Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

Abstract

Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.

Keywords: Age-related disease; Cancer; Mitochondrial homeostasis; SIRT3; SIRT3 activator; SIRT3 inhibitor.

Figure 1

The pros and cons of SIRT3 in type 2 diabetes, aging, neurodegeneration, liver disease, inflammatory disease, cardiovascular disease, cancer, kidney disease and obesity.

Figure 2

Structure and function of SIRT3. (A) The conserved enzymatic core of SIRT3 contains a NAD⁺ binding domain, a zinc binding motif and the binding sites of SIRT3 substrates. (B) The modification by SIRT3 is deacetylate its substrate with a NAD⁺ dependent manner. (C) Typical SIRT3 regulated biological function. SIRT3 assists mitochondria to maintain metabolic stability including the homeostasis of TCA cycle, Urea cycle, Amino acid metabolism, Fatty acid oxidation, ETC/OXPHOS, ROS detoxification and mitochondrial dynamics. Moreover, SIRT3 is closely related with oxidative stress, apoptosis, autophagy and inflammation.

Figure 3

SIRT3 in age-related disease. Age-related diseases are always accompanied with a decline in mitochondrial function, high oxidative stress and accumulation of toxic proteins. SIRT3 activates a range of substrates by deacetylation to promote mitochondrial function, enhance ATP production, accelerate ROS clearance, and maintain mitochondrial metabolic homeostasis. In addition, SIRT3 can activate mitophagy to accelerate mitochondrial renewal. It is worth noting that SIRT3 also inhibits the production of misfolded proteins and accelerates their clearance. The pink proteins represent the substrates of SIRT3. Gray circles represent acetylation modifications.

Figure 4

SIRT3 in cancer. SIRT3 plays a two-sided role in cancer. In most cancers, SIRT3 plays a tumor suppressor role. On the one hand, SIRT3 can maintain the stability of the cancer genome and inhibit carcinogenesis. On the other hand, SIRT3 inhibits the Warburg effect of cancer to inhibit the development of tumors. In addition, SIRT3 can inhibit tumor proliferation and metastasis. SIRT3 induced apoptosis and autophagy also involved in this progress. However, in some colorectal cancers and lung cancers, SIRT3 plays an oncogenic role by promoting proliferation and metastasis via deacetylation of specific substrates. The pink protein represents the substrate for SIRT3. Gray circles represent acetylation modifications.

Figure 5

SIRT3 in heart disease. Heart disease often manifests as dysfunction of cardiomyocytes, such as local hypoxia, death of cardiomyocytes, fibrosis, and the like. Dysfunction of cardiomyocytes ultimately leads to myocardial ischemia, cardiac hypertrophy, heart failure. SIRT3 can increase the mitochondrial function of cardiomyocytes and increase energy production by deacetylating its substrate. In addition, SIRT3 can deacetylate its substrates to inhibit AKT-mTOR/ERK1/2/TGF-β-smad3-induced myocardial fibrosis. During this process, SIRT3 can also activate GSK-3β to contribute to myocardial fibrosis inhibition. SIRT3 also directly inhibits cardiomyocytes apoptosis. Last but not the least, SIRT3 can eliminate ROS and activate mitophagy to inhibit cardiac remodeling. The pink protein represents the substrate for SIRT3. Gray circles represent acetylation modifications.

Figure 6

SIRT3 in metabolic disease. The body's energy metabolism, glycometabolism, fatty acid metabolism, and amino acid metabolism are generally imbalanced in metabolic diseases. SIRT3 can regulate a series of substrates to maintain the metabolic balance and stability of different organisms, and inhibit the occurrence and development of metabolic diseases. In addition, SIRT3 can inhibit the fibrosis of each organ and protect its normal function. It is worth noting that SIRT3 is also involved in the fight against viral infections and inflammatory responses. The pink protein represents the substrate for SIRT3. Gray circles represent acetylation modifications.

Figure 7

The NAD⁺-dependent SIRT3 deacetylation reaction process, SIRT3 activators and SIRT3 inhibitors. The NAD⁺-dependent SIRT3 deacetylation reaction process is roughly divided into four steps. I, The acetylated substrate and the NAD⁺ co-substrate binding to SIRT3. II, the acetyl group consequently transfer from substrate to ADP-ribose moiety of NAD⁺. III, Generation of bicyclic intermediates. IV, Produce the deacetylated protein. SIRT3 inhibitors are divided into five types. Substrate competitive SIRT3 inhibitors, Nicotinamide competitive SIRT3 inhibitors, chemical library screening-based SIRT3 inhibitors, structure-based SIRT3 inhibitors and other SIRT3 inhibitors. The chemical structures of representative SIRT3 inhibitors and activators are displayed in the figure.

Figure 8

Potential therapeutic strategies of representative SIRT3 inhibitors. (A) SIRT3 inhibitor discovered by classical pharmaceutical chemical method. (B) SIRT3 inhibitor discovered by DNA-encoded dynamic chemical library screen strategy. (C) SIRT3 inhibitor discovered by encoded library technology screen method.