Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany; Department of Cell Biology, Institute of Integrative Biology of the Cell (I2BC) UMR9198, CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France
Proteomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
Irina Kuznetsova
Harry Perkins Institute of Medical Research, The University of Western Australia, Nedlands, Australia; School of Molecular Sciences, The University of Western Australia, Crawley, Australia
Yvonne Hinze
Proteomics Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
Arnaud Mourier
The Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, Bordeaux, France
Harry Perkins Institute of Medical Research, The University of Western Australia, Nedlands, Australia; School of Molecular Sciences, The University of Western Australia, Crawley, Australia
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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.
