Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals.
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.
['Kühl|Inge|I|http://orcid.org/0000-0003-4797-0859', 'Miranda|Maria|M|http://orcid.org/0000-0002-0817-553X', 'Atanassov|Ilian|I|https://orcid.org/0000-0001-8259-2545', 'Kuznetsova|Irina|I|', 'Hinze|Yvonne|Y|', 'Mourier|Arnaud|A|', 'Filipovska|Aleksandra|A|http://orcid.org/0000-0002-6998-8403', 'Larsson|Nils-Göran|NG|http://orcid.org/0000-0001-5100-996X']
D000818:Animals D001259:Ataxia D020869:Gene Expression Profiling D055442:Metabolome D018345:Mice, Knockout D008928:Mitochondria D028361:Mitochondrial Diseases D018908:Muscle Weakness D020543:Proteome D014451:Ubiquinone
Cellular transcriptome mouse OXPHOS dysfunction Coenzyme Q biosynthesis Mitochondrial gene expression Mitoproteome One-carbon pathway biochemistry cell biology