Cover Story Current Issue

At the turn of the 19th century, Ivan Pavlov and others established that the secretion of pancreatic juice is induced upon entry of acidic chyme into the duodenum, and that this pancreatic secretion is accelerated by infusion of hydrochloric acid (HCL) into the stomach. Pavlov hypothesized that secretion of pancreatic juice is induced via a neuronal reflex; however, pancreatic secretion prevailed in dogs following denervation of the intestinal vagal and splanchnic nerves, indicating that pancreatic secretion must be mediated by another, as yet unknown, mechanism.

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Current Issue

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

Kimberly K. Richardson, Gareeballah Osman Adam, Wen Ling, Aaron Warren, ... Ha-Neui Kim

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.

 

Articles in Press

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

Kimberly K. Richardson, Gareeballah Osman Adam, Wen Ling, Aaron Warren, ... Ha-Neui Kim

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.

 

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Diabetes Conference 
22-24. Sep, Munich

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