Free mitochondrial transfer enhances bone regeneration through cathepsin H mediated cysteine cycle

Background Mitochondria, as crucial organelles in eukaryotic cells, are deeply involved in cellular energy metabolism and biogenesis. Currently, mitochondria have been found to transfer between cells and regulate a range of cellular functions and research has found that mitochondrial transfer has been shown to play an important role in regulating bone homeostasis. Methods Laser confocal imaging was used to confirm the occurrence of mitochondrial transfer between cells. JC-1 staining explains the state of free mitochondria in receptor cells. In order to reveal the relationship between the state and function of free mitochondria, osteogenic induction, Western blotting, flow cytometry, and in vivo experiments were conducted. RNA seq is used to analyze changes in cells. Different inhibitors were used to verify the specific mechanism of action of free mitochondrial transfer. Results Free mitochondrial transfer can improve the function of receptor cells through lysosomal pathway. Free mitochondria are degraded by cathepsin H (Ctsh) in lysosomes and release a large amount of cysteine after entering the receptor cells. In this process, the existence of membrane potential of free mitochondria is not critical. Cysteine, as the most important raw material for glutathione synthesis, can enhance the number and function of mitochondria in receptor cells. Conclusion Our study demonstrates that free mitochondrial transfer promotes bone regeneration by increasing cysteine supply, and provides innovative insights for understanding mitochondrial transfer.