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The Role of Mitochondrial Deacetylase SIRT3: Delivering Benefits of Calorie Restriction and Promoting Adult Stem Cell Function

  • Author(s): Brown, Katharine van Dyke
  • Advisor(s): Chen, Danica
  • et al.
Abstract

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

metabolic context.

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

HSCs.

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.

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