Sirtuin 3

Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix.[9] Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases SIRT3 expression in white and brown adipose tissue (WAT and BAT, respectively) and overexpression of SIRT3 in HIB1B brown adipocytes increases the expression of PGC-1α and UCP1, suggesting a role for SIRT3 in adaptive thermogenesis BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how SIRT3 affects thermogenesis in BAT is lacking and whether SIRT3 affects UCP1 activity directly is not known.

In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In Salmonella enterica, the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA) synthetase. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase SIRT3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, SIRT3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, SIRT3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by SIRT3.

Activation of the NMNAT2 enzyme, which catalyze an essential step in the nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway by SIRT3 may be a means of inhibiting axon degeneration and dysfunction.[10]

In addition to its reported mitochondrial function, some researchers have proposed a very small pool of active nuclear SIRT3 exists. This pool is reported to consist of the long form of SIRT3 and has been suggested to have histone deacetylase activity.[11] The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70.[12]

There is a strong association between SIRT3 alleles and longevity in males.[13]

Activation of SIRT3 inhibits the apoptosis leading to age-related macular degeneration.[10] SIRT3 induced mitophagy, inhibiting cell death, and thus could be used to treat neurodegenerative diseases.[10]

There is a significant body of published literature suggesting a strong mechanistic link between mitochondrial function, aging, and carcinogenesis.[13] SIRT3 inhibits cancers that depend upon glycolysis, but promotes cancers that depend upon oxidative phosphorylation.[10]

Sirt3 functions as a mitochondrial tumor suppressor protein. Although some evidence attributes SIRT3 activity in bypassing growth arrest in bladder carcinoma cells via regulation of p53 in the mitochondria.[14] Damaged and aberrant mitochondrial function, similar to gene mutations, may be an early event that ultimately leads to the development of cancers. Mice genetically altered to delete Sirt3 develop estrogen and progesterone receptor (ER/PR) positive breast mammary tumors. In tumor samples from women with breast cancer, SIRT3 expression was decreased, as compared to normal breast tissues. Thus, the Sirt3 knockout model may be used to investigate ER/PR positive breast tumor development.[15]