Mitochondrial 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. 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. 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. == Clinical significance ==