Scherbakov Dimitri, Duscha Stefan, Juskeviciene Reda, Restelli Lisa, Frank Stephan, Laczko Endre, Boettger Erik C
University of Zurich, IMM;
University of Zurich, IMM.
RNA. 2020 Dec 1;27(3):265-72. doi: 10.1261/rna.077347.120.
We have recently reported on an experimental model of mitochondrial mistranslation conferred by amino acid exchange V338Y in the mitochondrial ribosomal protein MrpS5. Here we used a combination of RNA-Seq and metabolic profiling of homozygous transgenic MrpS5V338Y/V338Y mice to analyze the changes associated with the V338Y mutation in post-mitotic skeletal muscle. Metabolic profiling demonstrated age-dependent metabolic changes in the mutant V338Y animals, which included enhanced levels of age-associated metabolites and which were accompanied by increased glycolysis, lipid desaturation and eicosanoid biosynthesis, and alterations of the pentose phosphate pathway. In addition, transcriptome signatures of aged V338Y mutant muscle pointed to elevated inflammation, likely reflecting the increased levels of bioactive lipids. Our findings indicate that mistranslation-mediated chronic impairment of mitochondrial function affects specific bioenergetic processes in muscle in an age-dependent manner.
我们最近报道了一种由线粒体核糖体蛋白MrpS5中的氨基酸交换V338Y导致线粒体错误翻译的实验模型。在此，我们结合RNA测序和纯合转基因MrpS5V338Y/V338Y小鼠的代谢谱分析，来分析有丝分裂后骨骼肌中与V338Y突变相关的变化。代谢谱分析表明，突变的V338Y动物存在年龄依赖性代谢变化，包括与年龄相关的代谢物水平升高，同时伴有糖酵解增加、脂质去饱和作用和类花生酸生物合成增加，以及磷酸戊糖途径的改变。此外，老年V338Y突变肌肉的转录组特征表明炎症加剧，这可能反映了生物活性脂质水平的增加。我们的研究结果表明，错误翻译介导的线粒体功能慢性损伤以年龄依赖性方式影响肌肉中的特定生物能量过程。
