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J Biol Chem. 2017 Oct 20;292(42):17312-17323. doi: 10.1074/jbc.M117.778720. Epub 2017 Aug 14.

Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3.

Author information

1
From the Department of Molecular and Integrative Physiology and.
2
the Proteomics Center, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 and.
3
Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
4
From the Department of Molecular and Integrative Physiology and jongsook@illinois.edu.

Abstract

Sirtuin 3 (SIRT3) deacetylates and regulates many mitochondrial proteins to maintain health, but its functions are depressed in aging and obesity. The best-studied sirtuin, SIRT1, counteracts aging- and obesity-related diseases by deacetylating many proteins, but whether SIRT1 has a role in deacetylating and altering the function of SIRT3 is unknown. Here we show that SIRT3 is reversibly acetylated in the mitochondria and unexpectedly is a target of SIRT1 deacetylation. SIRT3 is hyperacetylated in aged and obese mice, in which SIRT1 activity is low, and SIRT3 acetylation at Lys57 inhibits its deacetylase activity and promotes protein degradation. Adenovirus-mediated expression of SIRT3 or an acetylation-defective SIRT3-K57R mutant in diet-induced obese mice decreased acetylation of mitochondrial long-chain acyl-CoA dehydrogenase, a known SIRT3 deacetylation target; improved fatty acid β-oxidation; and ameliorated liver steatosis and glucose intolerance. These SIRT3-mediated beneficial effects were not observed with an acetylation-mimic SIRT3-K57Q mutant. Our findings reveal an unexpected mechanism for SIRT3 regulation via SIRT1-mediated deacetylation. Improving mitochondrial SIRT3 functions by inhibiting SIRT3 acetylation may offer a new therapeutic approach for obesity- and aging-related diseases associated with mitochondrial dysfunction.

KEYWORDS:

acetylation; aging; deacetylase; fatty acid oxidation; liver steatosis; mitochondria; obesity; post-translational modification; sirtuin

PMID:
28808064
PMCID:
PMC5655509
DOI:
10.1074/jbc.M117.778720
[Indexed for MEDLINE]
Free PMC Article

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