Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively. Very unexpectedly, we identify a new response pathway to OXPHOS dysfunction in which the intra-mitochondrial synthesis of coenzyme Q (ubiquinone, Q) and Q levels are profoundly decreased, pointing towards novel possibilities for therapy. Our extensive omics analyses provide a high-quality resource of altered gene expression patterns under severe OXPHOS deficiency comparing several mouse models, that will deepen our understanding, open avenues for research and provide an important reference for diagnosis and treatment.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The health status of the animals is specific pathogen free according to the Federation of the European Laboratory Animal Science Association (FELASA) recommendations. All animal procedures were conducted in accordance with European, national and institutional guidelines and protocols (no.: AZ.: 84-02.05.50.15.004 and AZ.: 84-02.04.2015.A103) were approved by the Landesamt für Natur, Umwelt und Verbraucherschutz, Nordrhein-Westfalen, Germany.
- Agnieszka Chacinska, Reviewing Editor, University of Warsaw, Poland
- Received: August 1, 2017
- Accepted: November 6, 2017
- Accepted Manuscript published: November 14, 2017 (version 1)
© 2017, Kühl et al.
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