title: Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology.
abstract: Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
authors.affiliation: Institute of Biotechnology, FI-00014 University of Helsinki, Finland.|BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.|Max Planck Institute for Heart and Lung Research, Cardiac Development and Remodelling (Department I), Bad Nauheim D-61231, Germany.
authors.forename: Marten
authors.initials: M
authors.lastname: Szibor
authors.affiliation: Institute of Biotechnology, FI-00014 University of Helsinki, Finland.|BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Dhandapani
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.affiliation: Institute of Biotechnology, FI-00014 University of Helsinki, Finland.|BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Kira M
authors.initials: KM
authors.lastname: Holmström
authors.affiliation: Institute of Biotechnology, FI-00014 University of Helsinki, Finland.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Max Planck Institute for Heart and Lung Research, Cardiac Development and Remodelling (Department I), Bad Nauheim D-61231, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Salwig
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main D-60590, Germany.|German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.|Cluster of Excellence "Macromolecular Complexes", Goethe-University, Frankfurt am Main D-60590, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main D-60590, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg D-39118, Germany.
authors.forename: Zemfira
authors.initials: Z
authors.lastname: Gizatullina
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg D-39118, Germany.
authors.forename: Timur
authors.identifier: 0000-0003-1723-1780
authors.initials: T
authors.lastname: Gainutdinov
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.|Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, TU Munich, Emil-Erlenmeyer-Forum 2, Freising-Weihenstephan 85350, Germany.|Member of German Center for Diabetes Research (DZD), Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Institute for Molecular Medicine Finland, FI-00014 University of Helsinki, Finland.
authors.forename: Jatin
authors.initials: J
authors.lastname: Nandania
authors.affiliation: Institute for Molecular Medicine Finland, FI-00014 University of Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: Max Planck Institute for Heart and Lung Research, Cardiac Development and Remodelling (Department I), Bad Nauheim D-61231, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Wietelmann
authors.affiliation: INSERM UMR 1141 and Université Paris 7, Hôpital Robert Debré, Paris 75019, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg D-39118, Germany.|Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
authors.forename: Frank N
authors.initials: FN
authors.lastname: Gellerich
authors.affiliation: Institute of Biotechnology, FI-00014 University of Helsinki, Finland howard.jacobs@helsinki.fi.|BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Howard T
authors.identifier: 0000-0003-1895-6003
authors.initials: HT
authors.lastname: Jacobs
authors.affiliation: Max Planck Institute for Heart and Lung Research, Cardiac Development and Remodelling (Department I), Bad Nauheim D-61231, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
mesh_terms: D000818:Animals; D002938:Ciona intestinalis / Q000201:enzymology; D003486:Cyanides / Q000008:administration & dosage / Q000633:toxicity; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D010829:Physiological Phenomena; D010940:Plant Proteins / Q000378:metabolism*; D020011:Protective Agents / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D000099188:Alternative Oxidase
chemical_list: D003486:Cyanides; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D020011:Protective Agents; D022661:RNA, Untranslated; D000099188:Alternative Oxidase; C110853:Gt(ROSA)26Sor non-coding RNA, mouse
keywords: Alternative oxidase; Mitochondria; Mitochondrial disease; Respiratory chain