Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals.
Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals.
复制标题
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的继发性辅酶Q缺乏症。
DOI：
10.7554/elife.30952
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发表时间：
2017-11-14
期刊：
影响因子：
7.7
通讯作者：
Larsson NG
中科院分区：
文献类型：
--
作者：
Kühl I;Miranda M;Atanassov I;Kuznetsova I;Hinze Y;Mourier A;Filipovska A;Larsson NG
氧化磷酸化（OXPHOS）系统的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，我们比较分析了五种基因敲除小鼠品系的线粒体蛋白质组学、细胞转录组学和靶向代谢组学，这些品系缺乏线粒体DNA基因表达所需的必要因子，导致OXPHOS功能障碍。此外，我们在对照小鼠和中年敲除小鼠的时间过程分析中分别描述了出生后发育过程中的顺序蛋白质变化和进行性OXPHOS功能障碍。出乎意料的是，我们发现了OXPHOS功能障碍的新反应途径，其中线粒体内辅酶Q（泛醌，Q）的合成和Q水平显著降低，为治疗提供了新的可能性。我们广泛的组学分析提供了几种小鼠模型中严重OXPHOS缺陷下基因表达模式改变的高质量资源，这将加深我们的理解，开辟研究途径，并为诊断和治疗提供重要参考。
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.