MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy

PLoS One. 2014 Dec 15;9(12):e114918. doi: 10.1371/journal.pone.0114918. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology*
  • Carrier Proteins / genetics*
  • DNA, Mitochondrial / genetics
  • Disease Models, Animal
  • Electron Transport Complex I / genetics
  • Female
  • Gene Dosage
  • Gene Knockdown Techniques*
  • Genes, Mitochondrial
  • Heart / physiopathology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Proteins
  • Myocardium / pathology*
  • Oxidative Phosphorylation


  • Carrier Proteins
  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Mto1 protein, mouse
  • Electron Transport Complex I

Grant support

This work was supported by German Federal Ministry of Education and Research (BMBF, Bonn, Germany) grants to the German Network for Mitochondrial Disorders (mitoNET, 01GM1113A-C), the National Genome Research Net (NGFN-Plus, No. 01GS0850, 01GS0851, 01GS0854) the German Center for Vertigo and Balance Disorders (no. 01EO0901) and by EU grants (EUMODIC, LSHG-2006-037188 and Infrafrontier Contracts No. 211404 and 01KX1012 to the GMC). In addition, T. W. is supported by the Emmy-Noether-Programm of the Deutsche Forschungsgemeinschaft, and I.W. by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, Project Z1 (Redox-Proteomics) and by the Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG project EXC 115. W.W. was also funded by the Helmholtz Alliance for Mental Health in an Ageing Society (HelMA) through the Initiative and Network Fund of the Helmholtz Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.