title: A mouse model of mitochondrial complex III dysfunction induced by myxothiazol.
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.
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden.
authors.forename: Mina
authors.initials: M
authors.lastname: Davoudi
authors.affiliation: Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kallijärvi
authors.affiliation: Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Marjavaara
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden.
authors.forename: Heike
authors.initials: H
authors.lastname: Kotarsky
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hansson
authors.affiliation: Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185, Sweden; Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014, Finland.
authors.forename: Per
authors.initials: P
authors.lastname: Levéen
authors.affiliation: 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.
authors.forename: Vineta
authors.initials: V
authors.lastname: Fellman
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008689:Methacrylates / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D013844:Thiazoles / Q000009:adverse effects
chemical_list: D000935:Antifungal Agents; D008689:Methacrylates; D013844:Thiazoles; C030517:myxothiazol; D014450:Electron Transport Complex III
keywords: BCS1L; Chemical inhibition of complex III; Experimental hepatopathy; Mitochondria; Mouse model; Respiratory chain complex III