The Role of Mitochondrial Deacetylase SIRT3: Delivering Benefits of Calorie Restriction and Promoting Adult Stem Cell Function
With the increase in the aging population, there has been a growing interest in
understanding the process of age-related physical decline and increased disease risk.
Research in model organisms has shown that aging, far from being a spontaneous
development, is actually a controlled process, with molecular mechanisms that can alter
the pace of cellular and tissue decline. The aim of this dissertation work was to gain
insight into the molecular mechanisms that can control this aging rate.
We found that SIRT3, a mitochondrial NAD+-dependent deacetylase, performs a vital role
during calorie restriction in mice to decrease oxidative damage in tissues. These results
led us to identify superoxide dismutase 2(SOD2) as a target protein of SIRT3, and
confirmed that SIRT3 can deacetylate SOD2 at two critical lysine residues (K53 and K89).
Deacetylation of these residues on SOD2 leads to an increase in SOD2 detoxification
activity. Furthermore, SOD2 is more deacetylated in the tissues of mice on calorie
restriction, but this effect is abrogated in mice that are deficient for SIRT3. These results
led us to develop a model whereby calorie restriction upregulates SIRT3 expression and
activity, leading to an increased deacetylation of SOD2. The increased activity level of
the deacetylated SOD2 has the effect of decreasing oxidative damage in tissues.
Concomitantly, we found that SIRT3 is required for the switch to fatty acid utilization during
calorie restriction. SIRT3 KO mice on calorie restriction have reduced beta- oxidation, lower
long chain-acyl CoA dehydrogenase activity (LCAD), and a preference for glucose uptake
and carbohydrate metabolism. Our findings indicate that other molecular adaptations that
occur during calorie restriction are insufficient to compensate for a SIRT3 deficiency in this
We also present our findings that SIRT3 is highly expressed in hematopoietic stem cells
(HSCs) as compared to differentiated hematopoietic cells, which led us to explore the role
SIRT3 was playing in this stem cell population. Our results indicate that SIRT3 is required as a stress-responsive protein that can protect stem cell function during conditions of
oxidative stress. These conditions can include serial transplant, chemical treatment, or
the increased oxidative stress associated with aging. Furthermore, we show that SIRT3
expression is decreased in HSCs from aged mice, and enforced expression of SIRT3 can
improve the function of aged HSCs, suggesting the potential for rejuvenation of aged
Our studies confirm the role that SIRT3 plays in protecting cells and tissues from oxidative
stress, as well as offer. Although to date, no lifespan data has been published on SIRT3
KO mice, the results presented here indicate that a relatively shortened lifespan or
healthspan would not be unexpected. These findings also open avenues for
understanding the role of SIRT3 in stem cell biology, both other stem cell types, and
potentially in human stem cell systems.