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Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice

Authors :
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
Source :
Molecular Metabolism, Vol 88, Iss , Pp 102012- (2024)
Publication Year :
2024
Publisher :
Elsevier, 2024.

Abstract

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.

Details

Language :
English
ISSN :
22128778
Volume :
88
Issue :
102012-
Database :
Directory of Open Access Journals
Journal :
Molecular Metabolism
Publication Type :
Academic Journal
Accession number :
edsdoj.b1c37c9a2bd346bf8f32edeea3efc5b8
Document Type :
article
Full Text :
https://doi.org/10.1016/j.molmet.2024.102012