Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis

Mitochondria are the powerhouse of eukaryotic cells, which regulate cell metabolism and differentiation.  Recently, mitochondrial transfer between cells has been shown to direct recipient cell fate. However, it is unclear whether mitochondria can translocate to stem cells and whether this transfer alters stem cell fate. Here, we examined mesenchymal stem cell (MSC) regulation by macrophages in the bone marrow environment. We found that macrophages promote osteogenic differentiation of MSCs by delivering mitochondria to MSCs. However, under osteoporotic conditions, macrophages with altered phenotypes and metabolic statuses release oxidatively damaged mitochondria. The transfer of dysfunctional mitochondria to MSCs triggers a reactive oxygen species burst, which leads to metabolic remodeling. We showed that abnormal metabolism in MSCs is caused by the abnormal succinate accumulation, which is a key factor in abnormal osteogenic differentiation. These results reveal that mitochondrial transfer from macrophages to MSCs allows metabolic crosstalk to regulate bone homeostasis. This mechanism identifies a potential target for the treatment of osteoporosis. The mRNA profiles of bone-derived macrophages of 8 weeks old sham and ovx mice The mRNA profiles of mesenchymal stem cells of 8 weeks mice with no treatment, co-cultured with RAW cells or LPS stimulated RAW cells