{"gene":"SIRT3","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2010,"finding":"SIRT3 directly deacetylates long-chain acyl-CoA dehydrogenase (LCAD) at lysine 42 in vitro and in vivo; hyperacetylation of LCAD reduces its enzymatic activity, and SIRT3-knockout mice show impaired fatty-acid oxidation during fasting.","method":"Mass spectrometry of mitochondrial proteins, in vitro deacetylation assay, SIRT3-KO mouse model with metabolic phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay plus in vivo genetic KO with specific substrate (K42) identified by MS, replicated across conditions","pmids":["20203611"],"is_preprint":false},{"year":2010,"finding":"SIRT3 is localized to the mitochondrial matrix and its expression is upregulated during fasting in liver and brown adipose tissue, consistent with a role as a metabolic sensor.","method":"Subcellular fractionation, tissue expression analysis in fasted vs. fed mice","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct fractionation and in vivo fasting experiments replicated across multiple studies","pmids":["20203611","22114326"],"is_preprint":false},{"year":2011,"finding":"SIRT3 directly deacetylates mitochondrial aldehyde dehydrogenase 2 (ALDH2); deacetylation increases acetaminophen toxic-metabolite binding to ALDH2, and SIRT3-KO mice are protected from acetaminophen hepatotoxicity.","method":"SIRT3-KO mouse model, direct substrate identification, in vivo hepatotoxicity assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypic rescue and direct substrate identified in one study","pmids":["21720390"],"is_preprint":false},{"year":2010,"finding":"Murine SIRT3 produces three protein isoforms (M1, M2, M3) from alternative transcripts; the longer M1 and M2 isoforms are targeted to mitochondria and processed to a mature form, while all three isoforms show deacetylase activity toward full-length protein substrates. The N-terminal amino acid of the mature M1 isoform was identified as Ile38 (majority) or Val42 by Edman degradation.","method":"Transient transfection, mitochondrial targeting assays, Edman degradation, deacetylase activity assays with acetylated peptide and protein substrates","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical assays (Edman degradation, enzymatic activity) with mutagenesis of ATG sites in a single rigorous study","pmids":["20677216"],"is_preprint":false},{"year":2019,"finding":"SIRT3 is SUMOylated in mitochondria; SUMOylation suppresses its catalytic deacetylase activity. During fasting, SENP1 translocates into mitochondria and deSUMOylates SIRT3, activating it and increasing fatty acid oxidation. SUMOylation-deficient Sirt3 mice show reduced fat mass and resistance to high-fat diet-induced obesity.","method":"SUMOylation assays, SENP1 knockdown/overexpression, mitochondrial fractionation, in vivo mouse models (fasting and HFD), mutant Sirt3 knock-in","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical SUMOylation assay, genetic SENP1 KO, SUMOylation-deficient mutant mice) from a single rigorous study","pmids":["31302001"],"is_preprint":false},{"year":2017,"finding":"SIRT3 depletion increases SOD2 acetylation, elevating mitochondrial superoxide and reducing endothelial nitric oxide. Angiotensin II-induced hypertension is associated with SIRT3 S-glutathionylation (redox inactivation) and consequent SOD2 hyperacetylation/inactivation. Mitochondria-targeted H2O2 scavenging prevented SIRT3 S-glutathionylation and reduced blood pressure in wild-type but not SIRT3-KO mice.","method":"SIRT3-KO mouse model, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant treatment, human hypertensive subject samples","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model, defined PTM (S-glutathionylation), pharmacological rescue, replicated in human samples","pmids":["28684630"],"is_preprint":false},{"year":2019,"finding":"SIRT3 deficiency in Sirt3-KO mice causes SOD2 hyperacetylation, vascular oxidative stress, endothelial dysfunction, vascular hypertrophy, NF-κB activation, vascular inflammation, and age-dependent hypertension. Transgenic SIRT3 overexpression prevents these effects and attenuates angiotensin II- and DOCA-salt-induced hypertension.","method":"Global SIRT3-KO and SIRT3-overexpressing transgenic mice, vascular function assays, SOD2 acetylation quantification, human mediastinal arteriole samples","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function mouse models, defined molecular substrate (SOD2), validated in human tissues","pmids":["31852393"],"is_preprint":false},{"year":2015,"finding":"SIRT3 enzymatic activity is enhanced by CDK1 (cyclin B1-CDK1)-mediated phosphorylation at Thr150/Ser159. Radiation induces CDK1 and SIRT3, and CDK1 relocalizes to mitochondria with SIRT3. Thr150Ala/Ser159Ala-mutant SIRT3 shows reduced mitochondrial protein deacetylation, reduced MnSOD activity, reduced ATP generation, and decreased clonogenicity and radioresistance.","method":"Site-directed mutagenesis, phosphorylation assays, mitochondrial fractionation, clonogenic survival assay, xenograft tumor model","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — phosphorylation site mutagenesis with multiple functional readouts (deacetylation, MnSOD activity, ATP, radioresistance) in one study","pmids":["26141949"],"is_preprint":false},{"year":2023,"finding":"SIRT3 functions as a delactylase that removes the lactyl moiety from lysine residues on non-histone proteins. Cyclin E2 (CCNE2) is identified as a SIRT3 delactylation substrate at K348; lactylated CCNE2 promotes HCC cell growth. Crystal structures of SIRT3 with lactyl-lysine peptides elucidate the mechanism of CCNE2 K348la delactylation.","method":"SILAC-based quantitative proteomics, crystallography, in vitro delactylation assay, in vivo HCC xenograft model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus proteomics identification of substrate plus in vivo tumor model, multiple orthogonal methods in one study","pmids":["36896611"],"is_preprint":false},{"year":2023,"finding":"SIRT3 exhibits delactylase activity toward the histone H4K16la site with higher activity than other human sirtuins. Crystal structures reveal the binding mechanism of lactyl-lysine peptides with SIRT3. A chemical probe (p-H4K16laAlk) pulled down SIRT3 from cell lysates, confirmed by proteomics.","method":"Biochemical delactylase assay, crystal structure determination, chemical probe pull-down with proteomic validation, fluorescent probe for real-time activity detection","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, enzymatic assay, and chemical probe pull-down in one study","pmids":["37720100"],"is_preprint":false},{"year":2019,"finding":"SIRT3 depletion in endothelial cells causes a shift toward higher mitochondrial respiration and ROS formation, reduces glycolytic enzyme PFKFB3 expression, and impairs glycolysis and angiogenesis. Endothelial-specific SIRT3 KO mice develop myocardial capillary rarefaction, reduced coronary flow reserve, perivascular fibrosis, and diastolic dysfunction.","method":"Endothelial-specific SIRT3 KO mice, Seahorse metabolic analysis, angiogenesis assays, echocardiography, histology","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with multiple functional readouts (metabolic, vascular, cardiac) and mechanistic pathway placement (PFKFB3)","pmids":["28935506"],"is_preprint":false},{"year":2019,"finding":"SIRT3 depletion impairs glutamine flux to the TCA cycle via glutamate dehydrogenase (GDH) and reduces acetyl-CoA pools, inducing autophagy and cell death in diffuse large B-cell lymphoma (DLBCL). SIRT3 KO attenuated B-cell lymphomagenesis in VavP-Bcl2 mice without affecting normal germinal center formation.","method":"SIRT3 KO mouse lymphoma model, metabolic flux analysis, GDH activity assay, pharmacological SIRT3 inhibitor (YC8-02)","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in disease model, defined metabolic mechanism (GDH/TCA/acetyl-CoA), pharmacological phenocopy","pmids":["31185214"],"is_preprint":false},{"year":2016,"finding":"SIRT3 overexpression in lung fibroblasts reverses TGF-β1-induced ROS production, mitochondrial DNA damage, and myofibroblast differentiation. SIRT3-KO mice show exacerbated bleomycin-induced pulmonary fibrosis with decreased OGG1 and increased 8-oxo-dG. SIRT3-overexpressing transgenic mice are protected from bleomycin-induced mtDNA damage and lung fibrosis.","method":"Adenovirus-mediated SIRT3 overexpression, SIRT3-KO mice, bleomycin lung fibrosis model, SIRT3 transgenic mice, mtDNA damage quantification","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with mechanistic link to OGG1/mtDNA protection","pmids":["27815257"],"is_preprint":false},{"year":2015,"finding":"Nuclear respiratory factor 2 (NRF-2) directly binds to the SIRT3 promoter and modulates SIRT3 transcript levels; NRF-2 knockdown or overexpression correspondingly reduces or increases SIRT3 expression.","method":"Bioinformatic promoter analysis, ChIP (NRF-2α binding to SIRT3 promoter), siRNA knockdown, overexpression in cell lines","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and knockdown/overexpression, single lab","pmids":["26109058"],"is_preprint":false},{"year":2018,"finding":"SIRT3 expression is downregulated during cell migration; SIRT3 controls ROS levels to repress Src oxidation and attenuate FAK activation, thereby inhibiting cell migration and metastasis. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells.","method":"Live cell imaging of mitochondria at leading edge, SIRT3 KD/OE, Src oxidation assay, FAK phosphorylation measurement, in vivo metastasis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging, defined molecular pathway (ROS→Src oxidation→FAK), loss/gain-of-function with in vivo validation","pmids":["29915029"],"is_preprint":false},{"year":2017,"finding":"SIRT3 deacetylates and activates citrate synthase (CS); MPP+-induced decrease in SIRT3 expression is associated with increased CS acetylation and reduced CS enzymatic activity, which is partially rescued by SIRT3 overexpression.","method":"SIRT3 overexpression in SH-SY5Y cells, CS activity assay, protein acetylation measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single cell model, partial rescue only; no direct deacetylation site identified","pmids":["28161643"],"is_preprint":false},{"year":2015,"finding":"SIRT3 deacetylates lactate dehydrogenase A (LDHA) and enhances its enzymatic activity in gastric cancer cells, promoting glycolysis.","method":"Co-immunoprecipitation, in vitro deacetylation assay, LDHA activity measurement, SIRT3 KD/OE in gastric cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, pulldown + activity assay without mutagenesis of specific lysine","pmids":["26121691"],"is_preprint":false},{"year":2020,"finding":"SIRT3 inhibits cardiac hypertrophy by accumulating in the nucleus under stress, interacting with PARP-1 via co-immunoprecipitation, and decreasing PARP-1 acetylation and activity.","method":"Adenovirus-mediated SIRT3 overexpression, co-immunoprecipitation, acetylation assay, cardiomyocyte hypertrophy model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP with acetylation measurement, no specific deacetylation site identified","pmids":["32139662"],"is_preprint":false},{"year":2022,"finding":"Mitochondrial NAD+ transporter SLC25A51 is required for SIRT3 activity; knockdown of Slc25a51 in hepatocytes decreases mitochondrial NAD+ and SIRT3 activity, reflected by increased acetylation of SIRT3 targets IDH2 and ACADL, and impairs mitochondrial oxygen consumption.","method":"shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, SIRT3 substrate acetylation by Western blot, Seahorse oxygen consumption assay, mouse liver-specific knockdown","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis between NAD+ transport and SIRT3 substrate acetylation; single lab, two orthogonal methods","pmids":["35932995"],"is_preprint":false},{"year":2021,"finding":"SIRT3 interacts with nuclear envelope proteins and heterochromatin-associated proteins; SIRT3 deficiency in human mesenchymal stem cells leads to detachment of lamina-associated domains from the nuclear lamina, increased chromatin accessibility, aberrant repetitive sequence transcription, and accelerated senescence. Re-introduction of SIRT3 rescues these phenotypes.","method":"CRISPR/Cas9 SIRT3 deletion, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, senescence assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal molecular readouts and rescue experiment, single lab","pmids":["33706382"],"is_preprint":false},{"year":2023,"finding":"SIRT3 deacetylates frataxin (FXN) at lysine 189; FXN hyperacetylation (K189) reduces iron-sulfur cluster synthesis and causes mitochondrial iron accumulation in cardiac macrophages, impairing efferocytosis and promoting cardiac inflammation. FXN K189R knock-in mice show improved macrophage efferocytosis and reduced cardiac fibrosis.","method":"Quantitative acetylome mass spectrometry, myeloid SIRT3 KO mice, FXN-K189R knock-in mice, iron-sulfur cluster assay, efferocytosis assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — acetylome MS identified specific site, knock-in mice with acetylation-defective mutation, multiple functional readouts (ISC synthesis, efferocytosis, inflammation)","pmids":["37646156"],"is_preprint":false},{"year":2023,"finding":"SIRT3 deacetylates PINK1, promoting mitophagy in liver fibrosis; SIRT3 also deacetylates NIPSNAP1. Simultaneous interference with PINK1 or NIPSNAP1 disrupts the ability of SIRT3 overexpression to improve mitophagy and attenuate ECM production in liver fibrosis models.","method":"Co-immunoprecipitation, acetylation assay, SIRT3 KO mice (CCl4 model), in vitro LX-2 cell overexpression/knockdown, mitophagy markers (LC3, p62, TOM20/LAMP1 colocalization)","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, acetylation measurement, genetic epistasis in KO mice; no specific acetylation site mapped by MS","pmids":["37417912"],"is_preprint":false},{"year":2023,"finding":"SIRT3 deacetylates LONP1 at lysine 145 (K145); LONP1 K145 hyperacetylation (mimicked by K145Q mutant) enhances oxidative phosphorylation to accelerate tumor growth, whereas the K145R deacetylation mutant restricts tumorigenesis. SIRT3-mediated K145 deacetylation facilitates ESCRT0-mediated K63-ubiquitination and degradation of oncogene LONP1.","method":"Mass spectrometry (deacetylation site), conditional intestinal Sirt3 KO mice (ApcMin/+), K145Q/K145R mutants, Seahorse metabolic assay, ubiquitination assay","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-identified deacetylation site, site-directed mutants with functional readouts, in vivo genetic model, mechanistic link to ubiquitination pathway","pmids":["36739437"],"is_preprint":false},{"year":2023,"finding":"SIRT3 deacetylates p53 at K320, reducing its transcriptional activity and protecting against PM2.5-induced pulmonary epithelial senescence and ferroptosis. PM2.5 decreases SIRT3 protein via the proteasome pathway by downregulating USP3.","method":"SIRT3 conditional KO mice (AT2 cell-specific), adenovirus-mediated SIRT3 overexpression, acetylation mapping by Western blot, RNA-seq/KEGG analysis, USP3 knockdown","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO, defined deacetylation site (K320), mechanistic pathway (USP3→SIRT3→p53Ac); single lab","pmids":["37348684"],"is_preprint":false},{"year":2024,"finding":"SIRT3 directly deacetylates PINK1 to promote mitophagy; PINK1 subsequently phosphorylates PKM2 at Ser127 to preserve its active tetrameric form, preventing nuclear translocation and β-catenin interaction, resulting in a metabolic shift in chondrocytes. Double-KO mice confirm the SIRT3-PINK1-PKM2 axis in protecting joint integrity.","method":"Direct deacetylation assay (SIRT3→PINK1), phosphorylation assay (PINK1→PKM2 S127), conditional SIRT3/PINK1 KO and double-KO mice, OA model","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct deacetylation and phosphorylation assays, specific sites identified, genetic double-KO model with functional rescue","pmids":["40087281"],"is_preprint":false},{"year":2022,"finding":"SIRT3 deacetylates TFAM at K5, K7, and K8 (identified by immunoprecipitation and mass spectrometry); decreased SIRT3 leads to TFAM hyperacetylation, mitochondrial dysfunction, and vascular dementia pathology.","method":"Co-immunoprecipitation, mass spectrometry for acetylation sites, SIRT3 knockdown with 3-TYP inhibitor, in vivo BCCAO VaD rat model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS-identified sites, in vivo model; single lab with pharmacological and genetic perturbation","pmids":["38547618"],"is_preprint":false},{"year":2022,"finding":"SIRT3 deficiency leads to hyperacetylation of succinate dehydrogenase, causing succinate accumulation that increases histone methylation on the Kruppel-like factor 4 (KLF4) promoter, suppressing KLF4 transcription and driving proinflammatory macrophage polarization in obesity.","method":"Macrophage-specific Sirt3 KO mice, succinate measurement, succinate dehydrogenase acetylation assay, KLF4 promoter histone methylation ChIP, HFD mouse model","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined substrate (SDH), metabolite measurement, and epigenetic readout; single lab","pmids":["36894333"],"is_preprint":false},{"year":2024,"finding":"SIRT3 binds to and deacetylates leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), modulating oxidative phosphorylation and oxidative stress; SIRT3-KO accelerates hPDLSC senescence while SIRT3 activation by honokiol delays senescence and promotes alveolar bone regeneration.","method":"Co-immunoprecipitation, SIRT3 KD/OE, in vitro senescence assays, in vivo DP mouse model with honokiol treatment","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional epistasis; no specific deacetylation site identified by MS; in vivo validation","pmids":["39557134"],"is_preprint":false},{"year":2023,"finding":"SIRT3 regulates SLC7A11 transcription through ATF4 in glioblastoma; SIRT3 inhibition leads to ferrous iron and ROS accumulation in mitochondria, triggering mitophagy and downregulating SLC7A11, sensitizing GBM cells to RSL3-induced ferroptosis. Forced SLC7A11 expression partially rescues viability upon SIRT3 knockdown.","method":"SIRT3 knockdown in GBM cells, RNA-seq, ATF4 pathway analysis, in vivo xenograft model, SLC7A11 rescue experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with RNA-seq pathway analysis and specific rescue experiment, in vivo validation; single lab","pmids":["38395990"],"is_preprint":false},{"year":2022,"finding":"Full-length SIRT3 (M1-SIRT3) expression in vivo prevents doxorubicin-induced cardiac dysfunction and remodeling. Deacetylase-deficient SIRT3 mutants are unable to prevent oxidative stress in cardiomyocytes, establishing that deacetylase activity is required for cardioprotection. Mass spectrometry identified 37 unique acetylation sites on cardiac mitochondrial proteins altered by doxorubicin.","method":"M1-SIRT3 and M3-SIRT3 transgenic mice, echocardiography, mass spectrometry of cardiac mitochondrial acetylome, deacetylase-deficient mutant adenoviruses in primary rat and human iPSC-derived cardiomyocytes","journal":"Circulation. Heart failure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — transgenic mouse model, MS acetylome, deacetylase-dead mutant, multiple orthogonal methods in one study","pmids":["35418250"],"is_preprint":false},{"year":2023,"finding":"The periostin/NAP1L2/SIRT3 axis mediates BCAA catabolism impairment in diabetic cardiomyopathy: periostin upregulates NAP1L2, which recruits SIRT3 to deacetylate H3K27ac on the promoters of BCAA catabolism enzymes BCAT2 and PP2Cm, resulting in their transcriptional suppression.","method":"RNA sequencing, ChIP for H3K27ac on BCAT2/PP2Cm promoters, periostin-KO and overexpression mice, CF-cardiomyocyte co-culture","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq, ChIP evidence for SIRT3 acting on histone acetylation at specific promoters; single lab with genetic mouse models","pmids":["37993768"],"is_preprint":false},{"year":2023,"finding":"S-sulfhydration of SIRT3 at CXXC sites of its zinc finger motif (by H2S/NaHS) enhances its deacetylase activity; mutation of these CXXC sites abolishes the anti-senescence effect of S-sulfhydration. SIRT3 S-sulfhydration stabilizes heterochromatin (H3K9me3/Lamin B1 interaction) and prevents mitochondrial fragmentation in BMSCs.","method":"S-sulfhydration assay, SIRT3 CXXC-site mutagenesis, SIRT3 KO cells and mice, in vivo OVX osteoporosis model with NaHS-pretreated BMSC transplantation","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined PTM with site-directed mutagenesis and functional rescue; single lab","pmids":["37146925"],"is_preprint":false},{"year":2016,"finding":"SIRT3 inhibits ovarian cancer metastasis and epithelial-to-mesenchymal transition (EMT) by downregulating Twist; an interaction between SIRT3 and Twist was detected by Co-IP. SIRT3 knockdown enhanced migration/invasion and liver metastasis in vivo, while overexpression suppressed them.","method":"Co-immunoprecipitation (SIRT3-Twist interaction), SIRT3 KD/OE in ovarian cancer cells, in vivo liver metastasis model, EMT marker analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction plus in vivo functional validation; no deacetylation of Twist demonstrated","pmids":["27216459"],"is_preprint":false},{"year":2022,"finding":"Sirt3 regulates osteocyte dendritic process formation and mechanosensing through the PKA/CREB signaling pathway, regulating E11/gp38 expression. Deletion of Sirt3 in osteocytes impairs dendritic processes and abolishes bone gain in response to exercise in vivo.","method":"Osteocyte-specific Sirt3 KO mice, exercise loading model, PKA/CREB pathway analysis, E11/gp38 expression, honokiol pharmacological activation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type specific KO with defined downstream pathway (PKA/CREB/E11) and pharmacological rescue; single lab","pmids":["36153410"],"is_preprint":false},{"year":2022,"finding":"AMPK activation promotes the SENP1-Sirt3 axis in renal proximal tubular cells, decreasing SUMOylation of Sirt3, reducing SOD2 acetylation and mitochondrial ROS, and protecting against acute kidney injury and subsequent fibrosis.","method":"Sirt3 SUMOylation-site mutant (KR) knock-in mice, metformin/AMPK pathway studies, AKI mouse models (FA and IRI), mitochondrial ROS measurement, metabolomics","journal":"Molecular therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in Sirt3 KR mice replicate findings from prior SENP1-Sirt3 study, metabolomics plus genetic/pharmacological convergence; confirms prior Molecular Cell findings","pmids":["37608549"],"is_preprint":false},{"year":2022,"finding":"1,4-dihydropyridine-based compounds identified as potent Sirt3-specific activators bind to the Sirtuin catalytic core independent of NAD+ and acylated peptides, stimulating turnover of peptide and protein substrates, and activate Sirt3 in cellular systems to regulate apoptosis and electron transport chain activity.","method":"In vitro sirtuin activity assay, binding assays, cell-based apoptosis and ETC activity assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted activity assay with binding and cellular validation; single study","pmids":["36228194"],"is_preprint":false}],"current_model":"SIRT3 is a mitochondrially localized, NAD+-dependent deacylase (deacetylase and delactylase) that is activated during fasting/caloric restriction via SENP1-mediated deSUMOylation and CDK1-mediated phosphorylation (T150/S159), and inactivated by S-glutathionylation or SUMOylation; it deacetylates a broad range of mitochondrial substrates—including LCAD (K42), SOD2, ALDH2, LONP1 (K145), frataxin (K189), PINK1, NIPSNAP1, LRPPRC, TFAM (K5/K7/K8), citrate synthase, and PARP-1—thereby regulating fatty acid oxidation, antioxidant defense, mitophagy, iron-sulfur cluster synthesis, macrophage efferocytosis, and heterochromatin stability; it also acts as a nuclear deacetylase under stress, and as a delactylase removing lactyl groups from histone H4K16 and non-histone proteins such as cyclin E2 (K348la) to suppress HCC growth."},"narrative":{"mechanistic_narrative":"SIRT3 is an NAD+-dependent mitochondrial matrix deacylase that functions as a metabolic and redox sensor, coupling nutrient status to the acetylation state of the mitochondrial proteome [PMID:20203611, PMID:22114326]. Its expression is driven transcriptionally by NRF-2 binding to the SIRT3 promoter [PMID:26109058] and upregulated during fasting [PMID:20203611, PMID:22114326], while its activity depends on mitochondrial NAD+ supplied through the transporter SLC25A51 [PMID:35932995]. SIRT3 deacetylates a broad set of mitochondrial substrates to govern distinct programs: LCAD at K42 to sustain fatty-acid oxidation [PMID:20203611], the antioxidant enzyme SOD2 to limit superoxide and preserve endothelial function [PMID:28684630, PMID:31852393], ALDH2 to modulate xenobiotic toxicity [PMID:21720390], frataxin at K189 to support iron-sulfur cluster synthesis and macrophage efferocytosis [PMID:37646156], LONP1 at K145 to direct its ubiquitin-dependent degradation and restrain tumor growth [PMID:36739437], TFAM at K5/K7/K8 [PMID:38547618], and PINK1 to promote mitophagy, including via a SIRT3–PINK1–PKM2 axis [PMID:37417912, PMID:40087281]. SIRT3 activity is tuned by multiple post-translational modifications: SUMOylation suppresses it and SENP1-mediated deSUMOylation activates it during fasting and AMPK signaling [PMID:31302001, PMID:37608549], CDK1-mediated phosphorylation at T150/S159 enhances it [PMID:26141949], S-glutathionylation inactivates it under oxidative stress [PMID:28684630], and S-sulfhydration of its zinc-finger CXXC sites stimulates it [PMID:37146925]. Beyond the matrix, SIRT3 accumulates in the nucleus under stress to deacetylate PARP-1 [PMID:32139662] and p53 at K320 [PMID:37348684], and interacts with nuclear-envelope and heterochromatin proteins to stabilize lamina-associated domains and prevent senescence [PMID:33706382]. SIRT3 additionally acts as a delactylase, removing lactyl groups from histone H4K16 and from non-histone proteins such as cyclin E2 at K348 to suppress hepatocellular carcinoma growth [PMID:36896611, PMID:37720100]. Through these activities SIRT3 broadly protects against oxidative stress, fibrosis, cardiac dysfunction, and inflammation while exerting context-dependent roles in tumor metabolism [PMID:31185214, PMID:27815257, PMID:29915029, PMID:35418250].","teleology":[{"year":2010,"claim":"Established SIRT3 as a fasting-induced mitochondrial deacetylase that directly controls a metabolic enzyme, defining its role as a nutrient-responsive regulator of fatty-acid oxidation.","evidence":"MS of mitochondrial proteins, in vitro deacetylation, and SIRT3-KO mice with metabolic phenotyping; subcellular fractionation in fasted vs fed mice","pmids":["20203611","22114326"],"confidence":"High","gaps":["Did not establish the full substrate repertoire","Mechanism linking fasting signals to SIRT3 activation not defined"]},{"year":2010,"claim":"Resolved the isoform structure and mitochondrial processing of SIRT3, showing multiple transcripts yield catalytically active deacetylase forms.","evidence":"Transient transfection, mitochondrial targeting assays, Edman degradation, and deacetylase activity assays in murine SIRT3","pmids":["20677216"],"confidence":"High","gaps":["Human isoform usage and tissue distribution not addressed","Relative in vivo activity of isoforms unresolved"]},{"year":2011,"claim":"Extended SIRT3 substrate range to ALDH2 and linked its deacetylation to xenobiotic detoxification phenotypes.","evidence":"SIRT3-KO mice with acetaminophen hepatotoxicity assay and direct substrate identification","pmids":["21720390"],"confidence":"High","gaps":["Specific ALDH2 acetylation site not mapped","Direction of net protection context-dependent"]},{"year":2015,"claim":"Identified post-translational activation of SIRT3 by CDK1 phosphorylation, connecting cell-cycle/DNA-damage signaling to mitochondrial deacetylase activity and radioresistance.","evidence":"Site-directed mutagenesis (T150A/S159A), phosphorylation assays, clonogenic and xenograft assays","pmids":["26141949"],"confidence":"High","gaps":["Whether phosphorylation alters substrate selectivity unknown","Structural basis of activation not defined"]},{"year":2015,"claim":"Showed transcriptional control of SIRT3 by NRF-2, placing SIRT3 expression downstream of a mitochondrial biogenesis transcription factor.","evidence":"Promoter bioinformatics, ChIP, siRNA knockdown and overexpression in cell lines","pmids":["26109058"],"confidence":"Medium","gaps":["Single lab","Physiological contexts where NRF-2 dominates SIRT3 regulation not defined"]},{"year":2017,"claim":"Defined redox inactivation of SIRT3 by S-glutathionylation, mechanistically linking oxidative stress to SOD2 hyperacetylation and hypertension.","evidence":"SIRT3-KO mice, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant, human samples","pmids":["28684630"],"confidence":"High","gaps":["Cysteine residue(s) of glutathionylation not pinpointed in this report","Reversal enzymology not characterized"]},{"year":2019,"claim":"Established SUMOylation as a reversible off-switch for SIRT3 and SENP1 as the fasting-activated deSUMOylase, defining a signaling route controlling fat metabolism.","evidence":"SUMOylation assays, SENP1 manipulation, mitochondrial fractionation, SUMO-deficient Sirt3 knock-in and HFD mouse models","pmids":["31302001"],"confidence":"High","gaps":["SUMO acceptor lysine context and SUMO ligase not fully defined","How SENP1 enters mitochondria mechanistically unresolved"]},{"year":2019,"claim":"Demonstrated cell-type-specific metabolic roles: endothelial SIRT3 supports glycolysis/angiogenesis via PFKFB3, and SIRT3 sustains glutamine flux to fuel lymphoma growth.","evidence":"Endothelial-specific and lymphoma SIRT3 KO mice, Seahorse and metabolic flux analysis, GDH activity, pharmacological inhibitor","pmids":["28935506","31185214"],"confidence":"High","gaps":["Tissue-specific substrate basis for opposing phenotypes not fully mapped","Mechanism of glycolytic regulation in endothelium incompletely defined"]},{"year":2021,"claim":"Revealed a nuclear/chromatin role for SIRT3 in maintaining lamina-associated domain attachment and preventing senescence, expanding its function beyond the matrix.","evidence":"CRISPR SIRT3 deletion in hMSCs, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, rescue","pmids":["33706382"],"confidence":"Medium","gaps":["Direct chromatin substrate(s) not identified","How matrix-targeted SIRT3 reaches the nucleus unresolved"]},{"year":2022,"claim":"Connected mitochondrial NAD+ import to SIRT3 catalytic competence, showing SLC25A51 is required to maintain SIRT3 substrate deacetylation.","evidence":"shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, substrate acetylation Western blots, Seahorse, mouse liver knockdown","pmids":["35932995"],"confidence":"Medium","gaps":["Single lab","Quantitative relationship between NAD+ levels and SIRT3 output not defined"]},{"year":2022,"claim":"Confirmed deacetylase activity is necessary for SIRT3 cardioprotection and that additional PTMs (S-sulfhydration) and metabolic substrates (SDH) integrate SIRT3 into redox, inflammation, and bone biology.","evidence":"M1/M3-SIRT3 transgenic mice with deacetylase-dead mutants, cardiac acetylome MS; CXXC-site mutagenesis; macrophage-specific KO with succinate/KLF4 readouts","pmids":["35418250","37146925","36894333"],"confidence":"High","gaps":["Substrates mediating each phenotype not all mapped","Interplay between distinct activating PTMs unresolved"]},{"year":2023,"claim":"Identified SIRT3 as a delactylase acting on histone H4K16la and non-histone cyclin E2 K348la, defining a tumor-suppressive epigenetic/metabolic function with structural mechanism.","evidence":"SILAC proteomics, crystal structures with lactyl-lysine peptides, in vitro delactylation assays, HCC xenografts, chemical-probe pull-down","pmids":["36896611","37720100"],"confidence":"High","gaps":["Full delactylation substrate landscape unknown","Relative physiological weight of deacetylase vs delactylase activity unresolved"]},{"year":2023,"claim":"Mapped specific deacetylation sites linking SIRT3 to iron-sulfur cluster synthesis (FXN K189) and oncogene turnover (LONP1 K145 via ESCRT/ubiquitination), with site-specific knock-in/mutant validation.","evidence":"Acetylome MS, FXN-K189R and LONP1 K145Q/K145R mutants, myeloid and intestinal Sirt3 KO mice, efferocytosis and ubiquitination assays","pmids":["37646156","36739437"],"confidence":"High","gaps":["How a single deacetylase coordinates these divergent programs unclear","Tissue-specific substrate prioritization not defined"]},{"year":2024,"claim":"Defined a SIRT3–PINK1–PKM2 mitophagy/metabolic axis with direct deacetylation and downstream phosphorylation events, validated genetically.","evidence":"Direct deacetylation and phosphorylation assays, conditional and double-KO mice in an osteoarthritis model","pmids":["40087281"],"confidence":"High","gaps":["PINK1 acetylation site(s) not mapped","Generality of the axis across tissues untested"]},{"year":null,"claim":"How SIRT3 substrate selection is partitioned across compartments (matrix deacetylation, nuclear deacetylation, and delactylation) and how its many activating/inhibiting PTMs are integrated in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for compartment-specific targeting","Quantitative hierarchy among PTM inputs unknown","Determinants of deacetylase vs delactylase preference undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,8,20,22,24,25]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,8,9,22]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[9,30]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17,19,23]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,11,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,6,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[21,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,22]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,19,30]}],"complexes":[],"partners":["SENP1","CDK1","PARP-1","LRPPRC","TFAM","PINK1","CCNE2","SLC25A51"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NTG7","full_name":"NAD-dependent protein deacetylase sirtuin-3, mitochondrial","aliases":["NAD-dependent protein delactylase sirtuin-3","Regulatory protein SIR2 homolog 3","SIR2-like protein 3"],"length_aa":399,"mass_kda":43.6,"function":"NAD-dependent protein deacetylase (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:19535340, PubMed:23283301, PubMed:24121500, PubMed:24252090). Activates or deactivates mitochondrial target proteins by deacetylating key lysine residues (PubMed:12186850, PubMed:12374852, PubMed:16788062, PubMed:18680753, PubMed:18794531, PubMed:23283301, PubMed:24121500, PubMed:24252090, PubMed:38146092). Known targets include ACSS1, IDH, GDH, SOD2, PDHA1, LCAD, SDHA, MRPL12 and the ATP synthase subunit ATP5PO (PubMed:16788062, PubMed:18680753, PubMed:19535340, PubMed:24121500, PubMed:24252090, PubMed:38146092). Contributes to the regulation of the cellular energy metabolism (PubMed:24252090). Important for regulating tissue-specific ATP levels (PubMed:18794531). In response to metabolic stress, deacetylates transcription factor FOXO3 and recruits FOXO3 and mitochondrial RNA polymerase POLRMT to mtDNA to promote mtDNA transcription (PubMed:23283301). Acts as a regulator of ceramide metabolism by mediating deacetylation of ceramide synthases CERS1, CERS2 and CERS6, thereby increasing their activity and promoting mitochondrial ceramide accumulation (By similarity). Regulates hepatic lipogenesis (By similarity). Uses NAD(+) substrate imported by SLC25A47, triggering downstream activation of PRKAA1/AMPK-alpha signaling cascade that ultimately downregulates sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance (By similarity). In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups, such as benzoyl and lactoyl, leading to protein debenzoylation and delactylation, respectively (PubMed:39524354, PubMed:36896611, PubMed:37720100). Catalyzes debenzoylation of PPIF and ACLY (PubMed:37720100). Mediates delactylation of CCNE2 and 'Lys-16' of histone H4 (H4K16la) (PubMed:36896611, PubMed:37720100)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9NTG7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRT3","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRT3","total_profiled":1310},"omim":[{"mim_id":"609576","title":"ACYL-CoA DEHYDROGENASE, LONG-CHAIN; ACADL","url":"https://www.omim.org/entry/609576"},{"mim_id":"604483","title":"SIRTUIN 5; SIRT5","url":"https://www.omim.org/entry/604483"},{"mim_id":"604481","title":"SIRTUIN 3; SIRT3","url":"https://www.omim.org/entry/604481"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIRT3"},"hgnc":{"alias_symbol":["SIR2L3"],"prev_symbol":[]},"alphafold":{"accession":"Q9NTG7","domains":[{"cath_id":"3.40.50.1220","chopping":"123-153_207-248_301-399","consensus_level":"medium","plddt":95.5063,"start":123,"end":399},{"cath_id":"3.30.1600.10","chopping":"156-204_250-292","consensus_level":"medium","plddt":89.9077,"start":156,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTG7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTG7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTG7-F1-predicted_aligned_error_v6.png","plddt_mean":75.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRT3","jax_strain_url":"https://www.jax.org/strain/search?query=SIRT3"},"sequence":{"accession":"Q9NTG7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NTG7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NTG7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTG7"}},"corpus_meta":[{"pmid":"20203611","id":"PMC_20203611","title":"SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20203611","citation_count":1398,"is_preprint":false},{"pmid":"23375372","id":"PMC_23375372","title":"SIRT3 reverses aging-associated degeneration.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23375372","citation_count":345,"is_preprint":false},{"pmid":"31852393","id":"PMC_31852393","title":"Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress.","date":"2019","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/31852393","citation_count":295,"is_preprint":false},{"pmid":"28684630","id":"PMC_28684630","title":"Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension.","date":"2017","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/28684630","citation_count":261,"is_preprint":false},{"pmid":"27686535","id":"PMC_27686535","title":"Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease.","date":"2016","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/27686535","citation_count":251,"is_preprint":false},{"pmid":"24324009","id":"PMC_24324009","title":"SirT3 regulates the mitochondrial unfolded protein response.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24324009","citation_count":243,"is_preprint":false},{"pmid":"33662874","id":"PMC_33662874","title":"Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis.","date":"2021","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/33662874","citation_count":227,"is_preprint":false},{"pmid":"36896611","id":"PMC_36896611","title":"SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/36896611","citation_count":212,"is_preprint":false},{"pmid":"22533670","id":"PMC_22533670","title":"SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/22533670","citation_count":200,"is_preprint":false},{"pmid":"24503539","id":"PMC_24503539","title":"Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24503539","citation_count":196,"is_preprint":false},{"pmid":"31302001","id":"PMC_31302001","title":"SENP1-Sirt3 Signaling Controls Mitochondrial Protein Acetylation and Metabolism.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31302001","citation_count":191,"is_preprint":false},{"pmid":"26138757","id":"PMC_26138757","title":"SIRT3 regulates progression and development of diseases of aging.","date":"2015","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/26138757","citation_count":173,"is_preprint":false},{"pmid":"21586315","id":"PMC_21586315","title":"SIRT3 and cancer: tumor promoter or suppressor?","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21586315","citation_count":165,"is_preprint":false},{"pmid":"22114326","id":"PMC_22114326","title":"SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism.","date":"2011","source":"Cold Spring Harbor symposia on quantitative biology","url":"https://pubmed.ncbi.nlm.nih.gov/22114326","citation_count":160,"is_preprint":false},{"pmid":"31160717","id":"PMC_31160717","title":"SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/31160717","citation_count":151,"is_preprint":false},{"pmid":"29643974","id":"PMC_29643974","title":"SIRT3: A New Regulator of Cardiovascular Diseases.","date":"2018","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/29643974","citation_count":149,"is_preprint":false},{"pmid":"33706382","id":"PMC_33706382","title":"SIRT3 consolidates heterochromatin and counteracts senescence.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33706382","citation_count":144,"is_preprint":false},{"pmid":"30131726","id":"PMC_30131726","title":"Acetylation of Mitochondrial Proteins in the Heart: The Role of SIRT3.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30131726","citation_count":138,"is_preprint":false},{"pmid":"30774023","id":"PMC_30774023","title":"SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30774023","citation_count":131,"is_preprint":false},{"pmid":"20685942","id":"PMC_20685942","title":"Mitochondrial SIRT3 and heart disease.","date":"2010","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/20685942","citation_count":129,"is_preprint":false},{"pmid":"37858064","id":"PMC_37858064","title":"Resveratrol reduces ROS-induced ferroptosis by activating SIRT3 and compensating the GSH/GPX4 pathway.","date":"2023","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/37858064","citation_count":125,"is_preprint":false},{"pmid":"28704962","id":"PMC_28704962","title":"SIRT3: Oncogene and Tumor Suppressor in Cancer.","date":"2017","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/28704962","citation_count":112,"is_preprint":false},{"pmid":"30132870","id":"PMC_30132870","title":"Emerging role of SIRT3 in endothelial metabolism, angiogenesis, and cardiovascular disease.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30132870","citation_count":104,"is_preprint":false},{"pmid":"28935506","id":"PMC_28935506","title":"Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28935506","citation_count":103,"is_preprint":false},{"pmid":"31185214","id":"PMC_31185214","title":"Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis.","date":"2019","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/31185214","citation_count":103,"is_preprint":false},{"pmid":"38744811","id":"PMC_38744811","title":"2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis.","date":"2024","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38744811","citation_count":102,"is_preprint":false},{"pmid":"37720100","id":"PMC_37720100","title":"Identification of SIRT3 as an eraser of H4K16la.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37720100","citation_count":93,"is_preprint":false},{"pmid":"36010672","id":"PMC_36010672","title":"The Role of SIRT3 in Exercise and Aging.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36010672","citation_count":93,"is_preprint":false},{"pmid":"28449871","id":"PMC_28449871","title":"SIRT3 and mitochondrial metabolism in neurodegenerative diseases.","date":"2017","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/28449871","citation_count":92,"is_preprint":false},{"pmid":"30485429","id":"PMC_30485429","title":"The novel relationship between Sirt3 and autophagy in myocardial ischemia-reperfusion.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30485429","citation_count":91,"is_preprint":false},{"pmid":"32468094","id":"PMC_32468094","title":"The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis.","date":"2020","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/32468094","citation_count":90,"is_preprint":false},{"pmid":"22016654","id":"PMC_22016654","title":"Sirt3, mitochondrial ROS, ageing, and carcinogenesis.","date":"2011","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22016654","citation_count":89,"is_preprint":false},{"pmid":"30126181","id":"PMC_30126181","title":"Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30126181","citation_count":88,"is_preprint":false},{"pmid":"26121691","id":"PMC_26121691","title":"SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26121691","citation_count":86,"is_preprint":false},{"pmid":"26141949","id":"PMC_26141949","title":"CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance.","date":"2015","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26141949","citation_count":85,"is_preprint":false},{"pmid":"29674007","id":"PMC_29674007","title":"Mst1 inhibits Sirt3 expression and contributes to diabetic cardiomyopathy through inhibiting Parkin-dependent mitophagy.","date":"2018","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29674007","citation_count":83,"is_preprint":false},{"pmid":"35100024","id":"PMC_35100024","title":"Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.","date":"2022","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/35100024","citation_count":82,"is_preprint":false},{"pmid":"27815257","id":"PMC_27815257","title":"SIRT3 blocks myofibroblast differentiation and pulmonary fibrosis by preventing mitochondrial DNA damage.","date":"2016","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27815257","citation_count":81,"is_preprint":false},{"pmid":"24192814","id":"PMC_24192814","title":"SIRT3: as simple as it seems?","date":"2013","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/24192814","citation_count":80,"is_preprint":false},{"pmid":"29129747","id":"PMC_29129747","title":"Mitochondrial SIRT3 and neurodegenerative brain disorders.","date":"2017","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/29129747","citation_count":77,"is_preprint":false},{"pmid":"28760703","id":"PMC_28760703","title":"Berberine-induced cardioprotection and Sirt3 modulation in doxorubicin-treated H9c2 cardiomyoblasts.","date":"2017","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/28760703","citation_count":71,"is_preprint":false},{"pmid":"30458637","id":"PMC_30458637","title":"Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases.","date":"2018","source":"Free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/30458637","citation_count":70,"is_preprint":false},{"pmid":"21720390","id":"PMC_21720390","title":"SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21720390","citation_count":70,"is_preprint":false},{"pmid":"37146925","id":"PMC_37146925","title":"S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis.","date":"2023","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/37146925","citation_count":69,"is_preprint":false},{"pmid":"35418250","id":"PMC_35418250","title":"Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress.","date":"2022","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/35418250","citation_count":68,"is_preprint":false},{"pmid":"26109058","id":"PMC_26109058","title":"Nuclear respiratory factor 2 induces SIRT3 expression.","date":"2015","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/26109058","citation_count":68,"is_preprint":false},{"pmid":"28717408","id":"PMC_28717408","title":"SIRT3 Enhances Mesenchymal Stem Cell Longevity and Differentiation.","date":"2017","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/28717408","citation_count":65,"is_preprint":false},{"pmid":"25332769","id":"PMC_25332769","title":"SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis.","date":"2014","source":"Cancer & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25332769","citation_count":64,"is_preprint":false},{"pmid":"38395990","id":"PMC_38395990","title":"Targeting SIRT3 sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38395990","citation_count":62,"is_preprint":false},{"pmid":"29915029","id":"PMC_29915029","title":"Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29915029","citation_count":62,"is_preprint":false},{"pmid":"36499074","id":"PMC_36499074","title":"Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36499074","citation_count":60,"is_preprint":false},{"pmid":"22119802","id":"PMC_22119802","title":"The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging.","date":"2011","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/22119802","citation_count":60,"is_preprint":false},{"pmid":"36336229","id":"PMC_36336229","title":"Sirt3 deficiency accelerates ovarian senescence without affecting spermatogenesis in aging mice.","date":"2022","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36336229","citation_count":60,"is_preprint":false},{"pmid":"37348684","id":"PMC_37348684","title":"PM2.5 contributed to pulmonary epithelial senescence and ferroptosis by regulating USP3-SIRT3-P53 axis.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37348684","citation_count":59,"is_preprint":false},{"pmid":"28161643","id":"PMC_28161643","title":"SIRT3 deacetylated and increased citrate synthase activity in PD model.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28161643","citation_count":59,"is_preprint":false},{"pmid":"37608549","id":"PMC_37608549","title":"AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury.","date":"2023","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37608549","citation_count":56,"is_preprint":false},{"pmid":"33508434","id":"PMC_33508434","title":"SIRT3 as a potential therapeutic target for heart failure.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33508434","citation_count":54,"is_preprint":false},{"pmid":"27791271","id":"PMC_27791271","title":"SirT3 and p53 Deacetylation in Aging and Cancer.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27791271","citation_count":53,"is_preprint":false},{"pmid":"27216459","id":"PMC_27216459","title":"Down-regulation of SIRT3 promotes ovarian carcinoma metastasis.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27216459","citation_count":52,"is_preprint":false},{"pmid":"27790619","id":"PMC_27790619","title":"SIRT3 in Cardiac Physiology and Disease.","date":"2016","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27790619","citation_count":50,"is_preprint":false},{"pmid":"37028501","id":"PMC_37028501","title":"Role of SIRT3 in mitochondrial biology and its therapeutic implications in neurodegenerative disorders.","date":"2023","source":"Drug discovery today","url":"https://pubmed.ncbi.nlm.nih.gov/37028501","citation_count":49,"is_preprint":false},{"pmid":"37646156","id":"PMC_37646156","title":"SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.","date":"2023","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/37646156","citation_count":44,"is_preprint":false},{"pmid":"32933202","id":"PMC_32933202","title":"SIRT1/SIRT3 Modulates Redox Homeostasis during Ischemia/Reperfusion in the Aging Heart.","date":"2020","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32933202","citation_count":43,"is_preprint":false},{"pmid":"36228194","id":"PMC_36228194","title":"Potent and Specific Activators for Mitochondrial Sirtuins Sirt3 and Sirt5.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36228194","citation_count":39,"is_preprint":false},{"pmid":"27393852","id":"PMC_27393852","title":"SIRT3 in cardiovascular diseases: Emerging roles and therapeutic implications.","date":"2016","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/27393852","citation_count":39,"is_preprint":false},{"pmid":"38234096","id":"PMC_38234096","title":"Hesperetin promotes diabetic wound healing by inhibiting ferroptosis through the activation of SIRT3.","date":"2024","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/38234096","citation_count":38,"is_preprint":false},{"pmid":"39157755","id":"PMC_39157755","title":"The role of SIRT3 in homeostasis and cellular health.","date":"2024","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39157755","citation_count":38,"is_preprint":false},{"pmid":"36435202","id":"PMC_36435202","title":"SIRT3 attenuates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome via autophagy.","date":"2022","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36435202","citation_count":38,"is_preprint":false},{"pmid":"36056557","id":"PMC_36056557","title":"SIRT3 regulates mitochondrial biogenesis in aging-related diseases.","date":"2022","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/36056557","citation_count":37,"is_preprint":false},{"pmid":"38242748","id":"PMC_38242748","title":"Context-dependent role of SIRT3 in cancer.","date":"2024","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38242748","citation_count":35,"is_preprint":false},{"pmid":"25806122","id":"PMC_25806122","title":"Expression of SIRT1 and SIRT3 varies according to age in mice.","date":"2015","source":"Anatomy & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25806122","citation_count":35,"is_preprint":false},{"pmid":"20677216","id":"PMC_20677216","title":"Characterization of murine SIRT3 transcript variants and corresponding protein products.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20677216","citation_count":34,"is_preprint":false},{"pmid":"32139662","id":"PMC_32139662","title":"SIRT3 inhibits cardiac hypertrophy by regulating PARP-1 activity.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32139662","citation_count":32,"is_preprint":false},{"pmid":"33231084","id":"PMC_33231084","title":"PGC-1α activates SIRT3 to modulate cell proliferation and glycolytic metabolism in breast cancer.","date":"2020","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/33231084","citation_count":32,"is_preprint":false},{"pmid":"27114304","id":"PMC_27114304","title":"Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27114304","citation_count":32,"is_preprint":false},{"pmid":"35571098","id":"PMC_35571098","title":"The Double-Edged Sword of SIRT3 in Cancer and Its Therapeutic Applications.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35571098","citation_count":31,"is_preprint":false},{"pmid":"38561088","id":"PMC_38561088","title":"SIRT3: A potential therapeutic target for liver fibrosis.","date":"2024","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38561088","citation_count":30,"is_preprint":false},{"pmid":"40087281","id":"PMC_40087281","title":"SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch.","date":"2025","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/40087281","citation_count":30,"is_preprint":false},{"pmid":"35932995","id":"PMC_35932995","title":"The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.","date":"2022","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/35932995","citation_count":29,"is_preprint":false},{"pmid":"32951306","id":"PMC_32951306","title":"Autophagy-Sirt3 axis decelerates hematopoietic aging.","date":"2020","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/32951306","citation_count":29,"is_preprint":false},{"pmid":"39000044","id":"PMC_39000044","title":"The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39000044","citation_count":29,"is_preprint":false},{"pmid":"38294557","id":"PMC_38294557","title":"SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38294557","citation_count":27,"is_preprint":false},{"pmid":"35409099","id":"PMC_35409099","title":"Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35409099","citation_count":27,"is_preprint":false},{"pmid":"36933487","id":"PMC_36933487","title":"Gastrodin alleviates rat chondrocyte senescence and mitochondrial dysfunction through Sirt3.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36933487","citation_count":27,"is_preprint":false},{"pmid":"35692409","id":"PMC_35692409","title":"The Role of SIRT3 in the Osteoporosis.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35692409","citation_count":26,"is_preprint":false},{"pmid":"38547618","id":"PMC_38547618","title":"Gastrodin alleviates mitochondrial dysfunction by regulating SIRT3-mediated TFAM acetylation in vascular dementia.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38547618","citation_count":26,"is_preprint":false},{"pmid":"35981603","id":"PMC_35981603","title":"Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation.","date":"2022","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35981603","citation_count":26,"is_preprint":false},{"pmid":"36598711","id":"PMC_36598711","title":"SIRT3 ameliorates polycystic ovary syndrome through FOXO1/PGC-1α signaling pathway.","date":"2023","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/36598711","citation_count":25,"is_preprint":false},{"pmid":"37417912","id":"PMC_37417912","title":"SIRT3 regulates mitophagy in liver fibrosis through deacetylation of PINK1/NIPSNAP1.","date":"2023","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37417912","citation_count":25,"is_preprint":false},{"pmid":"31085231","id":"PMC_31085231","title":"Probucol ameliorates EMT and lung fibrosis through restoration of SIRT3 expression.","date":"2019","source":"Pulmonary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31085231","citation_count":25,"is_preprint":false},{"pmid":"32229158","id":"PMC_32229158","title":"SIRT3 increases cisplatin sensitivity of small-cell lung cancer through apoptosis.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32229158","citation_count":25,"is_preprint":false},{"pmid":"37335900","id":"PMC_37335900","title":"SIRT3 Activator Honokiol Inhibits Th17 Cell Differentiation and Alleviates Colitis.","date":"2023","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37335900","citation_count":24,"is_preprint":false},{"pmid":"37993768","id":"PMC_37993768","title":"Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis.","date":"2023","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37993768","citation_count":24,"is_preprint":false},{"pmid":"36739437","id":"PMC_36739437","title":"Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36739437","citation_count":24,"is_preprint":false},{"pmid":"32468001","id":"PMC_32468001","title":"Effects of Sirt3‑autophagy and resveratrol activation on myocardial hypertrophy and energy metabolism.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/32468001","citation_count":24,"is_preprint":false},{"pmid":"39710830","id":"PMC_39710830","title":"Semaglutide protects against diabetes-associated cardiac inflammation via Sirt3-dependent RKIP pathway.","date":"2024","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39710830","citation_count":23,"is_preprint":false},{"pmid":"35086984","id":"PMC_35086984","title":"Mitochondrial deacetylase Sirt3 in vascular dysfunction and hypertension.","date":"2022","source":"Current opinion in nephrology and hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/35086984","citation_count":23,"is_preprint":false},{"pmid":"36153410","id":"PMC_36153410","title":"Sirt3 mediates the benefits of exercise on bone in aged mice.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36153410","citation_count":23,"is_preprint":false},{"pmid":"36894333","id":"PMC_36894333","title":"Mitochondrial dysfunction caused by SIRT3 inhibition drives proinflammatory macrophage polarization in obesity.","date":"2023","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/36894333","citation_count":23,"is_preprint":false},{"pmid":"39557134","id":"PMC_39557134","title":"SIRT3 alleviates mitochondrial dysfunction and senescence in diabetes-associated periodontitis by deacetylating LRPPRC.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39557134","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49539,"output_tokens":9151,"usd":0.142941,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19081,"output_tokens":4831,"usd":0.10809,"stage2_stop_reason":"end_turn"},"total_usd":0.251031,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"SIRT3 directly deacetylates long-chain acyl-CoA dehydrogenase (LCAD) at lysine 42 in vitro and in vivo; hyperacetylation of LCAD reduces its enzymatic activity, and SIRT3-knockout mice show impaired fatty-acid oxidation during fasting.\",\n      \"method\": \"Mass spectrometry of mitochondrial proteins, in vitro deacetylation assay, SIRT3-KO mouse model with metabolic phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay plus in vivo genetic KO with specific substrate (K42) identified by MS, replicated across conditions\",\n      \"pmids\": [\"20203611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIRT3 is localized to the mitochondrial matrix and its expression is upregulated during fasting in liver and brown adipose tissue, consistent with a role as a metabolic sensor.\",\n      \"method\": \"Subcellular fractionation, tissue expression analysis in fasted vs. fed mice\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct fractionation and in vivo fasting experiments replicated across multiple studies\",\n      \"pmids\": [\"20203611\", \"22114326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIRT3 directly deacetylates mitochondrial aldehyde dehydrogenase 2 (ALDH2); deacetylation increases acetaminophen toxic-metabolite binding to ALDH2, and SIRT3-KO mice are protected from acetaminophen hepatotoxicity.\",\n      \"method\": \"SIRT3-KO mouse model, direct substrate identification, in vivo hepatotoxicity assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypic rescue and direct substrate identified in one study\",\n      \"pmids\": [\"21720390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Murine SIRT3 produces three protein isoforms (M1, M2, M3) from alternative transcripts; the longer M1 and M2 isoforms are targeted to mitochondria and processed to a mature form, while all three isoforms show deacetylase activity toward full-length protein substrates. The N-terminal amino acid of the mature M1 isoform was identified as Ile38 (majority) or Val42 by Edman degradation.\",\n      \"method\": \"Transient transfection, mitochondrial targeting assays, Edman degradation, deacetylase activity assays with acetylated peptide and protein substrates\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical assays (Edman degradation, enzymatic activity) with mutagenesis of ATG sites in a single rigorous study\",\n      \"pmids\": [\"20677216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT3 is SUMOylated in mitochondria; SUMOylation suppresses its catalytic deacetylase activity. During fasting, SENP1 translocates into mitochondria and deSUMOylates SIRT3, activating it and increasing fatty acid oxidation. SUMOylation-deficient Sirt3 mice show reduced fat mass and resistance to high-fat diet-induced obesity.\",\n      \"method\": \"SUMOylation assays, SENP1 knockdown/overexpression, mitochondrial fractionation, in vivo mouse models (fasting and HFD), mutant Sirt3 knock-in\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical SUMOylation assay, genetic SENP1 KO, SUMOylation-deficient mutant mice) from a single rigorous study\",\n      \"pmids\": [\"31302001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT3 depletion increases SOD2 acetylation, elevating mitochondrial superoxide and reducing endothelial nitric oxide. Angiotensin II-induced hypertension is associated with SIRT3 S-glutathionylation (redox inactivation) and consequent SOD2 hyperacetylation/inactivation. Mitochondria-targeted H2O2 scavenging prevented SIRT3 S-glutathionylation and reduced blood pressure in wild-type but not SIRT3-KO mice.\",\n      \"method\": \"SIRT3-KO mouse model, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant treatment, human hypertensive subject samples\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model, defined PTM (S-glutathionylation), pharmacological rescue, replicated in human samples\",\n      \"pmids\": [\"28684630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT3 deficiency in Sirt3-KO mice causes SOD2 hyperacetylation, vascular oxidative stress, endothelial dysfunction, vascular hypertrophy, NF-κB activation, vascular inflammation, and age-dependent hypertension. Transgenic SIRT3 overexpression prevents these effects and attenuates angiotensin II- and DOCA-salt-induced hypertension.\",\n      \"method\": \"Global SIRT3-KO and SIRT3-overexpressing transgenic mice, vascular function assays, SOD2 acetylation quantification, human mediastinal arteriole samples\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function mouse models, defined molecular substrate (SOD2), validated in human tissues\",\n      \"pmids\": [\"31852393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIRT3 enzymatic activity is enhanced by CDK1 (cyclin B1-CDK1)-mediated phosphorylation at Thr150/Ser159. Radiation induces CDK1 and SIRT3, and CDK1 relocalizes to mitochondria with SIRT3. Thr150Ala/Ser159Ala-mutant SIRT3 shows reduced mitochondrial protein deacetylation, reduced MnSOD activity, reduced ATP generation, and decreased clonogenicity and radioresistance.\",\n      \"method\": \"Site-directed mutagenesis, phosphorylation assays, mitochondrial fractionation, clonogenic survival assay, xenograft tumor model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phosphorylation site mutagenesis with multiple functional readouts (deacetylation, MnSOD activity, ATP, radioresistance) in one study\",\n      \"pmids\": [\"26141949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 functions as a delactylase that removes the lactyl moiety from lysine residues on non-histone proteins. Cyclin E2 (CCNE2) is identified as a SIRT3 delactylation substrate at K348; lactylated CCNE2 promotes HCC cell growth. Crystal structures of SIRT3 with lactyl-lysine peptides elucidate the mechanism of CCNE2 K348la delactylation.\",\n      \"method\": \"SILAC-based quantitative proteomics, crystallography, in vitro delactylation assay, in vivo HCC xenograft model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus proteomics identification of substrate plus in vivo tumor model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36896611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 exhibits delactylase activity toward the histone H4K16la site with higher activity than other human sirtuins. Crystal structures reveal the binding mechanism of lactyl-lysine peptides with SIRT3. A chemical probe (p-H4K16laAlk) pulled down SIRT3 from cell lysates, confirmed by proteomics.\",\n      \"method\": \"Biochemical delactylase assay, crystal structure determination, chemical probe pull-down with proteomic validation, fluorescent probe for real-time activity detection\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, enzymatic assay, and chemical probe pull-down in one study\",\n      \"pmids\": [\"37720100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT3 depletion in endothelial cells causes a shift toward higher mitochondrial respiration and ROS formation, reduces glycolytic enzyme PFKFB3 expression, and impairs glycolysis and angiogenesis. Endothelial-specific SIRT3 KO mice develop myocardial capillary rarefaction, reduced coronary flow reserve, perivascular fibrosis, and diastolic dysfunction.\",\n      \"method\": \"Endothelial-specific SIRT3 KO mice, Seahorse metabolic analysis, angiogenesis assays, echocardiography, histology\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with multiple functional readouts (metabolic, vascular, cardiac) and mechanistic pathway placement (PFKFB3)\",\n      \"pmids\": [\"28935506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT3 depletion impairs glutamine flux to the TCA cycle via glutamate dehydrogenase (GDH) and reduces acetyl-CoA pools, inducing autophagy and cell death in diffuse large B-cell lymphoma (DLBCL). SIRT3 KO attenuated B-cell lymphomagenesis in VavP-Bcl2 mice without affecting normal germinal center formation.\",\n      \"method\": \"SIRT3 KO mouse lymphoma model, metabolic flux analysis, GDH activity assay, pharmacological SIRT3 inhibitor (YC8-02)\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in disease model, defined metabolic mechanism (GDH/TCA/acetyl-CoA), pharmacological phenocopy\",\n      \"pmids\": [\"31185214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT3 overexpression in lung fibroblasts reverses TGF-β1-induced ROS production, mitochondrial DNA damage, and myofibroblast differentiation. SIRT3-KO mice show exacerbated bleomycin-induced pulmonary fibrosis with decreased OGG1 and increased 8-oxo-dG. SIRT3-overexpressing transgenic mice are protected from bleomycin-induced mtDNA damage and lung fibrosis.\",\n      \"method\": \"Adenovirus-mediated SIRT3 overexpression, SIRT3-KO mice, bleomycin lung fibrosis model, SIRT3 transgenic mice, mtDNA damage quantification\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with mechanistic link to OGG1/mtDNA protection\",\n      \"pmids\": [\"27815257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nuclear respiratory factor 2 (NRF-2) directly binds to the SIRT3 promoter and modulates SIRT3 transcript levels; NRF-2 knockdown or overexpression correspondingly reduces or increases SIRT3 expression.\",\n      \"method\": \"Bioinformatic promoter analysis, ChIP (NRF-2α binding to SIRT3 promoter), siRNA knockdown, overexpression in cell lines\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and knockdown/overexpression, single lab\",\n      \"pmids\": [\"26109058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT3 expression is downregulated during cell migration; SIRT3 controls ROS levels to repress Src oxidation and attenuate FAK activation, thereby inhibiting cell migration and metastasis. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells.\",\n      \"method\": \"Live cell imaging of mitochondria at leading edge, SIRT3 KD/OE, Src oxidation assay, FAK phosphorylation measurement, in vivo metastasis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging, defined molecular pathway (ROS→Src oxidation→FAK), loss/gain-of-function with in vivo validation\",\n      \"pmids\": [\"29915029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT3 deacetylates and activates citrate synthase (CS); MPP+-induced decrease in SIRT3 expression is associated with increased CS acetylation and reduced CS enzymatic activity, which is partially rescued by SIRT3 overexpression.\",\n      \"method\": \"SIRT3 overexpression in SH-SY5Y cells, CS activity assay, protein acetylation measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell model, partial rescue only; no direct deacetylation site identified\",\n      \"pmids\": [\"28161643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIRT3 deacetylates lactate dehydrogenase A (LDHA) and enhances its enzymatic activity in gastric cancer cells, promoting glycolysis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, LDHA activity measurement, SIRT3 KD/OE in gastric cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pulldown + activity assay without mutagenesis of specific lysine\",\n      \"pmids\": [\"26121691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRT3 inhibits cardiac hypertrophy by accumulating in the nucleus under stress, interacting with PARP-1 via co-immunoprecipitation, and decreasing PARP-1 acetylation and activity.\",\n      \"method\": \"Adenovirus-mediated SIRT3 overexpression, co-immunoprecipitation, acetylation assay, cardiomyocyte hypertrophy model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP with acetylation measurement, no specific deacetylation site identified\",\n      \"pmids\": [\"32139662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mitochondrial NAD+ transporter SLC25A51 is required for SIRT3 activity; knockdown of Slc25a51 in hepatocytes decreases mitochondrial NAD+ and SIRT3 activity, reflected by increased acetylation of SIRT3 targets IDH2 and ACADL, and impairs mitochondrial oxygen consumption.\",\n      \"method\": \"shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, SIRT3 substrate acetylation by Western blot, Seahorse oxygen consumption assay, mouse liver-specific knockdown\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis between NAD+ transport and SIRT3 substrate acetylation; single lab, two orthogonal methods\",\n      \"pmids\": [\"35932995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT3 interacts with nuclear envelope proteins and heterochromatin-associated proteins; SIRT3 deficiency in human mesenchymal stem cells leads to detachment of lamina-associated domains from the nuclear lamina, increased chromatin accessibility, aberrant repetitive sequence transcription, and accelerated senescence. Re-introduction of SIRT3 rescues these phenotypes.\",\n      \"method\": \"CRISPR/Cas9 SIRT3 deletion, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, senescence assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal molecular readouts and rescue experiment, single lab\",\n      \"pmids\": [\"33706382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 deacetylates frataxin (FXN) at lysine 189; FXN hyperacetylation (K189) reduces iron-sulfur cluster synthesis and causes mitochondrial iron accumulation in cardiac macrophages, impairing efferocytosis and promoting cardiac inflammation. FXN K189R knock-in mice show improved macrophage efferocytosis and reduced cardiac fibrosis.\",\n      \"method\": \"Quantitative acetylome mass spectrometry, myeloid SIRT3 KO mice, FXN-K189R knock-in mice, iron-sulfur cluster assay, efferocytosis assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — acetylome MS identified specific site, knock-in mice with acetylation-defective mutation, multiple functional readouts (ISC synthesis, efferocytosis, inflammation)\",\n      \"pmids\": [\"37646156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 deacetylates PINK1, promoting mitophagy in liver fibrosis; SIRT3 also deacetylates NIPSNAP1. Simultaneous interference with PINK1 or NIPSNAP1 disrupts the ability of SIRT3 overexpression to improve mitophagy and attenuate ECM production in liver fibrosis models.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assay, SIRT3 KO mice (CCl4 model), in vitro LX-2 cell overexpression/knockdown, mitophagy markers (LC3, p62, TOM20/LAMP1 colocalization)\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, acetylation measurement, genetic epistasis in KO mice; no specific acetylation site mapped by MS\",\n      \"pmids\": [\"37417912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 deacetylates LONP1 at lysine 145 (K145); LONP1 K145 hyperacetylation (mimicked by K145Q mutant) enhances oxidative phosphorylation to accelerate tumor growth, whereas the K145R deacetylation mutant restricts tumorigenesis. SIRT3-mediated K145 deacetylation facilitates ESCRT0-mediated K63-ubiquitination and degradation of oncogene LONP1.\",\n      \"method\": \"Mass spectrometry (deacetylation site), conditional intestinal Sirt3 KO mice (ApcMin/+), K145Q/K145R mutants, Seahorse metabolic assay, ubiquitination assay\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-identified deacetylation site, site-directed mutants with functional readouts, in vivo genetic model, mechanistic link to ubiquitination pathway\",\n      \"pmids\": [\"36739437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 deacetylates p53 at K320, reducing its transcriptional activity and protecting against PM2.5-induced pulmonary epithelial senescence and ferroptosis. PM2.5 decreases SIRT3 protein via the proteasome pathway by downregulating USP3.\",\n      \"method\": \"SIRT3 conditional KO mice (AT2 cell-specific), adenovirus-mediated SIRT3 overexpression, acetylation mapping by Western blot, RNA-seq/KEGG analysis, USP3 knockdown\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO, defined deacetylation site (K320), mechanistic pathway (USP3→SIRT3→p53Ac); single lab\",\n      \"pmids\": [\"37348684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT3 directly deacetylates PINK1 to promote mitophagy; PINK1 subsequently phosphorylates PKM2 at Ser127 to preserve its active tetrameric form, preventing nuclear translocation and β-catenin interaction, resulting in a metabolic shift in chondrocytes. Double-KO mice confirm the SIRT3-PINK1-PKM2 axis in protecting joint integrity.\",\n      \"method\": \"Direct deacetylation assay (SIRT3→PINK1), phosphorylation assay (PINK1→PKM2 S127), conditional SIRT3/PINK1 KO and double-KO mice, OA model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct deacetylation and phosphorylation assays, specific sites identified, genetic double-KO model with functional rescue\",\n      \"pmids\": [\"40087281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT3 deacetylates TFAM at K5, K7, and K8 (identified by immunoprecipitation and mass spectrometry); decreased SIRT3 leads to TFAM hyperacetylation, mitochondrial dysfunction, and vascular dementia pathology.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry for acetylation sites, SIRT3 knockdown with 3-TYP inhibitor, in vivo BCCAO VaD rat model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS-identified sites, in vivo model; single lab with pharmacological and genetic perturbation\",\n      \"pmids\": [\"38547618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT3 deficiency leads to hyperacetylation of succinate dehydrogenase, causing succinate accumulation that increases histone methylation on the Kruppel-like factor 4 (KLF4) promoter, suppressing KLF4 transcription and driving proinflammatory macrophage polarization in obesity.\",\n      \"method\": \"Macrophage-specific Sirt3 KO mice, succinate measurement, succinate dehydrogenase acetylation assay, KLF4 promoter histone methylation ChIP, HFD mouse model\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined substrate (SDH), metabolite measurement, and epigenetic readout; single lab\",\n      \"pmids\": [\"36894333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT3 binds to and deacetylates leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), modulating oxidative phosphorylation and oxidative stress; SIRT3-KO accelerates hPDLSC senescence while SIRT3 activation by honokiol delays senescence and promotes alveolar bone regeneration.\",\n      \"method\": \"Co-immunoprecipitation, SIRT3 KD/OE, in vitro senescence assays, in vivo DP mouse model with honokiol treatment\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional epistasis; no specific deacetylation site identified by MS; in vivo validation\",\n      \"pmids\": [\"39557134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT3 regulates SLC7A11 transcription through ATF4 in glioblastoma; SIRT3 inhibition leads to ferrous iron and ROS accumulation in mitochondria, triggering mitophagy and downregulating SLC7A11, sensitizing GBM cells to RSL3-induced ferroptosis. Forced SLC7A11 expression partially rescues viability upon SIRT3 knockdown.\",\n      \"method\": \"SIRT3 knockdown in GBM cells, RNA-seq, ATF4 pathway analysis, in vivo xenograft model, SLC7A11 rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with RNA-seq pathway analysis and specific rescue experiment, in vivo validation; single lab\",\n      \"pmids\": [\"38395990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Full-length SIRT3 (M1-SIRT3) expression in vivo prevents doxorubicin-induced cardiac dysfunction and remodeling. Deacetylase-deficient SIRT3 mutants are unable to prevent oxidative stress in cardiomyocytes, establishing that deacetylase activity is required for cardioprotection. Mass spectrometry identified 37 unique acetylation sites on cardiac mitochondrial proteins altered by doxorubicin.\",\n      \"method\": \"M1-SIRT3 and M3-SIRT3 transgenic mice, echocardiography, mass spectrometry of cardiac mitochondrial acetylome, deacetylase-deficient mutant adenoviruses in primary rat and human iPSC-derived cardiomyocytes\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — transgenic mouse model, MS acetylome, deacetylase-dead mutant, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35418250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The periostin/NAP1L2/SIRT3 axis mediates BCAA catabolism impairment in diabetic cardiomyopathy: periostin upregulates NAP1L2, which recruits SIRT3 to deacetylate H3K27ac on the promoters of BCAA catabolism enzymes BCAT2 and PP2Cm, resulting in their transcriptional suppression.\",\n      \"method\": \"RNA sequencing, ChIP for H3K27ac on BCAT2/PP2Cm promoters, periostin-KO and overexpression mice, CF-cardiomyocyte co-culture\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq, ChIP evidence for SIRT3 acting on histone acetylation at specific promoters; single lab with genetic mouse models\",\n      \"pmids\": [\"37993768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S-sulfhydration of SIRT3 at CXXC sites of its zinc finger motif (by H2S/NaHS) enhances its deacetylase activity; mutation of these CXXC sites abolishes the anti-senescence effect of S-sulfhydration. SIRT3 S-sulfhydration stabilizes heterochromatin (H3K9me3/Lamin B1 interaction) and prevents mitochondrial fragmentation in BMSCs.\",\n      \"method\": \"S-sulfhydration assay, SIRT3 CXXC-site mutagenesis, SIRT3 KO cells and mice, in vivo OVX osteoporosis model with NaHS-pretreated BMSC transplantation\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined PTM with site-directed mutagenesis and functional rescue; single lab\",\n      \"pmids\": [\"37146925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIRT3 inhibits ovarian cancer metastasis and epithelial-to-mesenchymal transition (EMT) by downregulating Twist; an interaction between SIRT3 and Twist was detected by Co-IP. SIRT3 knockdown enhanced migration/invasion and liver metastasis in vivo, while overexpression suppressed them.\",\n      \"method\": \"Co-immunoprecipitation (SIRT3-Twist interaction), SIRT3 KD/OE in ovarian cancer cells, in vivo liver metastasis model, EMT marker analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction plus in vivo functional validation; no deacetylation of Twist demonstrated\",\n      \"pmids\": [\"27216459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sirt3 regulates osteocyte dendritic process formation and mechanosensing through the PKA/CREB signaling pathway, regulating E11/gp38 expression. Deletion of Sirt3 in osteocytes impairs dendritic processes and abolishes bone gain in response to exercise in vivo.\",\n      \"method\": \"Osteocyte-specific Sirt3 KO mice, exercise loading model, PKA/CREB pathway analysis, E11/gp38 expression, honokiol pharmacological activation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type specific KO with defined downstream pathway (PKA/CREB/E11) and pharmacological rescue; single lab\",\n      \"pmids\": [\"36153410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPK activation promotes the SENP1-Sirt3 axis in renal proximal tubular cells, decreasing SUMOylation of Sirt3, reducing SOD2 acetylation and mitochondrial ROS, and protecting against acute kidney injury and subsequent fibrosis.\",\n      \"method\": \"Sirt3 SUMOylation-site mutant (KR) knock-in mice, metformin/AMPK pathway studies, AKI mouse models (FA and IRI), mitochondrial ROS measurement, metabolomics\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in Sirt3 KR mice replicate findings from prior SENP1-Sirt3 study, metabolomics plus genetic/pharmacological convergence; confirms prior Molecular Cell findings\",\n      \"pmids\": [\"37608549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"1,4-dihydropyridine-based compounds identified as potent Sirt3-specific activators bind to the Sirtuin catalytic core independent of NAD+ and acylated peptides, stimulating turnover of peptide and protein substrates, and activate Sirt3 in cellular systems to regulate apoptosis and electron transport chain activity.\",\n      \"method\": \"In vitro sirtuin activity assay, binding assays, cell-based apoptosis and ETC activity assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted activity assay with binding and cellular validation; single study\",\n      \"pmids\": [\"36228194\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT3 is a mitochondrially localized, NAD+-dependent deacylase (deacetylase and delactylase) that is activated during fasting/caloric restriction via SENP1-mediated deSUMOylation and CDK1-mediated phosphorylation (T150/S159), and inactivated by S-glutathionylation or SUMOylation; it deacetylates a broad range of mitochondrial substrates—including LCAD (K42), SOD2, ALDH2, LONP1 (K145), frataxin (K189), PINK1, NIPSNAP1, LRPPRC, TFAM (K5/K7/K8), citrate synthase, and PARP-1—thereby regulating fatty acid oxidation, antioxidant defense, mitophagy, iron-sulfur cluster synthesis, macrophage efferocytosis, and heterochromatin stability; it also acts as a nuclear deacetylase under stress, and as a delactylase removing lactyl groups from histone H4K16 and non-histone proteins such as cyclin E2 (K348la) to suppress HCC growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRT3 is an NAD+-dependent mitochondrial matrix deacylase that functions as a metabolic and redox sensor, coupling nutrient status to the acetylation state of the mitochondrial proteome [#0, #1]. Its expression is driven transcriptionally by NRF-2 binding to the SIRT3 promoter [#13] and upregulated during fasting [#1], while its activity depends on mitochondrial NAD+ supplied through the transporter SLC25A51 [#18]. SIRT3 deacetylates a broad set of mitochondrial substrates to govern distinct programs: LCAD at K42 to sustain fatty-acid oxidation [#0], the antioxidant enzyme SOD2 to limit superoxide and preserve endothelial function [#5, #6], ALDH2 to modulate xenobiotic toxicity [#2], frataxin at K189 to support iron-sulfur cluster synthesis and macrophage efferocytosis [#20], LONP1 at K145 to direct its ubiquitin-dependent degradation and restrain tumor growth [#22], TFAM at K5/K7/K8 [#25], and PINK1 to promote mitophagy, including via a SIRT3–PINK1–PKM2 axis [#21, #24]. SIRT3 activity is tuned by multiple post-translational modifications: SUMOylation suppresses it and SENP1-mediated deSUMOylation activates it during fasting and AMPK signaling [#4, #34], CDK1-mediated phosphorylation at T150/S159 enhances it [#7], S-glutathionylation inactivates it under oxidative stress [#5], and S-sulfhydration of its zinc-finger CXXC sites stimulates it [#31]. Beyond the matrix, SIRT3 accumulates in the nucleus under stress to deacetylate PARP-1 [#17] and p53 at K320 [#23], and interacts with nuclear-envelope and heterochromatin proteins to stabilize lamina-associated domains and prevent senescence [#19]. SIRT3 additionally acts as a delactylase, removing lactyl groups from histone H4K16 and from non-histone proteins such as cyclin E2 at K348 to suppress hepatocellular carcinoma growth [#8, #9]. Through these activities SIRT3 broadly protects against oxidative stress, fibrosis, cardiac dysfunction, and inflammation while exerting context-dependent roles in tumor metabolism [#11, #12, #14, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established SIRT3 as a fasting-induced mitochondrial deacetylase that directly controls a metabolic enzyme, defining its role as a nutrient-responsive regulator of fatty-acid oxidation.\",\n      \"evidence\": \"MS of mitochondrial proteins, in vitro deacetylation, and SIRT3-KO mice with metabolic phenotyping; subcellular fractionation in fasted vs fed mice\",\n      \"pmids\": [\"20203611\", \"22114326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the full substrate repertoire\", \"Mechanism linking fasting signals to SIRT3 activation not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the isoform structure and mitochondrial processing of SIRT3, showing multiple transcripts yield catalytically active deacetylase forms.\",\n      \"evidence\": \"Transient transfection, mitochondrial targeting assays, Edman degradation, and deacetylase activity assays in murine SIRT3\",\n      \"pmids\": [\"20677216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human isoform usage and tissue distribution not addressed\", \"Relative in vivo activity of isoforms unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended SIRT3 substrate range to ALDH2 and linked its deacetylation to xenobiotic detoxification phenotypes.\",\n      \"evidence\": \"SIRT3-KO mice with acetaminophen hepatotoxicity assay and direct substrate identification\",\n      \"pmids\": [\"21720390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ALDH2 acetylation site not mapped\", \"Direction of net protection context-dependent\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified post-translational activation of SIRT3 by CDK1 phosphorylation, connecting cell-cycle/DNA-damage signaling to mitochondrial deacetylase activity and radioresistance.\",\n      \"evidence\": \"Site-directed mutagenesis (T150A/S159A), phosphorylation assays, clonogenic and xenograft assays\",\n      \"pmids\": [\"26141949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation alters substrate selectivity unknown\", \"Structural basis of activation not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed transcriptional control of SIRT3 by NRF-2, placing SIRT3 expression downstream of a mitochondrial biogenesis transcription factor.\",\n      \"evidence\": \"Promoter bioinformatics, ChIP, siRNA knockdown and overexpression in cell lines\",\n      \"pmids\": [\"26109058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological contexts where NRF-2 dominates SIRT3 regulation not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined redox inactivation of SIRT3 by S-glutathionylation, mechanistically linking oxidative stress to SOD2 hyperacetylation and hypertension.\",\n      \"evidence\": \"SIRT3-KO mice, S-glutathionylation assays, SOD2 acetylation measurement, mitochondria-targeted antioxidant, human samples\",\n      \"pmids\": [\"28684630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cysteine residue(s) of glutathionylation not pinpointed in this report\", \"Reversal enzymology not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established SUMOylation as a reversible off-switch for SIRT3 and SENP1 as the fasting-activated deSUMOylase, defining a signaling route controlling fat metabolism.\",\n      \"evidence\": \"SUMOylation assays, SENP1 manipulation, mitochondrial fractionation, SUMO-deficient Sirt3 knock-in and HFD mouse models\",\n      \"pmids\": [\"31302001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO acceptor lysine context and SUMO ligase not fully defined\", \"How SENP1 enters mitochondria mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated cell-type-specific metabolic roles: endothelial SIRT3 supports glycolysis/angiogenesis via PFKFB3, and SIRT3 sustains glutamine flux to fuel lymphoma growth.\",\n      \"evidence\": \"Endothelial-specific and lymphoma SIRT3 KO mice, Seahorse and metabolic flux analysis, GDH activity, pharmacological inhibitor\",\n      \"pmids\": [\"28935506\", \"31185214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific substrate basis for opposing phenotypes not fully mapped\", \"Mechanism of glycolytic regulation in endothelium incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a nuclear/chromatin role for SIRT3 in maintaining lamina-associated domain attachment and preventing senescence, expanding its function beyond the matrix.\",\n      \"evidence\": \"CRISPR SIRT3 deletion in hMSCs, Co-IP with nuclear/heterochromatin proteins, ATAC-seq, RNA-seq, rescue\",\n      \"pmids\": [\"33706382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin substrate(s) not identified\", \"How matrix-targeted SIRT3 reaches the nucleus unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected mitochondrial NAD+ import to SIRT3 catalytic competence, showing SLC25A51 is required to maintain SIRT3 substrate deacetylation.\",\n      \"evidence\": \"shRNA knockdown of Slc25a51, mitochondrial NAD+ measurement, substrate acetylation Western blots, Seahorse, mouse liver knockdown\",\n      \"pmids\": [\"35932995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative relationship between NAD+ levels and SIRT3 output not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed deacetylase activity is necessary for SIRT3 cardioprotection and that additional PTMs (S-sulfhydration) and metabolic substrates (SDH) integrate SIRT3 into redox, inflammation, and bone biology.\",\n      \"evidence\": \"M1/M3-SIRT3 transgenic mice with deacetylase-dead mutants, cardiac acetylome MS; CXXC-site mutagenesis; macrophage-specific KO with succinate/KLF4 readouts\",\n      \"pmids\": [\"35418250\", \"37146925\", \"36894333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates mediating each phenotype not all mapped\", \"Interplay between distinct activating PTMs unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SIRT3 as a delactylase acting on histone H4K16la and non-histone cyclin E2 K348la, defining a tumor-suppressive epigenetic/metabolic function with structural mechanism.\",\n      \"evidence\": \"SILAC proteomics, crystal structures with lactyl-lysine peptides, in vitro delactylation assays, HCC xenografts, chemical-probe pull-down\",\n      \"pmids\": [\"36896611\", \"37720100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full delactylation substrate landscape unknown\", \"Relative physiological weight of deacetylase vs delactylase activity unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped specific deacetylation sites linking SIRT3 to iron-sulfur cluster synthesis (FXN K189) and oncogene turnover (LONP1 K145 via ESCRT/ubiquitination), with site-specific knock-in/mutant validation.\",\n      \"evidence\": \"Acetylome MS, FXN-K189R and LONP1 K145Q/K145R mutants, myeloid and intestinal Sirt3 KO mice, efferocytosis and ubiquitination assays\",\n      \"pmids\": [\"37646156\", \"36739437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single deacetylase coordinates these divergent programs unclear\", \"Tissue-specific substrate prioritization not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a SIRT3–PINK1–PKM2 mitophagy/metabolic axis with direct deacetylation and downstream phosphorylation events, validated genetically.\",\n      \"evidence\": \"Direct deacetylation and phosphorylation assays, conditional and double-KO mice in an osteoarthritis model\",\n      \"pmids\": [\"40087281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PINK1 acetylation site(s) not mapped\", \"Generality of the axis across tissues untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIRT3 substrate selection is partitioned across compartments (matrix deacetylation, nuclear deacetylation, and delactylation) and how its many activating/inhibiting PTMs are integrated in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for compartment-specific targeting\", \"Quantitative hierarchy among PTM inputs unknown\", \"Determinants of deacetylase vs delactylase preference undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 8, 20, 22, 24, 25]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 8, 9, 22]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [9, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17, 19, 23]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 11, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 6, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [21, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 22]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 19, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SENP1\", \"CDK1\", \"PARP-1\", \"LRPPRC\", \"TFAM\", \"PINK1\", \"CCNE2\", \"SLC25A51\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}