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FLASH GENE
Symbol SIRT3 contributors: mct/pgu - updated : 15-10-2014
HGNC name sirtuin 3
HGNC id 14931
Location 11p15.5      Physical location : 215.030 - 236.362
Synonym name
  • mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase
  • sir2-like 3, sirtuin type 3
  • sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)
  • SIR2-like protein 3
  • NAD-dependent deacetylase sirtuin-3, mitochondrial
  • Synonym symbol(s) SIR2L3
    EC.number 3.5.1.-
    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
    Physical map
    LOC390028 11 similar to Olfactory receptor 4F3 LOC387731 11 similar to bA476I15.3 (novel protein similar to septin) LOC387732 11 LOC387732 RYD5 11p15.5 ligand binding protein RYD5 ODF3 11p15.5 outer dense fiber of sperm tails 3 BET1L 11p15.5 blocked early in transport 1 homolog (S. cerevisiae) like RIC-8 11p15.5 likely ortholog of mouse synembryn SIRT3 11p15.5 sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae) PSMD13 11p15.5 proteasome (prosome, macropain) 26S subunit, non-ATPase, 13 NALP6 11p15 NACHT, leucine rich repeat and PYD containing 6 FLJ22635 11p15.5 hypothetical protein FLJ22635 LOC387733 11 similar to putative haemopoietic membrane protein MRPS24P1 11p15.4 mitochondrial ribosomal protein S24 pseudogene IFITM2 11p15.5 interferon induced transmembrane protein 2 (1-8D) IFITM1 11p15.5 interferon induced transmembrane protein 1 (9-27) IFITM3 11p15.5 interferon induced transmembrane protein 3 (1-8U) PKP3 11p15 plakophilin 3 LOC387734 11 similar to beta 1,4-N-acetylgalactosaminyltransferase-transferase-III FLJ25045 11p15.5 hypothetical protein FLJ25045 SIGIRR 11p15.5 single Ig IL-1R-related molecule PTDSS2 11p15 phosphatidylserine synthase 2 RNH 11p15.5 ribonuclease/angiogenin inhibitor LOC387735 11 similar to Collagen alpha 1(V) chain precursor HRAS 11p15.5 v-Ha-ras Harvey rat sarcoma viral oncogene homolog DKFZp761L1518 11p15.5 hypothetical protein DKFZp761L1518 MGC35138 11p15.5 hypothetical protein MGC35138 C11orf13 11p15,5 chromosome 11 open reading frame 13 KIAA1542 11p15.5 CTD-binding SR-like protein rA9 IRF7 11p15,5 interferon regulatory factor 7 MUCDHL 11p15,5 mucin and cadherin-like SCT 11p15.5 secretin DRD4 11p15.5 dopamine receptor D4 LOC387736 11 LOC387736 DEAF1 11p15,5 deformed epidermal autoregulatory factor 1 (Drosophila) LOC283232 11p15.5 hypothetical protein LOC283232 EPS8L2 11p15.5 EPS8-like 2 TALDO1 11p15.5-p15.4 transaldolase 1 FLJ34283 11p15.5 hypothetical protein FLJ34283 NS3BP 11p15.5 NS3BP BM88 11p15.5 NS3BP SLC25A22 11p15.5 solute carrier family 25 (mitochondrial carrier: glutamate), member 22 LOC387737 11 LOC387737 LRDD 11pter-p15.5 leucine-rich and death domain containing
    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
  • 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
  • NMNAT3, the rate-limiting enzyme for mitochondrial NAD biosynthesis, is a new target and binding partner 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