Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Nedlands, Western Australia 6009, Australia.
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Cell Rep. 2018 Apr 3;23(1):127-142. doi: 10.1016/j.celrep.2018.03.033.
The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis and energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- and skeletal-muscle-specific knockout mice of the pentatricopeptide repeat domain protein 1, PTCD1, and show that its loss leads to severe cardiomyopathy and premature death. Our detailed transcriptome-wide and functional analyses of these mice enabled us to identify the molecular role of PTCD1 as a 16S rRNA-binding protein essential for its stability, pseudouridylation, and correct biogenesis of the mitochondrial large ribosomal subunit. We show that impaired mitoribosome biogenesis can have retrograde signaling effects on nuclear gene expression through the transcriptional activation of the mTOR pathway and upregulation of cytoplasmic protein synthesis and pro-survival factors in the absence of mitochondrial translation. Taken together, our data show that impaired assembly of the mitoribosome exerts its consequences via differential regulation of mitochondrial and cytoplasmic protein synthesis.
线粒体 RNA 生命周期的调控及其在核糖体生物发生和能量代谢中的作用尚不完全清楚。我们使用 CRISPR/Cas9 技术生成了心脏和骨骼肌特异性 pentatricopeptide repeat domain protein 1（PTCD1）敲除小鼠，并表明其缺失会导致严重的心肌病和过早死亡。我们对这些小鼠进行了详细的转录组范围和功能分析，从而确定了 PTCD1 的分子作用，即作为 16S rRNA 结合蛋白，对于其稳定性、假尿嘧啶化和线粒体大亚基核糖体的正确生物发生是必不可少的。我们表明，受损的线粒体核糖体生物发生会通过 mTOR 途径的转录激活以及细胞质蛋白合成和抗生存因子的上调，对核基因表达产生逆行信号效应，而无需线粒体翻译。总之，我们的数据表明，线粒体核糖体组装的受损会通过差异调节线粒体和细胞质蛋白合成来产生其后果。
