【Gene of the Week】Metabolism & Cardiovascular Diseases - SIRT3

The SIRT3 gene plays an important role in the pathogenesis of metabolic, cardiovascular, and neurodegenerative diseases. In this article, we review the functionality of SIRT3 and explore its role in metabolism & cardiovascular disease studies - bringing together insights to SIRT3 gene research developments to provide inspiration for your scientific innovation.

Background Information – SIRT3 Gene

Note: the mark ‘√’represents the corresponding models that available from Cyagen AI Knockout Mouse Model eBank.

Overview of SIRT3 Gene Research

The SIRT3 gene encodes a protein belonging to the sirtuin family of class III histone deacetylases, which exhibits nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. Human sirtuins have a range of molecular functions and have been discovered to be important proteins in processes such as aging, stress resistance, and metabolic regulation. In addition to protein deacetylation, studies have shown that human sirtuin can also act as an intracellular regulatory protein with single adenosine diphosphate (ADP)-ribosyltransferase (ART) activity. There are 3 types of sirtuins in mitochondria - SIRT3, SIRT4, and SIRT5 - which participate in the regulation of metabolic processes. Endogenous SIRT3 is a soluble protein in the mitochondrial matrix. Many publications have shown a strong connection between mitochondrial function, aging, and carcinogenesis.

Found exclusively in mitochondria, the SIRT3 protein eliminates reactive oxygen species, inhibits apoptosis, and prevents the formation of cancer cells. Additionally, SIRT3 has widespread implications, across nuclear gene expression, cancer, cardiovascular disease, neuroprotection, aging, and metabolic control. SIRT3 is associated with aging and Non-Alcoholic Fatty Liver Disease. Some of the pathways related to SIRT3 include organelle biogenesis and maintenance, as well as signaling events mediated by class III histone deacetylases (HDAC). Gene Ontology (GO) annotations related to the SIRT3 gene include enzyme binding and NAD+ ADP-ribosyltransferase activity.

Table 1: Effects of SIRT3 regulation on metabolic disorders and related pathways.

Table 2: Effects of SIRT3 regulation on cardiovascular disease and related pathways.

Table 3: Effects of SIRT3 regulation on neurodegenerative diseases and related pathways.

Oncology Studies

In tumor samples from women with breast cancer, SIRT3 expression was lower than in normal breast tissue. The SIRT3 knockout (KO) mouse model can be used to study the development of ER-/PR-positive breast tumors, as indicated by the immunohistochemistry (IHC) results included below. In addition, the mice can be used to study the role of fatty acid oxidation in diabetes, cardiovascular disease, steatosis, fasting, cold exposure, and longevity.

Figure 1: SIRT3 is a mouse tumor suppressor in mitochondria

A) SIRT3 knockout mice develop mammary tumors. The total number of mammary tumors in SIRT3 wild-type (+/+) and SIRT3 knockout (-/-) mice at 24 months of age

C) Representative H&E stain slides of mammary tissue in a SIRT3 wild-type (+/+) and a SIRT3 knockout (-/-)  mouse that developed a mammary tumor.

E) IHC staining for ER and PR status was performed on paraffin sections of mammary tumors from the seven tumor-bearing SIRT3^−/− mice. ER/PR levels were characterized as absent (−), intermediate (+), or strongly present throughout the sample (++).

SIRT3 Expression in Human Tissues

Relative expression of SIRT3 gene mRNA is comparable across humans and mice, with expression across numerous tissues. Generally, the highest expression of SIRT3 mRNA occurs in the brain, heart, and kidney tissue. However, the expression of SIRT3 mRNA appears to differ in the liver and ovary tissues between humans and mice – although more work needs to be done to normalize such mRNA expression data for an accurate comparison.

References：

1. Schwer B, North BJ, Frye RA, Ott M, Verdin E (August 2002). "The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase". Journal of Cell Biology. 158 (4): 647–57. 

2. Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP (October 2002). "SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13653–58. 

3. Gomes P , Viana S D , Nunes S , et al. The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders[J]. Agng Research Reviews, 2019, 57:100983.

4. Zhang J, Xiang H, Rong-Rong He R, Liu B (2020). "Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target". Theranostics (journal) 10 (18): 8315–8342. 

5. Scher MB, Vaquero A, Reinberg D (April 2007). "SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress". Genes Dev. 21 (8): 920–28.