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Dis Model Mech. 2017 Feb 1;10(2):163-171. doi: 10.1242/dmm.027839. Epub 2016 Dec 14.

Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology.

Author information

1
Institute of Biotechnology, FI-00014 University of Helsinki, Finland.
2
BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
3
Max Planck Institute for Heart and Lung Research, Cardiac Development and Remodelling (Department I), Bad Nauheim D-61231, Germany.
4
Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main D-60590, Germany.
5
German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
6
Cluster of Excellence "Macromolecular Complexes", Goethe-University, Frankfurt am Main D-60590, Germany.
7
Leibniz Institute for Neurobiology, Magdeburg D-39118, Germany.
8
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
9
Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, TU Munich, Emil-Erlenmeyer-Forum 2, Freising-Weihenstephan 85350, Germany.
10
Member of German Center for Diabetes Research (DZD), Ingolstaedter Landstrasse 1, Neuherberg 85764, Germany.
11
Institute for Molecular Medicine Finland, FI-00014 University of Helsinki, Finland.
12
INSERM UMR 1141 and Université Paris 7, Hôpital Robert Debré, Paris 75019, France.
13
Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
14
Institute of Biotechnology, FI-00014 University of Helsinki, Finland howard.jacobs@helsinki.fi.

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 AOXRosa26 mouse 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 AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.

KEYWORDS:

Alternative oxidase; Mitochondria; Mitochondrial disease; Respiratory chain

PMID:
28067626
PMCID:
PMC5312010
DOI:
10.1242/dmm.027839
[Indexed for MEDLINE]
Free PMC Article

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