Affinage

SIRT4

NAD-dependent protein lipoamidase sirtuin-4, mitochondrial · UniProt Q9Y6E7

Length
314 aa
Mass
35.2 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT4 is a mitochondrial NAD⁺-dependent enzyme that integrates nutrient sensing with amino acid, lipid, and central carbon metabolism through multiple catalytic activities — ADP-ribosylation, deacylation, deacetylation, lipoamidase, and decarbamylase activities — each directed at distinct metabolic substrates. SIRT4 ADP-ribosylates and inhibits glutamate dehydrogenase (GDH) to repress glutamine anaplerosis and amino acid-stimulated insulin secretion (PMID:16959573), removes methylglutaryl/hydroxymethylglutaryl/methylglutaconyl-lysine modifications to activate MCCC1 and promote leucine catabolism (PMID:28380376), deacetylates malonyl-CoA decarboxylase (MCD) to suppress fatty acid oxidation (PMID:23746352), acts as a lipoamidase on the pyruvate dehydrogenase complex to limit acetyl-CoA production (PMID:27246218), and functions as a decarbamylase that removes lysine carbamylation from ornithine transcarbamylase to regulate the urea cycle under amino acid insufficiency via the GCN2–ATF4 axis (PMID:37081161). SIRT4 expression is repressed downstream of mTORC1 signaling and induced by DNA damage, and its loss drives increased glutaminolysis, genomic instability, and spontaneous tumorigenesis in mice (PMID:23663782, PMID:23562301). Beyond mitochondrial metabolism, SIRT4 deacetylates cytosolic and nuclear substrates including Axin1 (activating Wnt/β-catenin signaling), ENO1 (modulating glycolysis and histone lactylation), and MTHFD2 (promoting its degradation to regulate NADPH and redox balance), and it interacts with OPA1 to promote mitochondrial fusion (PMID:35707358, PMID:40298941, PMID:35349697, PMID:29081403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 High

    The foundational enzymatic activity of SIRT4 was established: rather than being a deacetylase like other sirtuins, SIRT4 uses NAD⁺ to ADP-ribosylate GDH in mitochondria, thereby repressing glutamine-driven insulin secretion — answering whether mitochondrial sirtuins have non-deacetylase catalytic functions.

    Evidence In vitro ADP-ribosylation assay, SIRT4 KO mice, insulinoma cell knockdown, phosphodiesterase sensitivity in pancreatic β-cells

    PMID:16959573

    Open questions at the time
    • ADP-ribosylation stoichiometry and reversibility not determined
    • whether GDH is the sole ADP-ribosylation substrate was unknown
  2. 2007 High

    SIRT4 was localized to the mitochondrial matrix with cleavage at residue 28, and its interactome was expanded to include ANT2/ANT3 and insulin-degrading enzyme, establishing it as a hub within the mitochondrial protein network.

    Evidence Mitochondrial import assay, mass spectrometry co-IP, in vitro ADP-ribosyltransferase assay in INS-1E cells

    PMID:17715127

    Open questions at the time
    • functional consequences of ANT2/ANT3 interaction not defined
    • whether IDE interaction is direct or bridged was unclear
  3. 2013 High

    Multiple studies in 2013 converged to place SIRT4 at a metabolic crossroads: mTORC1 represses SIRT4 transcription via CREB2 destabilization to promote glutaminolysis; DNA damage induces SIRT4 to block glutamine catabolism (loss causes genomic instability and lung tumors in mice); SIRT4 deacetylates MCD to suppress fatty acid oxidation; and SIRT4 represses hepatic FAO through PPARα, establishing SIRT4 as a nutrient- and stress-responsive brake on both glutamine and lipid catabolism.

    Evidence SIRT4 KO mice (tumor and metabolic phenotypes), in vitro MCD deacetylation, rapamycin/proteasome epistasis, SIRT1-dependent hepatocyte FAO, Eμ-Myc lymphoma model

    PMID:23562301 PMID:23663782 PMID:23746352 PMID:24043310 PMID:24368766

    Open questions at the time
    • direct mechanism of PPARα repression by mitochondrial SIRT4 unresolved
    • whether MCD deacetylation and GDH ADP-ribosylation are coordinated under same signals unclear
    • structural basis for substrate selection unknown
  4. 2013 Medium

    SIRT4 was found to regulate mitochondrial ATP homeostasis through ANT2 and to interact with biotin-dependent carboxylases (MCCC, pyruvate carboxylase, propionyl-CoA carboxylase), hinting at broader metabolic substrate scope beyond GDH and MCD.

    Evidence ATP measurements in SIRT4 OE/KD cells, AMPK/PGC1α signaling; co-IP/MS of SIRT4 with carboxylases in C. elegans and mammalian cells

    PMID:23438705 PMID:24296486

    Open questions at the time
    • ANT2 interaction mechanism not fully reconstituted in vitro
    • no enzymatic activity on carboxylases demonstrated at this time
    • retrograde signaling pathway incompletely defined
  5. 2016 Medium

    Two new facets of SIRT4 biology emerged: SIRT4 functions as a lipoamidase that removes lipoyl modifications from the pyruvate dehydrogenase complex (expanding its catalytic repertoire), and SIRT4 inhibits mitochondrial fission by suppressing Drp1 phosphorylation and MEK/ERK signaling in cancer cells.

    Evidence In vitro lipoamidase assay with MS of acyl modifications; Drp1 phosphorylation and invasion assays in NSCLC cells

    PMID:27246218 PMID:27941873

    Open questions at the time
    • lipoamidase activity described via methods chapter — full primary data publication context needed
    • Drp1 regulation is indirect — direct SIRT4 substrate in this pathway unidentified
    • whether lipoamidase and deacetylase activities compete for NAD⁺ unknown
  6. 2017 High

    The physiologically relevant deacylase activity of SIRT4 was identified: removal of methylglutaryl-, hydroxymethylglutaryl-, and methylglutaconyl-lysine from MCCC1 activates leucine catabolism, with SIRT4 KO mice displaying dysregulated leucine metabolism and glucose intolerance — resolving the long-standing question of SIRT4's primary catalytic function.

    Evidence Structural biology, in vitro enzymatic reconstitution, mutagenesis, SIRT4 KO mouse metabolic phenotyping, leucine flux measurement

    PMID:28380376

    Open questions at the time
    • relative physiological contribution of deacylase vs. ADP-ribosyltransferase activities not quantified
    • structural basis for acyl-chain selectivity not fully resolved
  7. 2017 Medium

    SIRT4 was shown to interact with OPA1 and promote the long (fusion-competent) form of OPA1 in an enzymatic-activity-dependent manner, establishing a direct role for SIRT4 in mitochondrial dynamics beyond metabolic enzyme regulation.

    Evidence Reciprocal co-IP, SIRT4-H161Y catalytically dead mutant, mitochondrial morphology imaging in senescence models

    PMID:29081403

    Open questions at the time
    • whether SIRT4 directly deacylates OPA1 or acts indirectly is unknown
    • in vivo validation of OPA1 regulation lacking
  8. 2020 Medium

    A non-mitochondrial pool of SIRT4 was discovered at centrosomes, where it associates with tubulin and γ-TuRC components and deacetylates α-tubulin at K40, affecting mitotic progression — demonstrating that SIRT4 functions outside mitochondria.

    Evidence Confocal microscopy, MS interactome of mitotic cells, co-IP with tubulin/HDAC6, cell cycle analysis

    PMID:32846968

    Open questions at the time
    • how SIRT4 escapes mitochondrial import for centrosomal localization is unresolved
    • functional significance of tubulin deacetylation relative to HDAC6 unclear
  9. 2020 Medium

    The PAK6–SIRT4–ANT2 axis was delineated: PAK6 promotes SIRT4 proteolysis while SIRT4 deacetylates ANT2 at K105 to promote its ubiquitination and degradation, integrating SIRT4 into apoptosis regulation via mitochondrial adenine nucleotide transport.

    Evidence Co-IP, ubiquitination assays, flow cytometry, xenograft models

    PMID:32194820

    Open questions at the time
    • in vitro reconstitution of SIRT4-mediated ANT2 K105 deacetylation not shown
    • whether PAK6-mediated SIRT4 degradation is tissue-specific unknown
  10. 2022 Medium

    SIRT4's substrate repertoire expanded to extramitochondrial targets: SIRT4 deacetylates Axin1-K147 upon Wnt stimulation (disrupting the β-catenin destruction complex), deacetylates MTHFD2-K50 (promoting its CUL3-mediated degradation to reduce NADPH), and ADP-ribosylates MAT2A-E111 (inactivating S-adenosylmethionine production and suppressing HCC proliferation).

    Evidence In vitro deacetylation/ADP-ribosylation with site-specific mutagenesis, Wnt reporter assays, NADPH/ROS measurements, xenograft models, metabolomics

    PMID:35349697 PMID:35707358 PMID:36371321

    Open questions at the time
    • mechanism of SIRT4 translocation from mitochondria to cytoplasm upon Wnt stimulation uncharacterized
    • how ADP-ribosylation at a glutamic acid residue (MAT2A-E111) rather than lysine is catalyzed unknown
    • in vivo validation of Axin1 deacetylation lacking
  11. 2023 High

    SIRT4 was revealed as a decarbamylase — a fifth distinct enzymatic activity — that removes lysine 307 carbamylation from ornithine transcarbamylase (OTC) in an NAD⁺-dependent manner, inactivating the urea cycle; SIRT4 is transcriptionally induced by the amino acid insufficiency–sensing GCN2–eIF2α–ATF4 axis, linking amino acid stress to urea cycle control.

    Evidence In vitro NAD⁺-dependent decarbamylation reconstitution, site-specific modification identification, SIRT4 KO mice with blood ammonia and urea cycle metabolite measurements, ATF4/GCN2 epistasis, luciferase promoter reporter

    PMID:37081161

    Open questions at the time
    • whether decarbamylation is a general SIRT4 activity on other targets unknown
    • structural basis for carbamyl-lysine recognition unresolved
  12. 2025 Medium

    SIRT4 was shown to deacetylate the glycolytic enzyme ENO1 at K358, switching ENO1 from an RNA-binding to a glycolytic mode, boosting lactate production and driving histone lactylation (H3K9la, H3K18la) to promote pancreatic cancer stemness — establishing a direct link between SIRT4-mediated deacetylation and epigenetic reprogramming via metabolite signaling.

    Evidence In vitro deacetylation assay, ENO1-K358 mutagenesis, glycolytic flux and histone lactylation ChIP, sphere formation, calcium channel manipulation

    PMID:40298941

    Open questions at the time
    • generality of SIRT4-driven histone lactylation beyond pancreatic cancer unknown
    • relative contribution of ENO1 deacetylation vs. other SIRT4 activities to tumor biology unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: how SIRT4 selects among its five distinct catalytic activities (ADP-ribosylation, deacylation, deacetylation, lipoamidase, decarbamylase) for specific substrates under different metabolic conditions; the structural determinants of this multi-activity selectivity; and the mechanisms governing SIRT4 translocation between mitochondria and extra-mitochondrial compartments (centrosomes, cytosol).
  • no structural model of SIRT4 bound to any physiological substrate
  • mechanism of SIRT4 dual localization (mitochondria vs. centrosome/cytosol) unknown
  • relative physiological importance of each enzymatic activity in vivo not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 2
Localization
GO:0005739 mitochondrion 7 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
ANT2ENO1GDHMAT2AMCCC1MCDOPA1OTC

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SIRT4 is a mitochondrial enzyme that uses NAD+ to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity in pancreatic beta cells, thereby repressing amino acid-stimulated insulin secretion. GDH from SIRT4-deficient or calorie-restricted mice is insensitive to phosphodiesterase cleavage of ADP-ribose, confirming the modification in vivo. In vitro ADP-ribosylation assay, SIRT4 KO mice, insulinoma cell knockdown, phosphodiesterase sensitivity assay Cell High 16959573
2007 Human SIRT4 localizes to the mitochondrial matrix and is cleaved at amino acid 28 after import. SIRT4 exhibits no histone deacetylase activity but functions as an ADP-ribosyltransferase on histones and BSA. Mass spectrometry of co-immunoprecipitates identified insulin-degrading enzyme and ADP/ATP carrier proteins ANT2 and ANT3 as SIRT4 binding partners. Depletion of SIRT4 from INS-1E cells increases glucose-stimulated insulin secretion. Mitochondrial import assay, mass spectrometry, co-immunoprecipitation, in vitro ADP-ribosyltransferase assay, siRNA knockdown in INS-1E cells The Journal of Biological Chemistry High 17715127
2013 mTORC1 promotes glutamine anaplerosis by activating GDH through transcriptional repression of SIRT4; mTORC1 represses SIRT4 by promoting proteasome-mediated destabilization of CREB2, positioning SIRT4 downstream of mTORC1 in the control of glutaminolysis. mTORC1 activation/inhibition (rapamycin), SIRT4 overexpression/knockdown, CREB2 proteasome assay, metabolic flux analysis, cell proliferation assays Cell High 23663782
2013 DNA damage induces SIRT4 expression, which represses glutamine metabolism into the TCA cycle; SIRT4 loss leads to increased glutaminolysis, defective DNA damage responses, genomic instability, and spontaneous lung tumor development in SIRT4 KO mice, establishing SIRT4 as a component of the DNA damage response that blocks glutamine catabolism. SIRT4 KO mice (tumor development), DNA damage induction, glutamine metabolism assays, genomic instability assays, cell cycle arrest measurements Cancer Cell High 23562301
2013 SIRT4 deacetylates and inhibits malonyl-CoA decarboxylase (MCD), an enzyme that converts malonyl-CoA to acetyl-CoA; SIRT4 KO mice display elevated MCD activity and decreased malonyl-CoA in skeletal muscle and white adipose tissue, resulting in increased fatty acid oxidation and protection against diet-induced obesity. In vitro deacetylation assay, SIRT4 KO mice, metabolite measurements (malonyl-CoA), fatty acid oxidation assays, mass spectrometry Molecular Cell High 23746352
2013 SIRT4 represses hepatic fatty acid oxidation by suppressing PPARα transcriptional activity; SIRT4 null mouse hepatocytes exhibit higher rates of fatty acid oxidation, and this enhanced oxidation requires functional SIRT1, demonstrating cross-talk between mitochondrial and nuclear sirtuins. SIRT4 KO primary hepatocytes, fatty acid oxidation assays, PPARα target gene expression, SIRT1 inhibition epistasis Molecular and Cellular Biology High 24043310
2013 SIRT4 regulates mitochondrial ATP homeostasis by affecting uncoupling via adenine nucleotide translocator 2 (ANT2); loss of SIRT4 decreases cellular ATP levels in vitro and in vivo, while overexpression increases ATP levels. SIRT4 loss activates a retrograde mitochondria-to-nucleus signaling response involving AMPK and PGC1α. SIRT4 overexpression/knockdown, ATP measurements in vivo and in vitro, AMPK/PGC1α signaling assays, ANT2 interaction studies Aging Medium 24296486
2013 C. elegans SIR-2.2 and SIR-2.3 SIRT4 orthologs localize to mitochondria and interact with biotin-dependent carboxylases (pyruvate carboxylase, propionyl-CoA carboxylase, MCCC); mammalian SIRT4 similarly interacts with these acetylated carboxylases, identifying them as candidate substrates. Co-immunoprecipitation, mass spectrometry, mitochondrial fractionation, C. elegans genetics Mitochondrion Medium 23438705
2013 SIRT4 represses Myc-induced B cell lymphomagenesis by inhibiting mitochondrial glutamine metabolism; SIRT4 overexpression dampens glutamine utilization in Burkitt lymphoma cells and SIRT4 loss in Eμ-Myc mice accelerates lymphomagenesis with increased GDH activity. Genetic mouse model (Eμ-Myc × SIRT4 KO), glutamine uptake assays, GDH activity measurement, SIRT4 overexpression in Burkitt lymphoma cells The Journal of Biological Chemistry High 24368766
2016 SIRT4 inhibits mitochondrial fission in NSCLC cells by inhibiting Drp1 phosphorylation and weakening Drp1 recruitment to the mitochondrial membrane via Fis-1; SIRT4 also hampers MEK/ERK activity, linking reduced mitochondrial fission to suppressed invasive capacity. SIRT4 overexpression/siRNA in NSCLC cell lines, Drp1 phosphorylation western blot, confocal microscopy, invasion assays, ERK activity measurement Oncogene Medium 27941873
2017 SIRT4 removes three acyl modifications from lysine residues — methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine — which are intermediates in leucine oxidation. This deacylase activity activates MCCC1 (methylcrotonyl-CoA carboxylase 1) to control leucine catabolism; dysregulated leucine metabolism in SIRT4 KO mice leads to elevated insulin secretion and eventual glucose intolerance. Phylogenetics, structural biology, in vitro enzymatic assays, mutagenesis, SIRT4 KO mouse metabolic phenotyping, leucine flux measurements Cell Metabolism High 28380376
2017 SIRT4 interacts physically with OPA1 (dynamin-like GTPase) by co-immunoprecipitation; enzymatically active SIRT4 increases levels of the long form of OPA1 (L-OPA1), promoting mitochondrial fusion and counteracting fission/mitophagy. Enzymatically inactive SIRT4-H161Y mutant does not recapitulate this effect. Co-immunoprecipitation, CCCP-triggered mitochondrial stress assays, miR-15b inhibitor transfection, ionizing radiation-induced senescence models, live-cell mitochondrial morphology imaging Aging Medium 29081403
2016 miR-15b targets a functional binding site in the SIRT4 gene and negatively regulates SIRT4 expression; increased SIRT4 in senescent cells (via miR-15b downregulation) increases mitochondrial ROS, decreases mitochondrial membrane potential, and modulates the senescence-associated secretory phenotype (SASP). miR-15b mimic/inhibitor transfection, luciferase reporter assay (miR-15b binding site in SIRT4 3'UTR), mitochondrial ROS measurement, SASP cytokine profiling Aging Medium 26959556
2016 Identification of SIRT4 as a mitochondrial lipoamidase that removes lipoyl modifications from lysine residues of the pyruvate dehydrogenase complex (PDH), modulating its activity and controlling acetyl-CoA production from pyruvate. In vitro lipoamidase assay, mass spectrometry of acyl modifications, SIRT4 protein interaction studies (per review in PMID:27246218 describing original SIRT4 lipoamidase discovery) Methods in Molecular Biology Medium 27246218
2018 SIRT4 overexpression in mouse oocytes impairs meiotic progression by causing inadequate mitochondrial redistribution, lowered ATP, elevated ROS, and disrupted spindle/chromosome organization; phosphorylation of Ser293-PDHE1α mediates SIRT4 overexpression effects on metabolic activity and meiotic events, as shown by functional rescue experiments. SIRT4 overexpression/knockdown in mouse oocytes, live imaging, spindle morphology, ATP/ROS measurement, PDHE1α phosphorylation functional rescue Aging Cell Medium 29845740
2019 SIRT4 interacts with PTEN and regulates its stability through the lysosome pathway mediated by insulin-degrading enzyme (IDE); SIRT4 bridges PTEN and IDE for degradation in response to nutritional starvation, independently of PTEN acetylation or ubiquitination. Co-immunoprecipitation, SIRT4 overexpression, lysosome/proteasome inhibitor experiments, IDE knockdown epistasis, nutritional starvation stress models FASEB Journal Medium 30649986
2020 A fraction of SIRT4 localizes to centrosomes (in addition to mitochondria) and associates with microtubules; SIRT4 interacts with structural (α,β-tubulin, γ-tubulin, TUBGCP2, TUBGCP3) and regulatory (HDAC6) microtubule components. SIRT4 overexpression decreases acetylated α-tubulin (K40) and delays mitotic progression, reducing cell proliferation. Confocal spinning disk microscopy, co-immunoprecipitation, mass spectrometry of mitotic interactome, cell cycle analysis, SIRT4(ΔN28) truncation variant Cells Medium 32846968
2020 SIRT4 inhibits glutamine anaplerosis to potentiate TORC1 signaling in fed conditions by sparing mitochondrial glutamine from conversion to α-ketoglutarate; SIRT4 establishes retrograde control over anabolic TORC1-regulated pathways including lipogenesis, autophagy, and cell proliferation. SIRT4 overexpression/knockdown, TORC1 activity assays, glutamine flux measurements, rapamycin epistasis, autophagy assays Molecular and Cellular Biology Medium 31685549
2020 PAK6 forms a complex with SIRT4 and ANT2 in mitochondria; PAK6 promotes SIRT4 ubiquitin-mediated proteolysis, and SIRT4 deacetylates ANT2 at K105 promoting its ubiquitination and degradation. PAK6 directly phosphorylates ANT2 at T107 to inhibit apoptosis, with SIRT4 modulating ANT2 stability through deacetylation. Co-immunoprecipitation, immunofluorescence, immunoelectron microscopy, ubiquitination assay, flow cytometry, xenograft models Theranostics Medium 32194820
2021 SIRT4 activates methylcrotonyl-CoA carboxylase (MCCC) to promote BCAA (particularly leucine) catabolism in early adipogenesis; elevated BCAA catabolism precedes and promotes PPARγ activation, driving adipocyte differentiation. Metabolite profiling of adipocyte differentiation, SIRT4 KO cells/mice, MCCC activity assays, PPARγ expression analysis Cell Reports Medium 34260923
2022 SIRT4 translocates from mitochondria to the cytoplasm upon Wnt stimulation and deacetylates Axin1 at Lys147 within the RGS domain, disrupting the destruction complex by impairing β-TrCP assembly, thereby allowing β-catenin accumulation and Wnt pathway activation. SIRT4 subcellular fractionation upon Wnt stimulation, co-immunoprecipitation, Axin1-K147R mutagenesis, β-catenin accumulation assay, Wnt reporter assay Frontiers in Oncology Medium 35707358
2022 SIRT4 deacetylates MTHFD2 at conserved lysine 50 (K50); K50 deacetylation destabilizes MTHFD2 by promoting cullin 3 E3 ligase-mediated proteasomal degradation in response to folate deprivation, reducing NADPH production and increasing intracellular ROS to inhibit breast cancer cell growth. In vitro deacetylation assay, MTHFD2-K50R/K50Q mutagenesis, co-immunoprecipitation, proteasome inhibitor assays, NADPH/ROS measurements, breast cancer proliferation assays Journal of Molecular Cell Biology Medium 35349697
2022 SIRT4 ADP-ribosylates MAT2A at glutamic acid residue 111, inactivating it; loss of SIRT4 (via TRIM32-mediated degradation downstream of mTORC1-c-Myc) activates MAT2A, increases SAM production, and promotes HCC proliferation through epigenetic reprogramming. ADP-ribosylation assay identifying MAT2A residue E111, TRIM32 ubiquitination assay, metabolomics (methionine/SAM), xenograft models, RNA sequencing Cell & Bioscience Medium 36371321
2023 SIRT4 acts as a decarbamylase that removes lysine 307 carbamylation (OTCCP-K307) from ornithine transcarbamylase (OTC) in an NAD+-dependent manner, inactivating OTC and the urea cycle; SIRT4 expression is transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. Proteomic/interactome screening, in vitro decarbamylation assay (NAD+-dependent), SIRT4 KO cells and mice (urea cycle metabolite measurements, blood ammonia), ATF4/GCN2 epistasis, luciferase reporter for SIRT4 promoter Nature Metabolism High 37081161
2023 SIRT4 deacetylates GNPAT (glyceronephosphate O-acyltransferase) in lung epithelial cells; CSE (cigarette smoke extract) modulates GNPAT acetylation and protein levels by regulating SIRT4 expression, and GNPAT overexpression counters SIRT4 inhibition of ferroptosis, linking SIRT4-mediated deacetylation to ferroptosis in COPD. Immunoprecipitation (acetylation levels of GNPAT), SIRT4 overexpression/knockdown, ferroptosis assays (ROS, lipid peroxidation, GPX4), COPD mouse model Respiratory Research Medium 38041059
2023 SIRT4 hinders SIRT5's stabilizing interaction with glutaminase 1 (GLS1), facilitating GLS1 degradation; SIRT4 thereby inhibits glutaminolysis in intestinal fibroblasts, reducing α-ketoglutarate production and limiting KDM6-mediated H3K27me3 erasure at ECM component promoters to suppress fibrosis. Co-immunoprecipitation (SIRT4-SIRT5-GLS1 interaction), GLS1 protein stability assays, glutaminolysis metabolite measurements, H3K27me3 ChIP, fibrosis models (TGF-β treated fibroblasts, in vivo) Matrix Biology Medium 37541633
2024 SIRT4 reduces acetylation of HSP60 to facilitate assembly of the HSP60-HSP10 complex in mitochondria; this complex maintains activity of ETC complexes II and III, sustaining ATP generation. Glutamine activates SIRT4 by upregulating its synthesis and increasing NAD+ levels. SIRT4 overexpression, HSP60 acetylation immunoprecipitation assay, ETC complex activity assays, ATP measurement, ROS assays, burn sepsis mouse/cell model Redox Report Medium 38329114
2025 SIRT4 directly deacetylates ENO1 at K358, reducing ENO1's RNA-binding capacity and enhancing its glycolytic (2-PG substrate) affinity, boosting glycolytic activity and lactate production; increased lactate drives histone lactylation at H3K9 and H3K18, causing epigenetic reprogramming that promotes pancreatic cancer stem cell properties. SIRT4 expression is upregulated by α2δ1-mediated calcium signaling. In vitro deacetylation assay (SIRT4 on ENO1-K358), mutagenesis (ENO1-K358 acetylation mimetic/null), glycolytic flux assays, histone lactylation ChIP, sphere formation and tumor-initiating cell assays, calcium channel manipulation Advanced Science Medium 40298941
2014 Loss of SIRT4 in the brain leads to decreased expression and function of the glutamate transporter GLT-1, resulting in increased sensitivity to kainic acid-induced excitotoxicity; SIRT4 is upregulated in response to kainic acid treatment, indicating a stress-responsive neuroprotective role. SIRT4 KO mice, kainic acid excitotoxicity assay, glutamate transporter expression/activity measurement Journal of Neurochemistry Medium 25196144
2012 SIRT4 is highly expressed in glial cells (astrocytes) and radial glia in the brain and localizes to mitochondria. SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis in radial glial cells; an HI/HA patient GDH1 mutant (insensitive to SIRT4 ADP-ribosylation) accelerates glia development from radial glia. SIRT4 subcellular localization (brain fractionation, immunostaining), gliogenesis assays in CTX8 radial glia cells, GDH1 activity modulation, SIRT4/GDH1 overexpression Glia Medium 23281078
2017 Inactivation of Lsd1 (lysine-specific demethylase 1) triggers senescence in trophoblast stem cells through increased expression of SIRT4, a direct Lsd1-repressed target gene; Sirt4 overexpression recapitulates the senescence phenotype, and knockdown of Sirt4 concurrent with Lsd1 inactivation rescues glutamine anaplerosis, redox balance, and mitochondrial function. Lsd1 KO/inhibition in trophoblast stem cells, genome-wide transcriptional profiling, metabolomics, Sirt4 overexpression/knockdown rescue experiments Cell Death & Disease Medium 28230862

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 972 16959573
2013 The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 468 23663782
2013 SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer cell 367 23562301
2007 Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. The Journal of biological chemistry 332 17715127
2013 SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Molecular cell 297 23746352
2017 SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell metabolism 262 28380376
2019 UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer. Cancer letters 134 30905812
2013 SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging 132 24296486
2015 Tumour-suppressive function of SIRT4 in human colorectal cancer. British journal of cancer 128 26086877
2013 SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Molecular and cellular biology 121 24043310
2017 SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging 117 29081403
2016 MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4. Aging 113 26959556
2016 SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 111 27941873
2013 SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. The Journal of biological chemistry 95 24368766
2013 SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 91 24029877
2020 Exosomal miRNA-320a Is Released from hAMSCs and Regulates SIRT4 to Prevent Reactive Oxygen Species Generation in POI. Molecular therapy. Nucleic acids 89 32506013
2020 Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer. Frontiers in oncology 65 32373514
2019 SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPARδ signalling-mediated alternative activation of macrophages. Journal of experimental & clinical cancer research : CR 64 31744516
2018 SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation. Aging cell 64 29845740
2014 SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer & metabolism 64 25332769
2018 Molecular link between glucose and glutamine consumption in cancer cells mediated by CtBP and SIRT4. Oncogenesis 59 29540733
2006 Insulin secretion: SIRT4 gets in on the act. Cell 59 16959562
2016 SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis. Experimental and therapeutic medicine 58 28123512
2021 FOXM1-activated SIRT4 inhibits NF-κB signaling and NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in diabetic nephropathy. Experimental cell research 57 34626587
2019 SIRT4 and Its Roles in Energy and Redox Metabolism in Health, Disease and During Exercise. Frontiers in physiology 57 31447696
2015 SIRT4 Suppresses Inflammatory Responses in Human Umbilical Vein Endothelial Cells. Cardiovascular toxicology 57 25331589
2019 Mitochondrial Function, Metabolic Regulation, and Human Disease Viewed through the Prism of Sirtuin 4 (SIRT4) Functions. Journal of proteome research 55 30913880
2015 CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4. Cell death & disease 54 25633289
2016 SIRT4 regulates cancer cell survival and growth after stress. Biochemical and biophysical research communications 52 26775843
2021 SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis. Cell reports 51 34260923
2012 Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia 51 23281078
2010 Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochemistry and cell biology = Biochimie et biologie cellulaire 51 20651844
2015 Sirtuin-4 (SIRT4) is downregulated and associated with some clinicopathological features in gastric adenocarcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 48 26054687
2020 Mitochondrial PAK6 inhibits prostate cancer cell apoptosis via the PAK6-SIRT4-ANT2 complex. Theranostics 47 32194820
2014 Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid. Journal of neurochemistry 46 25196144
2018 SIRT4 acts as a tumor suppressor in gastric cancer by inhibiting cell proliferation, migration, and invasion. OncoTargets and therapy 44 30022839
2019 SIRT4 inhibits the proliferation, migration, and invasion abilities of thyroid cancer cells by inhibiting glutamine metabolism. OncoTargets and therapy 43 30992675
2020 Loss of SIRT4 promotes the self-renewal of Breast Cancer Stem Cells. Theranostics 42 32863939
2016 MicroRNA-497 Inhibits Cardiac Hypertrophy by Targeting Sirt4. PloS one 41 27992564
2017 Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4. Cell death & disease 40 28230862
2022 SIRT4 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the AKT/mTOR/Autophagy Pathway. Toxicology 39 35134463
2019 SIRT4 suppresses the PI3K/Akt/NF‑κB signaling pathway and attenuates HUVEC injury induced by oxLDL. Molecular medicine reports 39 31059091
2014 SIRT4 inhibits cigarette smoke extracts-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells via regulating NF-κB activity. Toxicology letters 39 24603126
2020 EX-527 Prevents the Progression of High-Fat Diet-Induced Hepatic Steatosis and Fibrosis by Upregulating SIRT4 in Zucker Rats. Cells 35 32365537
2020 SIRT4 suppresses the inflammatory response and oxidative stress in osteoarthritis. American journal of translational research 34 32509191
2013 Sirt4: the glutamine gatekeeper. Cancer cell 34 23597559
2019 SIRT4 regulates PTEN stability through IDE in response to cellular stresses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30649986
2024 Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction. International journal of biological sciences 32 38385071
2020 Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine Sparing in the Mitochondria. Molecular and cellular biology 32 31685549
2019 SIRT4 enhances the sensitivity of ER-positive breast cancer to tamoxifen by inhibiting the IL-6/STAT3 signal pathway. Cancer medicine 32 31573734
2016 Molecular modeling, dynamics studies and density functional theory approaches to identify potential inhibitors of SIRT4 protein from Homo sapiens : a novel target for the treatment of type 2 diabetes. Journal of biomolecular structure & dynamics 32 27800715
2020 HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. Journal of experimental & clinical cancer research : CR 31 32522234
2017 SIRT4 Is a Regulator of Insulin Secretion. Cell chemical biology 31 28644956
2022 mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell & bioscience 30 36371321
2021 VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway. Cell death & disease 30 34135317
2020 Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer. Oncology letters 30 32774484
2020 Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein. Cells 30 32846968
2009 Fluorescence in situ hybridization and chromosomal organization of the sirtuin 4 gene (Sirt4) in the mouse. Biochemical and biophysical research communications 29 19306844
2023 MiR-15b-5p and PCSK9 inhibition reduces lipopolysaccharide-induced endothelial dysfunction by targeting SIRT4. Cellular & molecular biology letters 28 37587410
2020 SIRT4 prevents excitotoxicity via modulating glutamate metabolism in glioma cells. Human & experimental toxicology 28 32081049
2023 Sirt4 deficiency promotes the development of atherosclerosis by activating the NF-κB/IκB/CXCL2/3 pathway. Atherosclerosis 27 37121164
2024 The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases. International journal of molecular sciences 26 39000044
2018 Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest. Oncology letters 26 30745932
2023 The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer. Cancer letters 24 36646410
2023 Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle. Nature metabolism 23 37081161
2018 Study of expression analysis of SIRT4 and the coordinate regulation of bovine adipocyte differentiation by SIRT4 and its transcription factors. Bioscience reports 23 30442871
2022 miR-15a-5p enhances the malignant phenotypes of colorectal cancer cells through the STAT3/TWIST1 and PTEN/AKT signaling pathways by targeting SIRT4. Cellular signalling 22 36332797
2021 miRNA-130b-5p promotes hepatic stellate cell activation and the development of liver fibrosis by suppressing SIRT4 expression. Journal of cellular and molecular medicine 22 34272822
2023 CSE triggers ferroptosis via SIRT4-mediated GNPAT deacetylation in the pathogenesis of COPD. Respiratory research 21 38041059
2022 Coenzyme Q10 Supplement Rescues Postovulatory Oocyte Aging by Regulating SIRT4 Expression. Current molecular pharmacology 21 33881976
2022 SIRT4 Expression Ameliorates the Detrimental Effect of Heat Stress via AMPK/mTOR Signaling Pathway in BMECs. International journal of molecular sciences 21 36362094
2021 SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3β/CyclinD1 pathway. Carcinogenesis 21 33315089
2019 Recovery of Olfactory Function After Excitotoxic Lesion of the Olfactory Bulbs Is Associated with Increases in Bulbar SIRT1 and SIRT4 Expressions. Molecular neurobiology 21 30661205
2022 Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism. Journal of molecular cell biology 20 35349697
2018 Knockout of SIRT4 decreases chemosensitivity to 5-FU in colorectal cancer cells. Oncology letters 20 30008852
2013 Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and mammals interact with pyruvate carboxylase and other acetylated biotin-dependent carboxylases. Mitochondrion 20 23438705
2024 Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation. Redox report : communications in free radical research 19 38329114
2020 miR-424-5p regulates cell proliferation and migration of esophageal squamous cell carcinoma by targeting SIRT4. Journal of Cancer 19 33033517
2024 Sodium butyrate blocks the growth of colorectal cancer by inhibiting the aerobic glycolysis mediated by SIRT4/HIF-1α. Chemico-biological interactions 17 39241941
2023 Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis. Journal of gynecologic oncology 17 37921598
2017 L-leucine stimulates glutamate dehydrogenase activity and glutamate synthesis by regulating mTORC1/SIRT4 pathway in pig liver. Animal nutrition (Zhongguo xu mu shou yi xue hui) 17 30175263
2023 SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation. Matrix biology : journal of the International Society for Matrix Biology 16 37541633
2018 Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage. Cancer management and research 16 30519106
2022 SIRT4 functions as a tumor suppressor during prostate cancer by inducing apoptosis and inhibiting glutamine metabolism. Scientific reports 15 35842463
2017 Decreased SIRT4 protein levels in endometrioid adenocarcinoma tissues are associated with advanced AJCC stage. Cancer biomarkers : section A of Disease markers 15 28582846
2025 SIRT4 Promotes Pancreatic Cancer Stemness by Enhancing Histone Lactylation and Epigenetic Reprogramming Stimulated by Calcium Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 40298941
2023 SIRT4 in ageing. Biogerontology 14 37067687
2022 SIRT4-Catalyzed Deacetylation of Axin1 Modulates the Wnt/β-Catenin Signaling Pathway. Frontiers in oncology 14 35707358
2018 DNA Methylation and Transcription Factors Competitively Regulate SIRT4 Promoter Activity in Bovine Adipocytes: Roles of NRF1 and CMYB. DNA and cell biology 14 30570339
2017 SIRT4 is upregulated in breast cancer and promotes the proliferation, migration and invasion of breast cancer cells. International journal of clinical and experimental pathology 14 31966549
2023 SIRT4 is a regulator of human skeletal muscle fatty acid metabolism influencing inner and outer mitochondrial membrane-mediated fusion. Cellular signalling 13 37858614
2020 Nuclear factor E2 related factor (NRF2) inhibits mast cell- mediated allergic inflammation via SIRT4-mediated mitochondrial metabolism. Annals of palliative medicine 13 33222465
2016 Identification of Sirtuin4 (SIRT4) Protein Interactions: Uncovering Candidate Acyl-Modified Mitochondrial Substrates and Enzymatic Regulators. Methods in molecular biology (Clifton, N.J.) 13 27246218
2023 Epigenetic activation of secretory phenotypes in senescence by the FOXQ1-SIRT4-GDH signaling. Cell death & disease 12 37516739
2020 Mammalian SIRT4 is a tumor suppressor of clear cell renal cell carcinoma by inhibiting cancer proliferation, migration and invasion. Cancer biomarkers : section A of Disease markers 12 32675395
2024 SIRT4 promotes neuronal apoptosis in models of Alzheimer's disease via the STAT2-SIRT4-mTOR pathway. American journal of physiology. Cell physiology 11 38586875
2022 SIRT4 Is Highly Expressed in Retinal Müller Glial Cells. Frontiers in neuroscience 11 35185463
2018 Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy. Archives of physiology and biochemistry 11 30572719
2017 Novel role of the SIRT4-OPA1 axis in mitochondrial quality control. Cell stress 11 31225445
2012 Inhibition of glutamate dehydrogenase and insulin secretion by KHG26377 does not involve ADP-ribosylation by SIRT4 or deacetylation by SIRT3. BMB reports 11 22917030