Kimberly K. Richardson , Gareeballah Osman Adam , Wen Ling , Aaron Warren , Adriana Marques-Carvalho , Jeff D. Thostenson , Kimberly Krager , Nukhet Aykin-Burns , Stephanie D. Byrum , Maria Almeida , Ha-Neui Kim
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Byrum , Maria Almeida , Ha-Neui Kim","doi":"10.1016/j.molmet.2024.102012","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><p>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.</p></div><div><h3>Methods</h3><p>To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of <em>Sirt3</em> in osteoclast lineage and mice with germline deletion of either <em>Sirt3</em> or its known target <em>Pink</em>1.</p></div><div><h3>Results</h3><p>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 <em>Sirt3</em> 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 <em>Sirt3</em> or <em>Atpif1</em> in osteoclast formation and mitochondrial function.</p></div><div><h3>Conclusions</h3><p>Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102012"},"PeriodicalIF":7.0000,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001431/pdfft?md5=a9155d0d1cfd89d98d7d2140e9f088ca&pid=1-s2.0-S2212877824001431-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice\",\"authors\":\"Kimberly K. 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Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice
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.
期刊介绍：
Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction.
We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.
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