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.
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Research Article|
August 09 2013
Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts
Qiuli Liang;
Qiuli Liang
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
‡Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, AL 35233, U.S.A.
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Gloria A. Benavides;
Gloria A. Benavides
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Athanassios Vassilopoulos;
Athanassios Vassilopoulos
§Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.
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David Gius;
David Gius
§Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.
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Victor Darley-Usmar;
Victor Darley-Usmar
1
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
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Jianhua Zhang
Jianhua Zhang
2
*Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
†Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.
‡Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, AL 35233, U.S.A.
2To whom correspondence should be addressed (email zhanja@uab.edu).
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Publisher: Portland Press Ltd
Received:
March 19 2013
Revision Received:
June 13 2013
Accepted:
June 17 2013
Accepted Manuscript online:
June 17 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 454 (2): 249–257.
Article history
Received:
March 19 2013
Revision Received:
June 13 2013
Accepted:
June 17 2013
Accepted Manuscript online:
June 17 2013
Citation
Qiuli Liang, Gloria A. Benavides, Athanassios Vassilopoulos, David Gius, Victor Darley-Usmar, Jianhua Zhang; Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts. Biochem J 1 September 2013; 454 (2): 249–257. doi: https://doi.org/10.1042/BJ20130414
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