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

Gareeballah Osman Adam; Kimberly K Richardson; Ankita Chalke; Qiang Fu; Jeff D Thostenson; Hutomo Tanoto; Yuxiao Zhou; Nukhet Aykin-Burns; Ha-Neui Kim

doi:10.1093/jbmrpl/ziaf092

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

JBMR Plus. 2025 May 19;9(7):ziaf092. doi: 10.1093/jbmrpl/ziaf092. eCollection 2025 Jul.

Authors

Gareeballah Osman Adam^{1

2}, Kimberly K Richardson^{1

2}, Ankita Chalke^{1

2}, Qiang Fu^{1

2}, Jeff D Thostenson^{1

3}, Hutomo Tanoto⁴, Yuxiao Zhou⁴, Nukhet Aykin-Burns⁵, Ha-Neui Kim^{1

2}

Affiliations

¹ Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
² Division of Endocrinology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
³ Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
⁴ Department of Mechanical Engineering, Texas A&M University, College Station, TX 77840, United States.
⁵ Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.

Abstract

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 Sirt3 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 Sirt3 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 Sirt3 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.

Keywords: ROS; SIRT3; bone resorption; ionizing radiation; mitochondria; osteoclast.