MTO1-Deficient Mouse Model Mirrors the Human Phenotype Showing Complex I Defect and Cardiomyopathy

• Published in: PloS one Vol. 9; no. 12; p. e114918
• Main Authors: Becker, Lore, Kling, Eva, Schiller, Evelyn, Zeh, Ramona, Schrewe, Anja, Hölter, Sabine M., Mossbrugger, Ilona, Calzada-Wack, Julia, Strecker, Valentina, Wittig, Ilka, Dumitru, Iulia, Wenz, Tina, Bender, Andreas, Aichler, Michaela, Janik, Dirk, Neff, Frauke, Walch, Axel, Quintanilla-Fend, Leticia, Floss, Thomas, Bekeredjian, Raffi, Gailus-Durner, Valérie, Fuchs, Helmut, Wurst, Wolfgang, Meitinger, Thomas, Prokisch, Holger, de Angelis, Martin Hrabě, Klopstock, Thomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.12.2014; Public Library of Science (PLoS)
• Subjects: Acidosis; Analysis; Anesthesia; Animals; Arrhythmia; Biology and Life Sciences; Bradycardia; Cardiology; Cardiomyopathies - genetics; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Cardiomyopathy; Carrier Proteins - genetics; Children; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA, Mitochondrial - genetics; Electron transport chain; Electron Transport Complex I - genetics; Female; Gene Dosage; Gene Knockdown Techniques; Genes; Genes, Mitochondrial; Genetic aspects; Heart; Heart - physiopathology; Heart diseases; Humans; Lactic acidosis; Male; Mammals; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Mutagenesis; Mutation; Myocardial diseases; Myocardium - pathology; Neurology; Optimization; Oxidative Phosphorylation; Pathology; Patients; Phenotypes; Phosphorylation; Physiology; Proteomics; Research and Analysis Methods; Signs and symptoms; Transcription factors; Translation (Genetics)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114918

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.