Sirtuin-3 promotes osteoclast maturation and bone loss by regulating mitochondrial ROS production during ionizing radiation exposure

Ionizing radiation (IR) exposure leads to mitochondrial alterations in osteoclasts and osteoblasts, contributing to musculoskeletal disintegration. Despite this, the mechanisms controlling mitochondrial activity in bone cells during IR exposure-associated bone disorders remain underexplored. Sirtuin-3 (SIRT3), a NAD-dependent mitochondrial deacetylase, is essential for the enhanced mitochondrial function in osteoclasts and the increased bone resorption observed in osteoporosis. However, it is still unclear whether and how SIRT3 drives IR exposure-induced bone disorders. Here, we show that deletion of <i>Sirt3</i> greatly attenuated the IR exposure-induced loss of bone mass in young adult mice. This effect was associated with impaired osteoclast maturation and function, thus suppressing excessive bone resorption. IR exposure also increased mitochondrial activity and ROS production in osteoclasts. Deletion of <i>Sirt3</i> abrogated these effects of IR exposure. The levels of mitochondrial superoxide dismutase 2 (SOD2), a major component of the metabolic machinery that handles ROS in the mitochondrial matrix, were significantly increased in osteoclasts by RANKL with an identical pattern as SIRT3. Deacetylation of lysine 68 of SOD2 enhanced the formation of giant osteoclasts and increased mitochondrial ROS production, mimicking the effects of IR exposure. Inhibition of mitochondrial ROS production via Mito-TEMPO recapitulated the effects of <i>Sirt3</i> deletion on osteoclast maturation and mitochondrial activity during IR exposure. These findings demonstrate that SIRT3 plays an essential role in IR exposure-induced bone resorption by promoting deacetylation in osteoclast mitochondria. Understanding the mechanisms of mitochondrial quality control and protein acetylation in osteoclasts could pave the way for developing novel strategies to counteract IR exposure-associated bone disorders.