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<p>Acyl-CoA dehydrogenase-9 (ACAD9) is classically known for its role in mitochondrial fatty acid β-oxidation and complex I assembly. Here, we identify ACAD9 deficiency as a clinically relevant risk factor for fragility fractures and reveal a previously unrecognized cytosolic function of ACAD9 in suppressing osteoclast differentiation, thereby protecting against osteoporosis. Mechanistically, while preserving its canonical mitochondrial role in complex I assembly, we find that ACAD9 also facilitates the formation of respiratory chain supercomplexes. Notably, in the cytosol, ACAD9 competitively binds to TRAF6, preventing its interaction with the E2 ubiquitin-conjugating complex UBC13/UEV1A, and thereby blocking K63-linked polyubiquitination and downstream activation of the RANK/TRAF6/TAK1/NFATc1 signaling cascade. Additionally, ACAD9 promotes K48-linked polyubiquitination of TRAF6, leading to its proteasomal degradation. Osteoclast-specific <i>Acad9</i> knockout mice exhibit increased osteoclast numbers and decreased bone mass. These findings uncover a novel extramitochondrial function of ACAD9 in regulating osteoclast differentiation and maturation, and offer potential therapeutic insights for targeting osteoclast hyperactivity in osteoporosis.</p><p></p>

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Moonlighting cytosolic function of ACAD9: suppression of TRAF6-mediated osteoclastogenesis and protection against osteoporosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月26日

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  • Mimi Wang,
  • Chao Yuan,
  • Yi Zhang,
  • Mengmeng Peng,
  • Yundie Liu,
  • Ruolin Liu,
  • Zhaode Feng,
  • Zhiwei Yang,
  • Hao Li,
  • Zhongbo Liu,
  • Ying Cheng

摘要

Acyl-CoA dehydrogenase-9 (ACAD9) is classically known for its role in mitochondrial fatty acid β-oxidation and complex I assembly. Here, we identify ACAD9 deficiency as a clinically relevant risk factor for fragility fractures and reveal a previously unrecognized cytosolic function of ACAD9 in suppressing osteoclast differentiation, thereby protecting against osteoporosis. Mechanistically, while preserving its canonical mitochondrial role in complex I assembly, we find that ACAD9 also facilitates the formation of respiratory chain supercomplexes. Notably, in the cytosol, ACAD9 competitively binds to TRAF6, preventing its interaction with the E2 ubiquitin-conjugating complex UBC13/UEV1A, and thereby blocking K63-linked polyubiquitination and downstream activation of the RANK/TRAF6/TAK1/NFATc1 signaling cascade. Additionally, ACAD9 promotes K48-linked polyubiquitination of TRAF6, leading to its proteasomal degradation. Osteoclast-specific Acad9 knockout mice exhibit increased osteoclast numbers and decreased bone mass. These findings uncover a novel extramitochondrial function of ACAD9 in regulating osteoclast differentiation and maturation, and offer potential therapeutic insights for targeting osteoclast hyperactivity in osteoporosis.