SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70.
There are seven SIRT isoforms in mammals, with diverse biological functions including gene regulation, metabolism, and apoptosis. Among them, SIRT3 is the only sirtuin whose increased expression has been shown to correlate with an extended life span in humans. In this study, we examined the role of SIRT3 in murine cardiomyocytes. We found that SIRT3 is a stress-responsive deacetylase and that its increased expression protects myocytes from genotoxic and oxidative stress-mediated cell death. We show that, like human SIRT3, mouse SIRT3 is expressed in two forms, a approximately 44-kDa long form and a approximately 28-kDa short form. Whereas the long form is localized in the mitochondria, nucleus, and cytoplasm, the short form is localized exclusively in the mitochondria of cardiomyocytes. During stress, SIRT3 levels are increased not only in mitochondria but also in the nuclei of cardiomyocytes. We also identified Ku70 as a new target of SIRT3. SIRT3 physically binds to Ku70 and deacetylates it, and this promotes interaction of Ku70 with the proapoptotic protein Bax. Thus, under stress conditions, increased expression of SIRT3 protects cardiomyocytes, in part by hindering the translocation of Bax to mitochondria. These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations.
Sundaresan
Nagalingam R
NR
University of Chicago Medical Center, Committee on Cellular and Molecular Physiology, Biological Science Division, University of Chicago, Chicago, Illinois 60637, USA.
Samant
Sadhana A
SA
Pillai
Vinodkumar B
VB
Rajamohan
Senthilkumar B
SB
Gupta
Mahesh P
MP
D000107:Acetylation; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism*; D001681:Biological Assay; D016923:Cell Death; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology* / Q000648:ultrastructure; D018384:Oxidative Stress; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D056566:Sirtuin 3; D037761:Sirtuins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; C000607791:SIRT3 protein, rat; C525046:Sirt3 protein, mouse; D051028:bcl-2-Associated X Protein; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins; D006655:Histone Deacetylases; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen