Open Access

Marten Szibor, Praveen K. Dhandapani, Eric Dufour, Kira Margareta Holmström, Yuan Zhuang, Isabelle Salwig, Ilka Wittig, Juliana Heidler, Zemfira Gizatullina, Timur Gainutdinov, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Jatin Nandania, Vidya Velagapudi, Astrid Wietelmann, Pierre Rustin, Frank Norbert Gellerich, Howard T. Jacobs, Thomas Braun

• 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.