Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.

破骨细胞在骨骼发育和骨折愈合中至关重要，但其代谢状态对这些过程的影响和潜在机制仍不清楚。在这里，通过使用破骨细胞特异性的小型 GTPase Rheb1 敲除小鼠，我们揭示了线粒体呼吸，而不是糖酵解，对于破骨细胞中组织蛋白酶 K (CTSK) 的产生至关重要，并且在雷帕霉素复合物 1 (mTORC1) 的机制靶点中受到 Rheb1 的调节。 ）独立的方式。从机制上讲，我们发现 Rheb1 与线粒体乙酰辅酶 A 的生成协调来促进 CTSK，而破骨细胞中乙酰辅酶 A 的可用性是提高 CTSK 的核心。重要的是，我们的研究结果表明，乙酰辅酶A可用性对CTSK的调节至关重要，可能会带来异常软骨内骨化的风险，这可能是饮酒导致骨折愈合不良的主要原因，靶向Rheb1可以成功地阻止这一过程。这些发现揭示了线粒体在破骨细胞中的关键作用，并为骨疾病提供了有效的治疗机会。