Bone organoids and mitochondrial reprogramming

Bone organoids have evolved from simple osteogenic spheroids to increasingly sophisticated systems incorporating vascular networks, bone marrow niches, and multicellular interactions, yet achieving functional maturation remains limited by long-term viability, tissue organization, and metabolic homeostasis. Mitochondrial metabolic homeostasis represents a promising strategy in this regard. Mitochondria serve as both the core of energy metabolism and a vital signaling hub governing bone development, remodeling, and homeostasis. The metabolic switch from glycolysis to oxidative phosphorylation in osteogenic lineage cells, regulated by mitochondrial programming, directly determines bone matrix synthesis and mineralization. This review systematically summarizes the fundamental mechanisms of mitochondria in osteogenic differentiation, calcium signaling, and bone quality control, and highlights how mechanical cues, electromagnetic stimulation, and biomaterial microenvironments drive functional maturation of bone organoids by targeting mitochondria. Bone organoid construction should integrate mitochondrial metabolic requirements across developmental stages, ensuring energy-redox adaptation, organelle quality control, and intercellular metabolic coupling among heterogeneous cell populations. Accordingly, we propose a novel strategy for next-generation bone organoid engineering focused on mitochondrial metabolic microenvironment modulation. Active intervention in cellular energy metabolism can significantly enhance organoid maturity and physiological fidelity, providing a new theoretical framework and technical route for developing high-fidelity bone organoid models.

This review delineates mitochondrial reprogramming as the core driver of bone organoid maturation. We highlight strategies targeting mitochondrial bioenergetics via physical cues, ions, and bioactive factors. Bridging molecular mechanisms with biomaterial design, this framework establishes standardized organoids with homeostatic resilience, advancing clinically translatable in vitro bone models.