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FLASH GENE
Symbol SIRT3 contributors: mct/pgu - updated : 15-10-2016
HGNC name sirtuin 3
HGNC id 14931
DNA
TYPE functioning gene
SPECIAL FEATURE head to head
text with PSMD13
STRUCTURE 21.33 kb     7 Exon(s)
10 Kb 5' upstream gene genomic sequence study
motif repetitive sequence   other
text structure VNTR polymorphism (72-bp repeat core ) in intron 5, with an allele-specific enhancer activity
MAPPING cloned Y linked N status provisional
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
7 - 2919 43 399 - 2010 20129246
7 splicing 2773 28 257 - 2010 20129246
using an alternate splice site compared to variant 1
EXPRESSION
Type widely
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestivesalivary gland   highly
Lymphoid/Immunespleen   highly
Nervousnervecranial nerve  highly
Reproductivefemale systemuteruscervix highly
 female systemovary  predominantly
Respiratorylung   highly
Urinarybladder   highly
Visualeye   highly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectiveadipose  highly
Muscular    
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period fetal
Text tissues
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • 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)
  • HOMOLOGY
    interspecies homolog to yeast Sir2
    ortholog to rattus Sirt3 predicted
    ortholog to murine Sirt3
    intraspecies homolog to SIR2
    Homologene
    FAMILY
  • sirtuin family, Sir2 family of NAD(+)-dependent protein deacetylases
  • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,membrane
    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
    PHYSIOLOGICAL PROCESS
    text protein ADP ribosylation, chromatin silencing
    PATHWAY
    metabolism
    signaling
    SIRT3 and FOXO3a comprise a potential mitochondrial signaling cascade response pathway
    a component
    INTERACTION
    DNA binding
    RNA
    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
    REGULATION
    ASSOCIATED DISORDERS
    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
    Susceptibility
  • 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
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • 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