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. Epub 2014 Mar 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / adverse effects*
  • Disease Models, Animal
  • Electron Transport Complex III / antagonists & inhibitors*
  • Electron Transport Complex III / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Methacrylates / adverse effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Thiazoles / adverse effects

Substances

  • Antifungal Agents
  • Methacrylates
  • Thiazoles
  • myxothiazol
  • Electron Transport Complex III