Sirtuins are
NAD+-dependent
enzymes that have been implicated in a wide range of cellular processes, including pathways that affect diabetes,
cancer, lifespan and
Parkinson's disease. To understand their cellular function in these age-related diseases, identification of
sirtuin targets and their subcellular localization is paramount.
SIRT3 (
sirtuin 3), a human homologue of Sir2 (silent information regulator 2), has been genetically linked to lifespan in the elderly. However, the function and localization of this
enzyme has been keenly debated. A number of reports have indicated that
SIRT3, upon proteolytic cleavage in the mitochondria, is an active
protein deacetylase against a number of mitochondrial targets. In stark contrast, some reports have suggested that full-length
SIRT3 exhibits nuclear localization and
histone deacetylase activity. Recently, a report comparing
SIRT3-/- and
SIRT+/+ mice have provided compelling evidence that endogenous
SIRT3 is mitochondrial and appears to be responsible for the majority of
protein deacetylation in this organelle. In this issue of the Biochemical Journal, Cooper et al. present additional results that address the mitochondrial and nuclear localization of
SIRT3. Utilizing fluorescence microscopy and cellular fractionation studies, Cooper et al. have shown that
SIRT3 localizes to the mitochondria and is absent in the nucleus. Thus this study provides additional evidence to establish
SIRT3 as a proteolytically modified, mitochondrial deacetylase.