Decreased SIRT3 in aged human mesenchymal stromal/stem cells increases cellular susceptibility to oxidative stress

Abstract

Sirtuin3 (SIRT3) is an important member of the sirtuin family of protein deacetylases that is localized to mitochondria and linked to lifespan extension in organisms ranging from yeast to humans. As aged cells have less regenerative capacity and are more susceptible to oxidative stress, we investigated the effect of ageing on SIRT3 levels and its correlation with antioxidant enzyme activities. Here, we show that severe oxidative stress reduces SIRT3 levels in young human mesenchymal stromal/stem cells (hMSCs). Overexpression of SIRT3 improved hMSCs resistance to the detrimental effects of oxidative stress. By activating manganese superoxide dismutase (MnSOD) and catalase (CAT), SIRT3 protects hMSCs from apoptosis under stress. SIRT3 expression, levels of MnSOD and CAT, as well as cell survival showed little difference in old versus young hMSCs under normal growth conditions, whereas older cells had a significantly reduced capacity to withstand oxidative stress compared to their younger counterparts. Expression of the short 28 kD SIRT3 isoform was higher, while the long 44 kD isoform expression was lower in young myocardial tissues compared with older ones. These results suggest that the active short isoform of SIRT3 protects hMSCs from oxidative injury by increasing the expression and activity of antioxidant enzymes. The expression of this short isoform decreases in cardiac tissue during ageing, leading to a reduced capacity for the heart to withstand oxidative stress.

Sirtuins, aging, and cardiovascular risks

“…In myocardial tissues, SIRT3 reduces levels of ROS by deacetylating the transcription factor FOXO3a, which can then enter the nucleus and bind to the promoter of the genes encoding Mn-SOD and catalase, increasing their expression Sundaresan et al 2009;Tan et al 2008;Wang et al 2014). Other reports also demonstrate that SIRT3 increases the activity of these antioxidant enzymes by the NF-kB pathway Wang et al 2014).…”

“…Moreover, Tseng et al (2014) observed that hypoxia induces SIRT3 to deacetylate FOXO3 and so preserves mitochondrial function and ensures cell survival at endothelial cell level. Wang et al (2014) propose that overexpression of SIRT3 enhances cells' ability to deal with oxidative stress and reduces stress-mediated cell injury by activating Mn-SOD and catalase; although, they did not detect any differences in gene and total protein expression of SIRT3 between young and old cardiac tissues. Klishadi et al (2015) showed that during acute myocardial ischemia reperfusion, when myocardium is exposed to an influx of ROS, SIRT3 protein levels in left ventricular ischemic tissue reduced significantly, indicating that the effect of ischemia on SIRT3 protein level is a local effect limited to the area of ischemia.…”

“…However, they exhibit cardiac hypertrophy at 8 weeks of age, expressed cardiac stress markers, had significantly higher heart/body weights ratio and interstitial fibrosis, and the ability to withstand oxidative stress is significantly reduced compared with wild-type mice (Hafner et al 2010;Sundaresan et al 2009;Wang et al 2014, Loffredo et al 2014. Moreover, cardiomyocytes cultured from SIRT3-deficient hearts produced higher levels of oxidative stress than did myocytes cultured from wild-type hearts (Ishikawa et al 2013;Sundaresan et al 2009).…”

“…Other reports also demonstrate that SIRT3 increases the activity of these antioxidant enzymes by the NF-kB pathway Wang et al 2014). Sundaresan et al (2009) observed that SIRT3 is a negative regulator of cardiac hypertrophy and demonstrated that SIRT3 is a stress-responsive deacetylase that blocks the cardiac hypertrophic response through activation of FOXO3 that in turn activated Mn-SOD2 and catalase, as well as by suppressing ROS-mediated Ras activation and the downstream MAPK/ERK and PI3K/ Akt signalling pathways.…”

“…Of note, the allele completely lacking enhancer activity is virtually absent in males older than 90 years (Bellizzi et al 2005). Another study indicates that SIRT3 is a marker associated with longevity in Italian females and German males (Bellizzi et al 2007;Wang et al 2014). It will be important to carry out comprehensive analyses of SIRT3 polymorphisms to confirm the link between SIRT3 and human longevity.…”