The effects of mitochondrial damages under stress or during aging on osteocytes networks homeostasis. The effects of mitochondrial damages under stress or during aging on osteocytes networks homeostasis

Using oligomycin A-treated MLO-Y4 cells and primary murine aging osteocytes as a model of cells with mitochondrial dysfunction, it is demonstrated that when mitochondria are damaged, osteocytes tend to release signaling compounds including adenosine diphosphate. We identified that the nucleotide membrane receptors P2Y2 and P2Y6 transduced the ADP signal to Mfn2, a critical regulator of osteocyte mitochondrial transfer. Whole RNA sequencing (RNA-seq) analysis of mouse cortical bone showed that mitochondrial metabolism is impaired in aged osteocytes, and there are more extracellular nucleotides released into the matrix in cortical bone in aged mice as compared to that in young mice. Aging decreases expression levels of P2Y2/P2Y6 and Mfn2. Overall design: This study profiled the transcriptional changes of osteocytes during aging or under stress conditions.

本研究以寡霉素A（oligomycin A）处理的MLO-Y4细胞与原代衰老小鼠骨细胞作为线粒体功能障碍细胞模型，证实线粒体受损时，骨细胞倾向于释放包括二磷酸腺苷（adenosine diphosphate）在内的信号化合物。本研究鉴定发现，核苷酸膜受体P2Y2与P2Y6可将ADP信号转导至Mfn2——后者是调控骨细胞线粒体转移的关键因子。对小鼠皮质骨开展的全转录组RNA测序（RNA-seq）分析显示，衰老骨细胞的线粒体代谢存在损伤；与年轻小鼠相比，衰老小鼠皮质骨的细胞外基质中释放的胞外核苷酸水平显著更高。衰老会下调P2Y2/P2Y6与Mfn2的表达水平。实验整体设计：本研究分析了骨细胞在衰老或应激条件下的转录组变化。