathione (GAN16C9B8O) ; Lactates
    Sprache Englisch
    Erscheinungsdatum 2023-02-11
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddad031
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: The Auxiliary NADH Dehydrogenase Plays a Crucial Role in Redox Homeostasis of Nicotinamide Cofactors in the Absence of the Periplasmic Oxidation System in Gluconobacter oxydans NBRC3293.

    Sriherfyna, Feronika Heppy / Matsutani, Minenosuke / Hirano, Kensuke / Koike, Hisashi / Kataoka, Naoya / Yamashita, Tetsuo / Nakamaru-Ogiso, Eiko / Matsushita, Kazunobu / Yakushi, Toshiharu

    Applied and environmental microbiology

    2021  Band 87, Heft 2

    Abstract: Gluconobacter ... ...

    Abstract Gluconobacter oxydans
    Mesh-Begriff(e) Gluconobacter oxydans/enzymology ; Gluconobacter oxydans/genetics ; Gluconobacter oxydans/metabolism ; Homeostasis ; NAD/metabolism ; NADH Dehydrogenase/metabolism ; NADP/metabolism ; Niacinamide/metabolism ; Oxidation-Reduction ; Periplasm/metabolism
    Chemische Substanzen NAD (0U46U6E8UK) ; Niacinamide (25X51I8RD4) ; NADP (53-59-8) ; NADH Dehydrogenase (EC 1.6.99.3)
    Sprache Englisch
    Erscheinungsdatum 2021-01-04
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 223011-2
    ISSN 1098-5336 ; 0099-2240
    ISSN (online) 1098-5336
    ISSN 0099-2240
    DOI 10.1128/AEM.02155-20
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: EPR studies of wild type and mutant Dre2 identify essential [2Fe--2S] and [4Fe--4S] clusters and their cysteine ligands.

    Zhang, Yan / Yang, Chunyu / Dancis, Andrew / Nakamaru-Ogiso, Eiko

    Journal of biochemistry

    2017  Band 161, Heft 1, Seite(n) 67–78

    Abstract: Yeast Dre2 (anamorsin or CIAPIN1) is an essential component for cytosolic Fe/S cluster biosynthesis. The C-terminal domain contains eight evolutionarily conserved cysteine residues, and we previously demonstrated that the yeast Dre2 overexpressed in ... ...

    Abstract Yeast Dre2 (anamorsin or CIAPIN1) is an essential component for cytosolic Fe/S cluster biosynthesis. The C-terminal domain contains eight evolutionarily conserved cysteine residues, and we previously demonstrated that the yeast Dre2 overexpressed in Escherichia coli contains one binuclear ([2Fe-2S]) cluster and one tetranuclear ([4Fe-4S]) cluster. In this study, we replaced each conserved cysteine with alanine and analyzed the effects by Electron Paramagnetic Resonance. Although the C311A mutant lacked both signals, our data clearly suggest that the [2Fe-2S] cluster is ligated to Cys252, Cys263, Cys266 and Cys268, whereas the [4Fe-4S] cluster is ligated to Cys311, Cys314, Cys322 and Cys325. By simulation analysis of the C263A and C322A data, we obtained the g-values for the [4Fe-4S] cluster (g
    Mesh-Begriff(e) Electron Spin Resonance Spectroscopy ; Iron-Sulfur Proteins/chemistry ; Iron-Sulfur Proteins/genetics ; Iron-Sulfur Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae/chemistry ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemische Substanzen Dre2 protein, S cerevisiae ; Iron-Sulfur Proteins ; Recombinant Proteins ; Saccharomyces cerevisiae Proteins
    Sprache Englisch
    Erscheinungsdatum 2017-01
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 218073-x
    ISSN 1756-2651 ; 0021-924X
    ISSN (online) 1756-2651
    ISSN 0021-924X
    DOI 10.1093/jb/mvw054
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency.

    Broxton, Chynna N / Kaur, Prabhjot / Lavorato, Manuela / Ganesh, Smruthi / Xiao, Rui / Mathew, Neal D / Nakamaru-Ogiso, Eiko / Anderson, Vernon E / Falk, Marni J

    JCI insight

    2022  Band 7, Heft 20

    Abstract: Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) ... ...

    Abstract Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.
    Mesh-Begriff(e) Adult ; Animals ; Humans ; Thiamine ; Caenorhabditis elegans/metabolism ; Dihydrolipoamide Dehydrogenase/genetics ; Dihydrolipoamide Dehydrogenase/metabolism ; Thioctic Acid ; Riboflavin ; Carnitine ; Pyruvates ; Adenosine Triphosphate
    Chemische Substanzen Thiamine (X66NSO3N35) ; Dihydrolipoamide Dehydrogenase (EC 1.8.1.4) ; Thioctic Acid (73Y7P0K73Y) ; Riboflavin (TLM2976OFR) ; Carnitine (S7UI8SM58A) ; Pyruvates ; Adenosine Triphosphate (8L70Q75FXE)
    Sprache Englisch
    Erscheinungsdatum 2022-10-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.156222
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Apoptosis-inducing Factor (AIF) and Its Family Member Protein, AMID, Are Rotenone-sensitive NADH:Ubiquinone Oxidoreductases (NDH-2).

    Elguindy, Mahmoud M / Nakamaru-Ogiso, Eiko

    The Journal of biological chemistry

    2015  Band 290, Heft 34, Seite(n) 20815–20826

    Abstract: Apoptosis-inducing factor (AIF) and AMID (AIF-homologous mitochondrion-associated inducer of death) are flavoproteins. Although AIF was originally discovered as a caspase-independent cell death effector, bioenergetic roles of AIF, particularly relating ... ...

    Abstract Apoptosis-inducing factor (AIF) and AMID (AIF-homologous mitochondrion-associated inducer of death) are flavoproteins. Although AIF was originally discovered as a caspase-independent cell death effector, bioenergetic roles of AIF, particularly relating to complex I functions, have since emerged. However, the role of AIF in mitochondrial respiration and redox metabolism has remained unknown. Here, we investigated the redox properties of human AIF and AMID by comparing them with yeast Ndi1, a type 2 NADH:ubiquinone oxidoreductase (NDH-2) regarded as alternative complex I. Isolated AIF and AMID containing naturally incorporated FAD displayed no NADH oxidase activities. However, after reconstituting isolated AIF or AMID into bacterial or mitochondrial membranes, N-terminally tagged AIF and AMID displayed substantial NADH:O₂ activities and supported NADH-linked proton pumping activities in the host membranes almost as efficiently as Ndi1. NADH:ubiquinone-1 activities in the reconstituted membranes were highly sensitive to 2-n-heptyl-4-hydroxyquinoline-N-oxide (IC₅₀ = ∼1 μm), a quinone-binding inhibitor. Overexpressing N-terminally tagged AIF and AMID enhanced the growth of a double knock-out Escherichia coli strain lacking complex I and NDH-2. In contrast, C-terminally tagged AIF and NADH-binding site mutants of N-terminally tagged AIF and AMID failed to show both NADH:O₂ activity and the growth-enhancing effect. The disease mutant AIFΔR201 showed decreased NADH:O₂ activity and growth-enhancing effect. Furthermore, we surprisingly found that the redox activities of N-terminally tagged AIF and AMID were sensitive to rotenone, a well known complex I inhibitor. We propose that AIF and AMID are previously unidentified mammalian NDH-2 enzymes, whose bioenergetic function could be supplemental NADH oxidation in cells.
    Mesh-Begriff(e) Apoptosis Inducing Factor/genetics ; Apoptosis Inducing Factor/metabolism ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Cloning, Molecular ; Electron Transport Complex I/genetics ; Electron Transport Complex I/metabolism ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Escherichia coli Proteins/genetics ; Gene Expression ; Gene Library ; Genetic Complementation Test ; Humans ; Isoenzymes/deficiency ; Isoenzymes/genetics ; Kinetics ; Membrane Proteins/deficiency ; Membrane Proteins/genetics ; Mitochondrial Membranes ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mutation ; NAD/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
    Chemische Substanzen AIFM1 protein, human ; ferroptosis suppressor protein 1, human ; Apoptosis Inducing Factor ; Apoptosis Regulatory Proteins ; Escherichia coli Proteins ; Isoenzymes ; Membrane Proteins ; Mitochondrial Proteins ; NuoH protein, E coli ; Recombinant Proteins ; NAD (0U46U6E8UK) ; Electron Transport Complex I (EC 7.1.1.2)
    Sprache Englisch
    Erscheinungsdatum 2015-06-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M115.641498
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Radiation activates myeloperoxidase (MPO) to generate active chlorine species (ACS) via a dephosphorylation mechanism - inhibitory effect of LGM2605.

    Mishra, Om P / Popov, Anatoliy V / Pietrofesa, Ralph A / Hwang, Wei-Ting / Andrake, Mark / Nakamaru-Ogiso, Eiko / Christofidou-Solomidou, Melpo

    Biochimica et biophysica acta. General subjects

    2020  Band 1864, Heft 7, Seite(n) 129548

    Abstract: Background: Radiation exposure of tissues is associated with inflammatory cell influx. Myeloperoxidase (MPO) is an enzyme expressed in granulocytes, such as neutrophils (PMN) and macrophages, responsible for active chlorine species (ACS) generation. The ...

    Abstract Background: Radiation exposure of tissues is associated with inflammatory cell influx. Myeloperoxidase (MPO) is an enzyme expressed in granulocytes, such as neutrophils (PMN) and macrophages, responsible for active chlorine species (ACS) generation. The present study aimed to: 1) determine whether exposure to γ-irradiation induces MPO-dependent ACS generation in murine PMN; 2) elucidate the mechanism of radiation-induced ACS generation; and 3) evaluate the effect of the synthetic lignan LGM2605, known for ACS scavenging properties.
    Methods: MPO-dependent ACS generation was determined by using hypochlorite-specific 3'-(p-aminophenyl) fluorescein (APF) and a highly potent MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), and confirmed in PMN derived from MPO
    Results: γ-radiation increased MPO-dependent ACS generation dose-dependently in human MPO and in wild-type murine PMN, but not in PMN from MPO
    Conclusions: We demonstrate that γ-radiation induces MPO-dependent generation of ACS, which is dependent, at least in part, by protein tyrosine and Ser/Thr dephosphorylation and is reduced by LGM2605. This study identified for the first time a novel protein dephosphorylation-dependent mechanism of radiation-induced MPO activation.
    Mesh-Begriff(e) Animals ; Butylene Glycols/pharmacology ; Chlorine/metabolism ; Glucosides/pharmacology ; Mice ; Mice, Inbred C57BL ; Peroxidase/metabolism ; Phosphorylation
    Chemische Substanzen Butylene Glycols ; Glucosides ; LGM2605 ; Chlorine (4R7X1O2820) ; Peroxidase (EC 1.11.1.7)
    Sprache Englisch
    Erscheinungsdatum 2020-02-05
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbagen.2020.129548
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel: Radiation activates myeloperoxidase (MPO) to generate active chlorine species (ACS) via a dephosphorylation mechanism - inhibitory effect of LGM2605

    Mishra, Om P / Popov, Anatoliy V / Pietrofesa, Ralph A / Hwang, Wei-Ting / Andrake, Mark / Nakamaru-Ogiso, Eiko / Christofidou-Solomidou, Melpo

    Biochimica et biophysica acta. 2020 July, v. 1864, no. 7

    2020  

    Abstract: Radiation exposure of tissues is associated with inflammatory cell influx. Myeloperoxidase (MPO) is an enzyme expressed in granulocytes, such as neutrophils (PMN) and macrophages, responsible for active chlorine species (ACS) generation. The present ... ...

    Abstract Radiation exposure of tissues is associated with inflammatory cell influx. Myeloperoxidase (MPO) is an enzyme expressed in granulocytes, such as neutrophils (PMN) and macrophages, responsible for active chlorine species (ACS) generation. The present study aimed to: 1) determine whether exposure to γ-irradiation induces MPO-dependent ACS generation in murine PMN; 2) elucidate the mechanism of radiation-induced ACS generation; and 3) evaluate the effect of the synthetic lignan LGM2605, known for ACS scavenging properties.MPO-dependent ACS generation was determined by using hypochlorite-specific 3′-(p-aminophenyl) fluorescein (APF) and a highly potent MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), and confirmed in PMN derived from MPO⁻/⁻ mice. Radiation-induced MPO activation was determined by EPR spectroscopy and computational analysis identified tyrosine, serine, and threonine residues near MPO's active site.γ-radiation increased MPO-dependent ACS generation dose-dependently in human MPO and in wild-type murine PMN, but not in PMN from MPO⁻/⁻ mice. LGM2605 decreased radiation-induced, MPO-dependent ACS. Protein tyrosine phosphatase (PTP) and protein serine/threonine phosphatase (PSTP) inhibitors decreased the radiation-induced increase in ACS. Peroxidase cycle results demonstrate that tyrosine phosphorylation blocks MPO Compound I formation by preventing catalysis on H₂O₂ in the active site of MPO. EPR data demonstrate that γ-radiation increased tyrosyl radical species formation in a dose-dependent manner.We demonstrate that γ-radiation induces MPO-dependent generation of ACS, which is dependent, at least in part, by protein tyrosine and Ser/Thr dephosphorylation and is reduced by LGM2605. This study identified for the first time a novel protein dephosphorylation-dependent mechanism of radiation-induced MPO activation.
    Schlagwörter active sites ; benzoic acids ; catalytic activity ; chlorine ; dephosphorylation ; dose response ; electron paramagnetic resonance spectroscopy ; fluorescein ; gamma radiation ; humans ; hydrazides ; hydrogen peroxide ; lignans ; macrophages ; mice ; myeloperoxidase ; neutrophils ; peroxidase ; phosphorylation ; protein-tyrosine-phosphatase ; serine ; threonine ; tissues ; tyrosine
    Sprache Englisch
    Erscheinungsverlauf 2020-07
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel
    ZDB-ID 840755-1
    ISSN 0304-4165
    ISSN 0304-4165
    DOI 10.1016/j.bbagen.2020.129548
    Datenquelle NAL Katalog (AGRICOLA)

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