Lysosome–Iron–Mitochondria Axis in Osteoclasts: Iron as a Central Player

Osteoporosis, a widespread skeletal disorder, arises from excessive bone loss, heightening fragility and fracture risk. Osteoclasts, the major type of bone-resorbing cells, are believed to contribute to this loss. Osteoclast bone resorption relies on 2 important organelles: lysosomes for matrix degradation and mitochondria for energy supply. Iron, a critical linker between lysosomes and mitochondria, has emerged as a critical mediator of osteoclast activity. However, the intricate interplay between lysosomes, mitochondria, and iron in osteoclasts and osteoporosis remains poorly understood. This review aims to bridge this knowledge gap by examining the lysosome–iron–mitochondria axis in osteoclasts. Firstly, we summarized the modulatory function of lysosomes in iron metabolism and iron’s involvement in lysosomal biogenesis and function. Next, we conducted a comprehensive analysis on the contribution of iron in mitochondrial function and its implications for osteoclast activity. Subsequently, we highlighted emerging insights into the lysosome–mitochondria crosstalk in iron metabolism. Finally, we delved into the discussion of how dysregulation of this lysosome–iron–mitochondria axis may drive osteoporosis progression and proposed innovative therapeutic strategies targeting this axis to mitigate osteoclast-mediated bone loss.