Mitochondrial regulation of bone homeostasis via mitochondria transfer [RNA-seq]. Mitochondrial regulation of bone homeostasis via mitochondria transfer [RNA-seq]

Recent studies have demonstrated that mitochondria can be transferred between different cell types to control metabolic homeostasis. However, whether the mitochondria transfer network occurred in the skeletal system or regulate skeletal metabolic homeostasis in vivo is not fully elucidated. Herein, we found that osteolineage cells transfer mitochondria to CD11b+ myeloid, B220+ lymphoid and hematopoietic stem and progenitor cells (HSPCs), of which monocytes/macrophages received the most transferred mitochondria. This process was inhibited by GC treatment contributing to the progression of glucocorticoid-induced osteoporosis (GIOP). Further analysis demonstrated that osteolineage cells transfer mitochondria to osteoclastic lineage cells via Miro1 mediated direct contact, and altered the glutathione metabolism, leading to the ferroptosis of osteoclastic lineage cells, thus inhibiting osteoclast activities. These findings revealed an unappreciated mechanism of mitochondrial regulation of skeletal metabolic homeostasis via mitochondria transfer and provide new insights of the mechanism of GIOP progression. Overall design: Comparative gene expression profile analysis of RNA-seq data in BMM, mOCs and OCPs with or without mitochondrial transplant

既往研究已证实，线粒体可在不同细胞类型间转移以调控代谢稳态。然而，线粒体转移网络是否存在于骨骼系统，或是可在体内调控骨骼代谢稳态，目前仍未完全阐明。本研究发现，成骨系细胞可将线粒体转移至CD11b阳性髓系细胞（CD11b+ myeloid）、B220阳性淋巴系细胞（B220+ lymphoid）以及造血干细胞和祖细胞（hematopoietic stem and progenitor cells，HSPCs），其中单核细胞/巨噬细胞获取的线粒体数量最多。该过程可被糖皮质激素（GC）治疗所抑制，进而参与糖皮质激素诱导的骨质疏松症（glucocorticoid-induced osteoporosis，GIOP）的病情进展。进一步分析显示，成骨系细胞通过Miro1介导的直接接触，将线粒体转移至破骨系细胞，并改变其谷胱甘肽代谢，诱导破骨系细胞发生铁死亡，最终抑制破骨细胞活性。本研究揭示了一条此前未被认知的、通过线粒体转移调控骨骼代谢稳态的机制，同时为糖皮质激素诱导的骨质疏松症的病情进展机制提供了新的见解。整体实验设计：对存在或不存在线粒体移植的骨髓单核细胞（Bone Marrow Mononuclear Cells，BMM）、成熟破骨细胞（Mature Osteoclasts，mOCs）及破骨细胞前体细胞（Osteoclast Progenitor Cells，OCPs）的RNA测序（RNA-seq）数据开展比较基因表达谱分析。