Bidirectional mitochondrial transfer in the osteoimmune microenvironment: mechanisms and therapeutic perspectives

The maintenance of bone homeostasis relies on a dynamic interplay between skeletal and immune cells. Traditional paracrine and receptor-based models cannot fully explain the reciprocal communication that underpins bone remodeling. Intercellular mitochondrial transfer refers to the movement of one or more mitochondria from a donor cell to a recipient cell. In this review, this term is distinguished from the intercellular transfer of mitochondrial components, which is described separately according to the nature of the transferred material. Mitochondrial transfer occurs via three primary pathways: direct contact, extracellular vesicles (EVs), and free mitochondrial release. Emerging evidence positions intercellular mitochondrial transfer as a novel form of organelle-level communication in the regulation of bone homeostasis. Although mitochondrial transfer has been documented extensively in bone-related pathologies, its context-dependent, bidirectional regulatory roles within the osteoimmune microenvironment have yet to be systematically elucidated. To address this gap, we systematically summarize the molecular mechanisms governing mitochondrial transfer within the osteoimmune microenvironment, with a particular emphasis on the bidirectional communication network between skeletal cells and immune cells. We further discuss its dual pathophysiological roles in bone-related disorders and highlight emerging therapeutic strategies based on mitochondrial transfer. We also propose a novel framework for bone remodeling interventions that centers on precise control of both transfer directionality and mitochondrial quality. This conceptual integration provides a theoretical foundation and translational guidance for precision regenerative medicine and immunometabolic therapies in bone-related diseases.