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Jacobs, H.T.* ; Szibor, M.* ; Rathkolb, B. ; da Silva Buttkus, P. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Calzada-Wack, J. ; Dragano, N.R.V. ; Garrett, L. ; Gerlini, R. ; Hölter, S.M. ; Klein-Rodewald, T. ; Kraiger, M. ; Leuchtenberger, S. ; Marschall, S. ; Östereicher, M.A. ; Pfannes, K. ; Sanz-Moreno, A. ; Seisenberger, C. ; Spielmann, N. ; Stoeger, C. ; Wurst, W. ; Fuchs, H. ; Hrabě de Angelis, M. ; Gailus-Durner, V.

AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease.

Biochim. Biophys. Acta-Mol. Basis Dis. 1869:166760 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
The alternative oxidase, AOX, provides a by-pass of the cytochrome segment of the mitochondrial respiratory chain when the chain is unavailable. AOX is absent from mammals, but AOX from Ciona intestinalis is benign when expressed in mice. Although non-protonmotive, so does not contribute directly to ATP production, it has been shown to modify and in some cases rescue phenotypes of respiratory-chain disease models. Here we studied the effect of C. intestinalis AOX on mice engineered to express a disease-equivalent mutant of Uqcrh, encoding the hinge subunit of mitochondrial respiratory complex III, which results in a complex metabolic phenotype beginning at 4-5 weeks, rapidly progressing to lethality within a further 6-7 weeks. AOX expression delayed the onset of this phenotype by several weeks, but provided no long-term benefit. We discuss the significance of this finding in light of the known and hypothesized effects of AOX on metabolism, redox homeostasis, oxidative stress and cell signaling. Although not a panacea, the ability of AOX to mitigate disease onset and progression means it could be useful in treatment.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Alternative Oxidase ; Complex Iii ; Growth Impairment ; Hyperglycemia ; Insulin Sensitivity ; Mitochondrial Disease; Cytochrome-c-oxidase; Alternative-oxidase; Respiratory-chain; Bc(1) Complex; Mitochondria; Expression; Protein; Apoptosis; Mutation; Defects
ISSN (print) / ISBN 0925-4439
e-ISSN 1878-2434
Journal Biochimica et Biophysica Acta - Molecular Basis of Disease
Quellenangaben Volume: 1869, Issue: 7, Pages: , Article Number: 166760 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)
Grants European Research Council (ERC)
Academy of Finland
European Research Council
German Center for Diabetes Research (DZD)
German Federal Ministry of Education and Research