WBSCR16 Deficiency Drives Adaptive Metabolic Flexibility Via Impaired Mitochondrial 16S rRNA Maturation. WBSCR16 Deficiency Drives Adaptive Metabolic Flexibility Via Impaired Mitochondrial 16S rRNA Maturation

Mitochondrial rRNAs play important roles in regulating mtDNA-encoded gene expression and energy metabolism subsequently. However, the proteins that regulate mitochondrial 16S rRNA processing remain poorly understood. Herein, we generated adipose-specific Wbscr16-/- mice and cells, both of which exhibited dramatic mitochondrial changes. Subsequently, WBSCR16 was identified as a 16S rRNA-binding protein essential for the cleavage of 16S rRNA-mt-tRNALeu, facilitating 16S rRNA processing and mitochondrial ribosome assembly. Additionally, WBSCR16 recruited RNase P subunit MRPP3 to nascent 16S rRNA and assisted in this specific cleavage. Furthermore, evidence showed that adipose-specific Wbscr16 ablation promotes energy wasting via lipid preference in brown adipose tissue, leading to excess energy expenditure and resistance to obesity. In contrast, overexpression of WBSCR16 upregulated 16S rRNA processing and induced a preference for glucose utilization in both transgenic mouse models and cultured cells. These findings suggest that WBSCR16 plays essential roles in mitochondrial 16S rRNA processing in mammals, and is the key mitochondrial protein to balance glucose and lipid metabolism. Overall design: Comparative gene expression profiling analysis of RNA-seq data for Floxed brown adipose tissues and WBSCR16 knockout tissues (Floxed and AWBSCR16 KO).

线粒体核糖体RNA（mitochondrial rRNAs）在调控线粒体DNA（mtDNA）编码的基因表达及后续能量代谢过程中发挥关键作用。然而，目前对于调控线粒体16S核糖体RNA（mitochondrial 16S rRNA）加工的相关蛋白仍知之甚少。本研究构建了脂肪组织特异性Wbscr16敲除小鼠与细胞模型，两类模型均呈现出显著的线粒体异常改变。后续研究鉴定出WBSCR16是一种可结合16S rRNA的蛋白质，其对于16S rRNA-线粒体转运RNA亮氨酸（mt-tRNALeu）的切割过程不可或缺，可有效促进16S rRNA加工与线粒体核糖体组装。此外，WBSCR16能够招募核糖核酸酶P（RNase P）亚基MRPP3至新生16S rRNA，辅助完成该特异性切割反应。进一步实验证实，脂肪组织特异性Wbscr16敲除可通过促使棕色脂肪组织优先利用脂质，引发过度能量消耗并产生肥胖抵抗，进而导致能量消耗异常。与之相反，在转基因小鼠模型与培养细胞中过表达WBSCR16可上调16S rRNA加工过程，并诱导细胞及组织偏向利用葡萄糖。上述研究结果表明，WBSCR16在哺乳动物线粒体16S rRNA加工过程中发挥核心作用，是维持糖脂代谢平衡的关键线粒体蛋白质。整体实验设计：针对野生型floxed棕色脂肪组织与WBSCR16敲除组织的RNA测序（RNA-seq）数据开展比较基因表达谱分析（样本分为floxed对照组与WBSCR16敲除组）。