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Year of publication
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- English (72)
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Keywords
- Elastic scattering (2)
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- RHIC (2)
- Alternative oxidase (1)
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Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Szibor, Marten ; Dhandapani, Praveen K. ; Dufour, Eric ; Holmström, Kira Margareta ; Zhuang, Yuan ; Salwig, Isabelle ; Wittig, Ilka ; Heidler, Juliana ; Gizatullina, Zemfira ; Gainutdinov, Timur ; Fuchs, Helmut ; Gailus-Durner, Valérie ; Hrabé de Angelis, Martin ; Nandania, Jatin ; Velagapudi, Vidya ; Wietelmann, Astrid ; Rustin, Pierre ; Gellerich, Frank Norbert ; Jacobs, Howard T. ; Braun, Thomas
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.
Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia
(2020)
Szibor, Marten ; Schreckenberg, Rolf ; Gizatullina, Zemfira ; Dufour, Eric ; Wiesnet, Marion ; Dhandapani, Praveen K. ; Debska‐Vielhaber, Grazyna ; Heidler, Juliana ; Wittig, Ilka ; Nyman, Tuula A. ; Gärtner, Ulrich ; Hall, Andrew R. ; Pell, Victoria ; Viscomi, Carlo ; Krieg, Thomas ; Murphy, Michael P. ; Braun, Thomas ; Gellerich, Frank Norbert ; Schlüter, Klaus‐Dieter ; Jacobs, Howard T.
Cardiac ischaemia‐reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re‐perfused post‐ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post‐anoxic heart mitochondria. However, post‐ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up‐regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro‐fibrotic and pro‐apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label‐free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC‐derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.