NAD-dependent protein deacetylase sirtuin-3, mitochondrial

SIRT3 (NAD-dependent protein deacetylase sirtuin-3, mitochondrial) is a NAD-dependent deacetylase that regulates mitochondrial protein function by deacetylating lysine residues on key metabolic enzymes including SOD2, PDHA1, SDHA, and ATP synthase subunits (UniProt: Q9NTG7). Beyond acetylation, SIRT3 also performs debenzoylation and delactylation of proteins such as PPIF and ACLY. The enzyme contributes to cellular energy homeostasis, mitochondrial ATP regulation, and metabolic stress responses through FOXO3-mediated mtDNA transcription and AMPK signaling pathways.

SIRT3 is primarily a mitochondrial protein with roles in regulating lipogenesis, ceramide metabolism, and tissue-specific ATP levels (UniProt: Q9NTG7). No inherent disease associations are listed in UniProt, though its metabolic functions implicate it in energy-dependent cellular processes.

In Alzheimer's disease, SIRT3 expression is significantly reduced in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change is −0.725 across quantified fractions, indicating consistent downregulation. This reduction may impair mitochondrial oxidative metabolism and ATP production, potentially contributing to the bioenergetic deficits characteristic of AD neurodegeneration.