title: MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.
abstract: Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany; German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kling
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany; German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Schiller
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany; German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Zeh
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.affiliation: Functional Proteomics, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Strecker
authors.affiliation: Functional Proteomics, Goethe-University Frankfurt, Frankfurt am Main, Germany; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Iulia
authors.initials: I
authors.lastname: Dumitru
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Wenz
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Research Unit Analytical Pathology - Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Janik
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Research Unit Analytical Pathology - Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Raffi
authors.initials: R
authors.lastname: Bekeredjian
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Technical University Munich, Chair of Developmental Genetics, c/o Helmholtz Zentrum München, Neuherberg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Max-Planck-Institute of Psychiatry, Munich, Germany; German Center for Vertigo and Balance Disorders, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; German Center for Vertigo and Balance Disorders, Munich, Germany; Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technical University Munich, Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany; German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environment and Health, Neuherberg, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; German Center for Vertigo and Balance Disorders, Munich, Germany; German Network for Mitochondrial Disorders (mitoNET), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D055785:Gene Knockdown Techniques; D050259:Genes, Mitochondrial; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins; D009206:Myocardium / Q000473:pathology*; D010085:Oxidative Phosphorylation; D016601:RNA-Binding Proteins
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C492007:Mto1 protein, mouse; D016601:RNA-Binding Proteins; D042967:Electron Transport Complex I