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.

中文翻译：

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线粒体功能障碍的转录组学和蛋白质组学景观揭示了哺乳动物继发性辅酶 Q 缺乏症

氧化磷酸化 (OXPHOS) 系统功能障碍是人类疾病的主要原因，其细胞后果非常复杂。在这里，我们对缺乏线粒体 DNA 基因表达所需的基本因素的五种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，导致 OXPHOS 功能障碍。此外，我们分别在对照小鼠和中年基因敲除的时间过程分析中描述了出生后发育过程中的连续蛋白质变化和进行性 OXPHOS 功能障碍。非常出乎意料的是，我们发现了一种对 OXPHOS 功能障碍的新反应途径，其中辅酶 Q（泛醌，Q）的线粒体内合成和 Q 水平显着降低，为治疗指明了新的可能性。