SIRT3 Is a Stress-Responsive Deacetylase in Cardiomyocytes That Protects Cells from Stress-Mediated Cell Death by Deacetylation of Ku70

Abstract

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 ϳ44-kDa long form and a ϳ28-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.

SIRT3 protects from hypoxia and staurosporine-mediated cell death by maintaining mitochondrial membrane potential and intracellular pH

“…Previously, protection from apoptotic cell death due to an SIRT3-increased expression has been described in cardiomyocytes where Ku70, a DNA-repair factor and inhibitor of Bax-mediated apoptosis, is deacetylated by SIRT3 hindering the translocation of Bax to mitochondria. 35 Herewith, we propose an alternative or parallel mechanism for SIRT3 protection. SIRT3 by increasing CA VB catalytic activity and by inhibiting HKII mitochondrial binding reduces the glycolytic rate and decreases intracellular acidification.…”

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

“…In addition to amplifying IL1β and ROS signalling, SIRT3 may also influence beta cell function and mass by other mechanisms, including deacetylation of Ku70 [46] and glutamate dehydrogenase [20,47], and the regulation of ATP production [41].…”

Roles of SIRT3 in heart failure: from bench to bedside

“…However, a controversial report argued that endogenous SIRT3 is located in the nucleus and translocates into mitochondria under cellular stress or following over-expression of SIRT3 (Scher et al, 2007). In the study of Sundaresan et al (2008), full length SIRT3 localized to the mitochondria, nucleus, and cytoplasm, while the short form localized exclusively to the mitochondria of the mouse cardiomyocytes. These results were confirmed by recent studies (Chen et al, 2015b).…”

“…Since loss of cardiomyocytes due to cell death is the main cause of cardiac dysfunction following MI, inhibition of apoptosis or necrosis is a critical necessity. It has been shown that SIRT3 is able to protect cardiomyocytes from apoptosis induced by genotoxic and oxidative stress through an extra-mitochondrial pathway by deacetylating Ku-70 (Sundaresan et al, 2008). Sundaresan et al (2008) examined the cell survival by subjecting cardiomyocytes to the stress of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or H 2 O 2 .…”

“…It has been shown that SIRT3 is able to protect cardiomyocytes from apoptosis induced by genotoxic and oxidative stress through an extra-mitochondrial pathway by deacetylating Ku-70 (Sundaresan et al, 2008). Sundaresan et al (2008) examined the cell survival by subjecting cardiomyocytes to the stress of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or H 2 O 2 . They observed a reduction of apoptosis mediated by Bax which is hindered by Ku-70 binding, and confirmed that increased binding of Bax and Ku-70 is due to the deacetylation of Ku-70 by SIRT3.…”