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.

氧化磷酸化（OXPHOS）系统的功能障碍是人类疾病的主要原因，细胞后果非常复杂。在这里，我们目前对五种基因敲除小鼠品系的线粒体蛋白质组，细胞转录组和靶向代谢组学进行比较分析，这些品系缺乏线粒体DNA基因表达所需的必需因子，从而导致OXPHOS功能障碍。此外，我们分别描述了控制小鼠和中年基因敲除的时间过程分析中的出生后发育和进行性OXPHOS功能障碍期间蛋白质的顺序变化。非常出乎意料的是，我们发现了一种针对OXPHOS功能障碍的新反应途径，其中线粒体内辅酶Q（泛醌，Q）和Q水平的合成大大降低，这为治疗提供了新的可能性。