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OBJECTIVES

The mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive.

METHODS

To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of Sirt3 in osteoclast lineage and mice with germline deletion of either Sirt3 or its known target Pink1.

RESULTS

SIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of Sirt3 dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of Sirt3 or Atpif1 in osteoclast formation and mitochondrial function.

CONCLUSIONS

Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.

OBJECTIVES

METHODS

To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of Sirt3 in osteoclast lineage and mice with germline deletion of either Sirt3 or its known target Pink1.

RESULTS

CONCLUSIONS

Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.

目的

随着年龄的增长，破骨细胞中线粒体脱乙酰酶 SIRT3 的增加会导致骨吸收增加和线粒体功能增强；但 SIRT3 如何驱动骨吸收仍不清楚。

方法

为了确定 SIRT3 在破骨细胞线粒体中的作用，我们使用了条件性敲除破骨细胞谱系中 Sirt3 的小鼠和 Sirt3 或其已知靶点 Pink1 种系缺失的小鼠。

结果

SIRT3 以 PINK1 非依赖性的方式刺激破骨细胞中线粒体的质量，促进线粒体活性和破骨细胞成熟和功能，从而导致雌性而不是雄性小鼠的骨丢失。对全球蛋白质组和乙酰基组的定量分析表明，Sirt3 的缺失极大地增加了破骨细胞线粒体蛋白的乙酰化，特别是 ATP 酶抑制因子 1（ATPIF1），这是一种线粒体自噬所必需的蛋白。通过 mdivi-1 抑制线粒体自噬可以重现 Sirt3 缺失或 Atpif1 在破骨细胞形成和线粒体功能中的作用。