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Symbol SIRT3 contributors: mct/pgu - updated : 15-10-2016
HGNC name sirtuin 3
HGNC id 14931
  • N-terminal peptide sequence signal for mitochondrial localization
  • a deacetylase sirtuin-type core domain
  • N- and C-terminal regions regulate its activity against glutamate dehydrogenase and a peptide substrate (roles for these regions in substrate recognition and Sirtuin regulation)
    interspecies homolog to yeast Sir2
    ortholog to rattus Sirt3 predicted
    ortholog to murine Sirt3
    intraspecies homolog to SIR2
  • sirtuin family, Sir2 family of NAD(+)-dependent protein deacetylases
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    text exclusively mitochondrial
    basic FUNCTION
  • acting as a NAD-dependent deacetylase
  • activating mitochondria functions and playing an important role in adaptive thermogenesis in brown adipose
  • may play a role in life span
  • important for regulation of mitochondrial metabolism, cell survival, and longevity
  • major mitochondrial deacetylase, having evolved to control reversible lysine acetylation in the mitochondria
  • can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase
  • essential role of SIRT3 in the survival of cardiomyocytes in stress situations
  • might function in nucleus
  • by participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers
  • NAD(+)-dependent protein deacetylases that regulate cellular functions through deacetylation of a wide range of protein targets
  • required to maintain cell survival after genotoxic stress in a NAD+-dependent manner
  • with SIRT4, modulate mitochondrial function in response to its [NADH]/[NAD+] ratio by regulating the activity of key metabolic enzymes
  • stimulates deacetylation of MRPL10, consequently regulating protein synthesis in mammalian mitochondria
  • mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress
  • essential player in enhancing the mitochondrial glutathione antioxidant defense system during caloric restriction suggesting that SIRT3-dependent mitochondrial adaptations may be a central mechanism of aging retardation, and age-related hearing loss
  • during caloric restriction, promotes a more reductive environment in mitochondria of multiple tissues, thereby enhancing the glutathione antioxidant defense system
  • mediates reduction of oxidative stress by stimulating IDH2 activity and increasing NADPH levels under stress conditions
  • integral regulator of mitochondrial function and its depletion results in hyperacetylation of critical mitochondrial proteins that protect against hepatic lipotoxicity under conditions of nutrient excess
  • acts as a tumor suppressor via its ability to suppress reactive oxygen species (ROS) and regulate hypoxia inducible factor 1A (HIF1A)
  • acts to suppress the growth of tumors, at least in part through its ability to suppress ROS and HIF1A
  • SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity
  • plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle
  • link between SIRT3, mitochondrial DNA variability and mitochondrial functionality, three fundamental components of the cellular stress response
  • SIRT3-mediated deacetylation has recently emerged as a major mechanism regulating the activity of mitochondrial oxidative and intermediary metabolism
  • key role for SIRT3 in the maintenance of oxidative metabolism that may be especially important in the heart
  • SIRT3 is a potential regulator of IDH2-dependent functions in cancer cell metabolism
  • can protect cells from mitochondrial oxidative stress and this effect is almost entirely dependent on IDH2
  • key factor in a coordinate up-regulation of oxidative metabolism and antioxidant pathways in response to acute and chronic caloric restriction
  • exhibits a previously unappreciated role in the nucleus, modulating the expression of some stress-related and nuclear-encoded mitochondrial genes
  • plays an important role in skeletal muscle mitochondrial substrate choice and metabolic flexibility in part by regulating PDH function through deacetylation
  • role for SIRT3 in the suppression of epidermal differentiation via lowering oxidative stress
  • novel function of SIRT3 which was found to be involved in mitosis
  • is not a tubulin deacetylase but regulates the attachment of spindle microtubules to the kinetochore and the subsequent chromosome alignment by increasing spindle dynamics
  • major mitochondria NAD+-dependent deacetylase, may target mitochondrial proteins for lysine deacetylation and also regulate cellular functions
  • acts as a prosurvival factor playing an essential role to protect cortical neurons under H2O2 induced oxidative stress, possibly through regulating mitochondrial Ca2+ homeostasis and mitochondrial biogenesis
  • role in keratinocyte differentiation, wound healing, chronological aging, ultraviolet radiation (UVR) and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)
  • CELLULAR PROCESS protein, post translation
    text protein ADP ribosylation, chromatin silencing
    SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway
    a component
    DNA binding
    small molecule metal binding, cofactor,
  • Zn2+
  • protein
  • FOXO3a is also a mitochondrial protein and forms a physical interaction with SIRT3 in mitochondria
  • physically binds to XRCC6 and deacetylates it, and this promotes interaction of XRCC6 with the proapoptotic protein BAX
  • MRPL10 novel substrate of the NAD+-dependent deacetylase, SIRT3 (interacts with the N-terminal domain of MRPL10)
  • activates IDH2, thereby increasing NADPH levels in mitochondria
  • binds to, deacetylates and activates SOD2
  • SDHA and SDHB interacted specifically with SIRT3 (SIRT3 may be an important physiological regulator of SDH activity)
  • ability of SIRT3 to protect cells from oxidative stress was dependent on IDH2
  • deacetylates FOXO3 to protect mitochondria against oxidative damage
  • interaction of SIRT3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
  • LONP1 is a target of SIRT3, likely at K917
  • stabilizes FOXO3 via deacetylation, which enhances the mitochondrial antioxidant defense system to increase the adaptive capacity of endothelial cells (ECs) during hypoxia
  • HSPE1 is a functional SIRT3 substrate and that, in response to prolonged fasting, SIRT3 levels modulate mitochondrial protein folding
  • NMNAT3, the rate-limiting enzyme for mitochondrial NAD biosynthesis, is a new target and binding partner of SIRT3
  • MIPEP may contribute to the maintenance of mitochondrial quality during caloric restriction (CR) via activation of SIRT3
  • cell & other
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in skeletal muscle in states of diabetes and obesity is an important component of the pathogenesis of type 2 diabetes, which can induce altered mitochondrial function, increase ROS production and oxidative stress, and lead to insulin resistance
  • to survival at oldest age
  • to metabolic syndrome
  • Variant & Polymorphism SNP , repeat
  • VNTR with enhancer activity associated to longevity
  • SNP in SIRT3 gene is suggestive of a genetic association with the metabolic syndrome
  • Candidate gene
    Therapy target
  • SIRT3-deficient mice exhibit striking mitochondrial protein hyperacetylation
  • Sirt3 plays an essential role in the Caloric restriction-mediated prevention of age-related cochlear cell death and hearing loss in mice
  • Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling
  • mice lacking Sirt3 (Sirt3KO) placed on a high-fat diet show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type