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  2. A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

  • Biochem Biophys Res Commun. 2014 Apr 18;446(4):1079-84. doi: 10.1016/j.bbrc.2014.03.058.
Mina Davoudi 1 Jukka Kallijärvi 2 Sanna Marjavaara 2 Heike Kotarsky 1 Eva Hansson 1 Per Levéen 3 Vineta Fellman 4
Affiliations

Affiliations

  • 1 Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden.
  • 2 Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland.
  • 3 Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden; Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland.
  • 4 Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden; Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland; Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki 00029, Finland. Electronic address: Vineta.Fellman@med.lu.se.
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 overt hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.

Keywords

BCS1L; Chemical inhibition of complex III; Experimental hepatopathy; Mitochondria; Mouse model; Respiratory chain complex III.

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