Document Detail


Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts.
MedLine Citation:
PMID:  23767918     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics.
Authors:
Qiuli Liang; Gloria A Benavides; Athanassios Vassilopoulos; David Gius; Victor Darley-Usmar; Jianhua Zhang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Biochemical journal     Volume:  454     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-08-12     Completed Date:  2013-11-04     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  249-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Autophagy* / drug effects
Caspase 3 / metabolism
Cells, Cultured
Culture Media / metabolism
Embryo, Mammalian / cytology
Energy Metabolism* / drug effects
Enzyme Activation / drug effects
Fibroblasts / metabolism*
MAP Kinase Signaling System* / drug effects
Mice
Mice, Knockout
Microtubule-Associated Proteins / metabolism
Oxidative Phosphorylation* / drug effects
Phosphorylation / drug effects
Protein Isoforms / metabolism
Protein Processing, Post-Translational / drug effects
Sirtuin 3 / genetics,  metabolism*
TOR Serine-Threonine Kinases / metabolism
Tubulin Modulators / pharmacology
Grant Support
ID/Acronym/Agency:
R01 NS064090/NS/NINDS NIH HHS; R01-NS064090/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Culture Media; 0/MAP1LC3 protein, mouse; 0/Microtubule-Associated Proteins; 0/Protein Isoforms; 0/Sirt3 protein, mouse; 0/Tubulin Modulators; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.5.1.-/Sirtuin 3

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