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

By Marten Szibor, Praveen K. Dhandapani, Eric Dufour, Kira M. Holmstrom, Yuan Zhuang, Isabelle Salwig, Ilka Wittig, Juliana Heidler, Zemfira Gizatullina, Timur Gainutdinov, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Jatin Nandania, Vidya Velagapudi, Astrid Wietelmann, Pierre Rustin, Frank N. Gellerich, Howard T. Jacobs, Thomas Braun and German Mouse Clinic Consortium

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 AOX(Rosa26) 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 AOX(Rosa26) mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo

Topics: Mitochondria, Mitochondrial disease, Respiratory chain, Alternative oxidase, ALTERNATIVE-OXIDASE, NATIVE ELECTROPHORESIS, PROTEIN COMPLEXES, ACUTE LETHALITY, HUMAN-CELLS, MICE, MITOCHONDRIA, DROSOPHILA, DEFECTS, DEFICIENCY, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine, Mitochondria, Mitochondrial disease, Respiratory chain, Alternative oxidase, ALTERNATIVE-OXIDASE, NATIVE ELECTROPHORESIS, PROTEIN COMPLEXES, ACUTE LETHALITY, HUMAN-CELLS, MICE, MITOCHONDRIA, DROSOPHILA, DEFECTS, DEFICIENCY, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine
Publisher: Company of Biologists Ltd
Year: 2017
OAI identifier: oai:helda.helsinki.fi:10138/178992
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