Mitochondrial Communication Networks in the Bone Microenvironment: From the Maintenance of Homeostasis to...

Intercellular mitochondrial transfer has recently emerged as an important concept in bone biology, providing a new framework for understanding immune-metabolic cross-talk within the bone microenvironment. This microenvironment is a dynamic system that is both metabolically active and immunologically complex, and its homeostasis relies on finely tuned communication among multiple cellular populations. Increasing evidence suggests that mitochondrial transfer is a key mechanism integrating these diverse signaling networks. In this review, we systematically summarize recent advances in mitochondrial transfer among osteolineage cells, immune cells, and vascular-associated cells, and we further discuss its multiple roles in bone remodeling, tissue repair, and the pathogenesis of osseous diseases. At the mechanistic level, special emphasis is placed on the Mitochondrial Rho GTPase 1 (MIRO1)-mediated mitochondrial transport pathway, through which mitochondria are transferred from osteolineage cells to myeloid cells, thereby driving metabolic reprogramming and modulating susceptibility to ferroptosis, ultimately helping to suppress excessive osteoclastogenesis. From a pathological perspective, dysregulated mitochondrial transfer is increasingly recognized as a common feature across a range of skeletal disorders. In glucocorticoid-induced osteoporosis (GIOP), impairment of MIRO1-dependent mitochondrial transport promotes ferroptosis resistance in osteoclast precursors. In osteoarthritis, aberrant mitochondria accelerate cartilage degeneration by disrupting coenzyme A (CoA) metabolism through Nudix Hydrolase 8 (NUDT8) and subsequently activating the cGAS-STING signaling pathway. In bone metastasis, inflammatory signals triggered by mitochondrial deoxyribonucleic acid (mtDNA) release exhibit both pro-tumorigenic and anti-tumorigenic regulatory effects. Based on these mechanisms, this manuscript also critically evaluates the translational potential of several therapeutic strategies, including mesenchymal stem cell-derived mitochondrial transplantation, nanocarrier delivery systems, and the modulation of tunneling nanotubes. Overall, targeting intercellular mitochondrial transport may offer new therapeutic opportunities for metabolic intervention and immunomodulation in bone diseases.