Background:
Osteoporosis is a common skeletal disorder characterized by excessive bone loss, leading to increased fragility and an increased risk of fractures. Osteoclasts, the bone-resorbing cells, are widely recognized as central players in this process. Osteoclast-mediated bone resorption relies critically on two organelles: lysosomes, which degrade the bone matrix, and mitochondria, which provide the necessary energy. Iron, acting as a key connector between lysosomes and mitochondria, has emerged as an essential regulator of osteoclast activity. However, the complex interplay between lysosomes, mitochondria, and iron in osteoclasts and in the context of osteoporosis remain poorly understood.

Significance of this review:
This review focuses on the vital interconnections among lysosomes, iron metabolism, and mitochondria in osteoclasts. Lysosomes not only serve as the primary site for bone matrix degradation but also regulate intracellular iron mobilization. Mitochondria rely on iron to maintain energy metabolism, meeting the high metabolic demands of osteoclasts. Iron thus functions as a central mediator linking these two organelles.

Based on the pivotal roles of lysosomes and mitochondria in osteoclast-mediated bone resorption, we propose the concept of a “lysosome–iron–mitochondria axis.” Within this axis, lysosomes convert ferric iron to ferrous iron in their specialized acidic environment, enabling mitochondrial utilization for energy production and reactive oxygen species (ROS) generation, which in turn drives osteoclast bone-resorbing activity. The review systematically summarizes: the regulatory role of lysosomes in iron metabolism (Figure a), the critical contribution of iron to mitochondrial function (Figure a), and the crosstalk between lysosomes and mitochondria in iron handling (Figure b). Additionally, we highlight the roles of key cellular signaling pathways—calcium signaling, mTORC1, HIF, and AMPK—in modulating this lysosome–iron–mitochondria axis (Figure c). Finally, we discuss strategies and potential applications for precisely targeting this axis to regulate osteoclast activity and bone metabolism.

Future Perspectives:
The newly defined lysosome–iron–mitochondria axis offers a comprehensive framework to understand osteoclast metabolic regulation. Targeting this axis could pave the way for novel therapeutic strategies for osteoporosis and related metabolic bone disorders. Modulating lysosomal acidification, optimizing iron availability, or enhancing lysosome–mitochondria communication may provide new avenues for drug development. This organelle-centric perspective not only deepens our understanding of bone resorption mechanisms but also carries translational potential. In conditions of excessive osteoclast activity, such as osteoporosis, inhibition of this axis could reduce bone resorption; conversely, in diseases where osteoclast dysfunction impairs bone homeostasis, like osteopetrosis, restoring this axis may help promote balanced bone remodeling and regeneration.

The complete study is accessible via DOI: 10.34133/research.0840