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Title: A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

Highlights: • Reversible chemical inhibition of complex III in wild type mouse. • Myxothiazol causes decreased complex III activity in mouse liver. • The model is useful for therapeutic trials to improve mitochondrial function. - Abstract: Myxothiazol is a respiratory chain complex III (CIII) inhibitor that binds to the ubiquinol oxidation site Qo of CIII. It blocks electron transfer from ubiquinol to cytochrome b and thus inhibits CIII activity. It has been utilized as a tool in studies of respiratory chain function in in vitro and cell culture models. We developed a mouse model of biochemically induced and reversible CIII inhibition using myxothiazol. We administered myxothiazol intraperitoneally at a dose of 0.56 mg/kg to C57Bl/J6 mice every 24 h and assessed CIII activity, histology, lipid content, supercomplex formation, and gene expression in the livers of the mice. A reversible CIII activity decrease to 50% of control value occurred at 2 h post-injection. At 74 h only minor histological changes in the liver were found, supercomplex formation was preserved and no significant changes in the expression of genes indicating hepatotoxicity or inflammation were found. Thus, myxothiazol-induced CIII inhibition can be induced in mice for four days in a row without overtmore » hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.« less
Authors:
 [1] ; ;  [2] ; ;  [1] ;  [1] ;  [3] ;  [1] ;  [3] ;  [3]
  1. Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden)
  2. Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland)
  3. (Finland)
Publication Date:
OSTI Identifier:
22416386
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 446; Journal Issue: 4; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL CULTURES; COMPLEXES; DOSES; ELECTRON TRANSFER; ELECTROPHORESIS; EOSIN; GENES; HEMATOXYLIN; HISTOLOGY; IN VITRO; INFLAMMATION; INHIBITION; LIPIDS; LIVER; MICE; MITOCHONDRIA; OXIDATION; PROTEINS; SULFUR