SIRT3 (sirtuin 3; HGNC:14931, NCBI Gene ID 23410) is a human locus mapped to chromosome band 11p15.5 that encodes mitochondrial matrix NAD+-dependent protein deacetylase Sirtuin 3 (399 aa precursor cleaved to 257 aa active enzyme; EC 2.3.1.286). SIRT3 acts in global mitochondrial proteome deacetylation -> activation of SOD2, IDH2, LCAD, HMGCS2 & Electron Transport Chain Complexes I–V, together with SIRT4 (Companion Mitochondrial Sirtuin 4 Gene), SIRT5 (Companion Mitochondrial Sirtuin 5 Gene), and SIRT1 (Nuclear Sirtuin Inducing PGC-1alpha -> SIRT3). Encodes the principal mitochondrial matrix NAD+-dependent deacetylase sirtuin 3 that activates oxidative metabolism, ketogenesis, and SOD2 antioxidant defense.
Approved Symbol
SIRT3
Chromosomal Locus
11p15.5
Encoded Product
Mitochondrial matrix NAD+-dependent protein deacetylase Sirtuin 3 (399 aa precursor cleaved to 257 aa active enzyme; EC 2.3.1.286)
Primary Pathway
Global mitochondrial proteome deacetylation -> activation of SOD2, IDH2, LCAD, HMGCS2 & Electron Transport Chain Complexes I–V
Clinical / Therapeutic Role
VNTR enhancer & G477T alleles were the first sirtuin polymorphisms linked to human survival beyond age 90; protects against cardiac hypertrophy & noise-induced deafness
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 7-exon gene located at the telomeric tip of chromosome 11p15.5 containing an estrogen-related receptor alpha (ESRRA)/PGC-1alpha (PPARGC1A) response element in its promoter and a polymorphic 72-bp variable number tandem repeat (VNTR) enhancer in intron 5; encodes a 399-residue precursor whose N-terminal 142-amino-acid mitochondrial targeting sequence is cleaved by mitochondrial processing peptidase (MPP) inside the matrix to yield the active 28 kDa enzyme.
Cellular & Tissue Expression Profile: Expressed at highest levels inside the mitochondrial matrix of metabolically oxidative tissues: cardiac myocytes, slow-twitch skeletal muscle fibers, brown adipocytes, hepatic hepatocytes, and renal proximal tubule epithelial cells, with expression induced by fasting, caloric restriction, and endurance exercise.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Serves as the master deacetylase of the mitochondrial proteome (Sirt3-knockout mitochondria exhibit massive hyperacetylation, whereas Sirt4- or Sirt5-knockout mitochondria do not): during fasting or caloric restriction, matrix NAD+ activates SIRT3 to deacetylate and activate long-chain acyl-CoA dehydrogenase (LCAD, fatty acid beta-oxidation), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, ketogenesis), pyruvate dehydrogenase, Complex I (NDUFA9) and Complex II (SDHA) of the respiratory chain, and manganese superoxide dismutase 2 (SOD2 at Lys68/Lys122) plus isocitrate dehydrogenase 2 (IDH2, generating mitochondrial NADPH for glutathione reductase) to quench reactive oxygen species.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Historically the first human sirtuin gene shown to correlate with extreme human longevity: in Italian centenarian cohorts, a silent G477T variant (rs11555236) and an active intron 5 VNTR allele with enhanced transcriptional activity were significantly enriched in males surviving past age 90 and 100.
Therapeutic & Clinical Pharmacology: Restoring mitochondrial NAD+ and SIRT3 activity (via nicotinamide riboside, NMN, CD38 inhibition, or honokiol) prevents mitochondrial permeability transition pore (mPTP) opening, blocks angiotensin-II cardiac hypertrophy and fibrosis, and protects cochlear spiral ganglion neurons from noise-induced hearing loss.