Mitochondria, long regarded primarily as cellular powerhouses, are increasingly recognized as multifaceted regulators of tissue development and regeneration. Beyond supplying ATP, they modulate signaling pathways, control redox balance, and actively participate in intercellular communication through dynamic morphological changes and extracellular release of their components. These noncanonical functions have profound implications for organ development, tissue repair, and age-related degeneration. In this context, our recent findings highlight unexpected and essential roles of mitochondria in both bone and muscle biology.
In bone, mitochondrial components are abundantly detected in the extracellular matrix, suggesting active secretion and functional roles beyond bioenergetics. We identified that mature osteoblasts directly release mitochondria and mitochondrial-derived vesicles (MDVs), which promote the differentiation and maturation of osteoprogenitors. Using Col1a1-Cre; mito-GFP reporter mice, in which GFP is specifically expressed in osteoblast mitochondria, we demonstrated that osteogenic induction stimulates mitochondrial fragmentation and donut formation, followed by extracellular secretion via CD38/cADPR signaling. Importantly, supplementation with secreted mitochondria or MDVs, as well as enhancing mitochondrial fission through Opa1 knockdown, Fis1 overexpression, or bongkrekic acid treatment, accelerated osteoblast maturation, whereas mitochondrial fusion promotion impaired bone formation. These findings suggest that mitochondrial morphology in mature osteoblasts is adapted for extracellular secretion, and secreted mitochondria and MDVs are critical promoters of bone formation.
In skeletal muscle, mitochondria-associated antioxidant enzymes, particularly peroxiredoxins (PRDX3 and PRDX5), are emerging as key regulators of myogenesis and muscle homeostasis. We found that loss of PRDX5 impaired mitochondrial function and transport, reduced Rhot1 and Trak1 expression, and caused defective nuclear spreading, leading to clustered myonuclei. In vivo, Prdx5-/- mice exhibited diminished mitochondrial potential, exercise intolerance, and impaired regeneration. Moreover, dual deficiency of PRDX3 and PRDX5 in Prdx3-/-; Prdx5-/- mice accelerated muscle aging, characterized by early reductions in muscle mass and strength, along with increased oxidative stress–induced atrophy. Therefore, enhancing PRDX activity may represent a therapeutic strategy against age-related muscle degeneration.
Together, our findings uncover unprecedented roles of mitochondria in bone and muscle: as extracellular mediators of osteogenesis and as regulators of nuclear organization and aging in skeletal muscle. These results highlight mitochondria as multifaceted players in tissue regeneration, extending well beyond their canonical role in energy production.