TY - JOUR
T1 - Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3
AU - Kwon, Sanghoon
AU - Seok, Sunmi
AU - Yau, Peter
AU - Li, Xiaoling
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - Funding Information:
This work was supported by National Institutes of Health Grants DK062777 and DK095842 and a Basic Science Award 1-16-IBS-156 from the American Diabetes Association (to J. K. K.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2017/10/20
Y1 - 2017/10/20
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M117.778720
DO - 10.1074/jbc.M117.778720
M3 - Article
C2 - 28808064
AN - SCOPUS:85032012251
SN - 0021-9258
VL - 292
SP - 17312
EP - 17323
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -