Affinage

SOD2

Superoxide dismutase [Mn], mitochondrial · UniProt P04179

Round 2 corrected
Length
222 aa
Mass
24.8 kDa
Annotated
2026-04-28
130 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOD2 (MnSOD) is the principal mitochondrial matrix antioxidant enzyme, catalyzing dismutation of superoxide radical to hydrogen peroxide as a manganese-dependent homotetramer, thereby protecting Fe–S cluster-containing respiratory chain complexes (I, II) and aconitase from oxidative inactivation (PMID:1394426, PMID:7493016, PMID:26208779). Its activity is positively regulated by SIRT3-mediated deacetylation at K68 and CDK4-mediated phosphorylation at S106, while peroxynitrite-mediated nitration of the active-site Tyr34 is inactivating (PMID:21566644, PMID:25578653, PMID:9484232); acetylation at K68 switches SOD2 from a tetrameric dismutase to a monomeric iron-incorporating peroxidase that promotes cancer stemness via mtROS–HIF2α signaling (PMID:31160585, PMID:31591207). Homozygous loss-of-function SOD2 variants cause lethal neonatal dilated cardiomyopathy in mice and humans, and transcriptional control is mediated by FOXO3a, NF-κB (requiring C/EBPβ cofactor), and nuclear SIRT1, with translational upregulation via HuR binding the SOD2 3′UTR upon matrix detachment (PMID:7493016, PMID:31494578, PMID:12239572, PMID:16850160, PMID:20089851, PMID:35594792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    Determination of the 2.2 Å crystal structure established that SOD2 operates as a homotetramer with a novel 4-helix-bundle interface that positions four independent Mn active sites, providing the first atomic framework for understanding catalysis and regulation.

    Evidence X-ray crystallography of human mitochondrial MnSOD

    PMID:1394426

    Open questions at the time
    • Mechanism of superoxide entry into the active site channel not resolved at this resolution
    • No structure with substrate or product analogs
  2. 1995 High

    Mouse knockout studies answered whether SOD2 is essential: Sod2−/− mice die neonatally with dilated cardiomyopathy and loss of mitochondrial Fe–S cluster enzyme activities, establishing SOD2 as the non-redundant mitochondrial superoxide scavenger required for oxidative phosphorylation and organismal survival.

    Evidence Homozygous Sod2 knockout mice with cytochemical enzyme activity assays; complementary studies showed TNF-R1-mediated MnSOD induction and requirement for mitochondrial targeting

    PMID:7493016 PMID:7599209

    Open questions at the time
    • Relative contributions of individual respiratory complex damage versus aconitase loss to lethality were not separated
    • Tissue-specific conditional knockouts not yet available at this stage
  3. 1998 High

    Two advances resolved tissue-specific vulnerability and a key inactivation mechanism: pharmacological SOD mimetic rescue of Sod2−/− cardiac/hepatic pathology unmasked an obligate role for SOD2 in preventing CNS spongiform neurodegeneration, and biochemical reconstitution showed peroxynitrite (not NO or H₂O₂ alone) inactivates SOD2 via Tyr34 nitration.

    Evidence MnTBAP rescue of Sod2−/− mice with neuropathology analysis; in vitro peroxynitrite inactivation with electrospray mass spectrometry mapping of Tyr34, Tyr45, Tyr193 modifications

    PMID:9462746 PMID:9484232

    Open questions at the time
    • In vivo relevance of Tyr34 nitration in disease settings not yet demonstrated
    • Peroxynitrite-mediated dityrosine cross-linking stoichiometry and reversibility unclear
  4. 2002 High

    Identification of FOXO3a as a direct transcriptional activator of SOD2 linked insulin/Akt signaling to mitochondrial antioxidant defense, explaining how quiescent or nutrient-deprived cells upregulate SOD2 and connecting SOD2 to the conserved DAF-16/FOXO longevity pathway.

    Evidence Overexpression and dominant-negative FOXO3a constructs with mRNA, protein, ROS, and apoptosis readouts in mammalian cells

    PMID:12239572

    Open questions at the time
    • Whether FOXO3a binds the SOD2 promoter directly or through intermediaries was not resolved by ChIP in this study
    • Relative contribution of FOXO3a versus NF-κB to SOD2 transcription in different cell types not quantified
  5. 2006 Medium

    Discovery that C/EBPβ is an obligate cofactor for NF-κB-dependent SOD2 induction resolved how TNF drives SOD2 transcription: C/EBPβ is required for NF-κB p65 binding and histone acetylation at the intronic TNF-response element, and SOD2 expression alone bypasses the survival requirement for C/EBPβ.

    Evidence C/EBPβ-deficient fibroblasts with ectopic rescue, ChIP for NF-κB p65 and histone acetylation at SOD2 intronic element

    PMID:16850160

    Open questions at the time
    • Whether C/EBPβ physically interacts with p65 at the SOD2 locus or acts through chromatin remodeling was not distinguished
    • Role of C/EBPβ in non-TNF stimuli for SOD2 transcription not tested
  6. 2011 High

    Two regulatory mechanisms were defined: SIRT3 directly deacetylates SOD2 at K68 to activate its dismutase function, and USP36 deubiquitinates K48-linked polyubiquitin chains on SOD2 to prevent proteasomal degradation, establishing that SOD2 activity and abundance are under distinct post-translational control.

    Evidence In vitro deacetylation reconstitution with K68 mutagenesis and enzyme activity assays (SIRT3); co-IP, yeast two-hybrid, ubiquitination/cycloheximide chase (USP36)

    PMID:21268071 PMID:21566644

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting SOD2 for K48-linked ubiquitination was not determined
    • Relative contribution of K68 acetylation versus other acetylation sites to total SOD2 activity regulation not quantified
  7. 2013 High

    CDK4 was identified as a mitochondrial kinase that phosphorylates SOD2 at S106 to enhance activity in response to low-dose ionizing radiation, while rigorous immunolocalization definitively confirmed SOD2 is exclusively mitochondrial matrix-resident with no peroxisomal pool.

    Evidence In vitro kinase assay with S106A mutagenesis and mitochondria-targeted dominant-negative CDK4 in vivo; multi-modal immunoelectron microscopy and subcellular fractionation across tissues

    PMID:23744526 PMID:25578653

    Open questions at the time
    • Whether CDK4-mediated S106 phosphorylation operates outside of radiation contexts is unknown
    • Phosphatase that reverses S106 phosphorylation not identified
  8. 2015 High

    Overexpressed SOD2 was shown to generate a sustained mitochondrial H₂O₂ flux that activates AMPK and drives aerobic glycolysis, revealing a paradoxical pro-tumorigenic role for the canonical tumor suppressor when expression is elevated in cancer cells.

    Evidence SOD2 siRNA, AMPK inhibition, Seahorse metabolic profiling, transformation assays, clinical specimen correlation

    PMID:25651975

    Open questions at the time
    • Threshold of SOD2 expression at which the switch from tumor suppression to promotion occurs is not defined
    • Whether catalase co-expression fully reverses the metabolic reprogramming was not tested
  9. 2017 High

    The SIRT3–SOD2 K68 deacetylation axis was shown to operate in disease-relevant settings: angiotensin II-induced S-glutathionylation of SIRT3 causes SOD2 hyperacetylation in hypertension, and SIRT3-dependent SOD2 activation is required for osteoblast differentiation and bone formation.

    Evidence Sirt3−/−, SOD2+/− mice, angiotensin II infusion with human patient samples; SIRT3 knockdown/overexpression with SOD2 rescue in osteoblast differentiation

    PMID:28684630 PMID:28914882

    Open questions at the time
    • Whether other SIRT3 substrates contribute to hypertensive pathology independently of SOD2 not fully excluded
    • Site-specific acetylation status of SOD2 in hypertensive human patients not mapped
  10. 2019 High

    K68 acetylation was found to fundamentally switch SOD2's quaternary structure and catalytic identity: acetylated K68 destabilizes the tetramer, favoring iron-incorporating monomers with peroxidase activity that stabilize HIF2α and drive cancer stemness gene expression, and a human homozygous SOD2 missense variant (G181V) was identified as a cause of lethal neonatal dilated cardiomyopathy, confirming the mouse phenotype in humans.

    Evidence Physical K68-Ac protein via amber codon suppression, size-exclusion chromatography, metal analysis, xenograft/transformation assays, HIF2α stabilization/siRNA; exome sequencing of patient with lentiviral complementation rescue in fibroblasts

    PMID:31160585 PMID:31494578 PMID:31591207

    Open questions at the time
    • In vivo fraction of endogenous SOD2 that is monomeric/iron-bound in tumors not quantified
    • Whether peroxidase activity of monomeric SOD2 has physiological substrates beyond H₂O₂ is unknown
  11. 2021 Medium

    Molecular dynamics and physical K68-Ac reconstitution explained how acetylation destabilizes the α1/α2 helix interface to promote monomer formation and iron incorporation, and a novel acyl modification—K132 propionylation—was identified as an additional SIRT3-reversible mechanism that suppresses SOD2 activity.

    Evidence Amber codon suppression with metal and peroxidase assays plus molecular dynamics; global propionylation proteomics in zebrafish intestine with SIRT3 de-propionylation

    PMID:33867840 PMID:34142031

    Open questions at the time
    • K132 propionylation has only been characterized in zebrafish; relevance in mammalian systems is untested
    • Full structural model of monomeric Fe-SOD2 at atomic resolution is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase targeting SOD2, the structural basis of the tetramer-to-monomer transition at atomic resolution, the in vivo stoichiometry of K68 acetylation in normal versus tumor tissues, and whether the peroxidase activity of monomeric SOD2 has specific endogenous substrates or signaling targets beyond bulk H₂O₂.
  • E3 ligase for SOD2 ubiquitination unknown
  • No high-resolution structure of monomeric Fe-SOD2-K68Ac
  • Quantitative in vivo acetylation stoichiometry at K68 in human tissues not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016209 antioxidant activity 7 GO:0016491 oxidoreductase activity 6
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CDK4CEBPBELAVL1FOXO3ARELASIRT3USP36

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Crystal structure of human mitochondrial manganese superoxide dismutase (SOD2) determined at 2.2 Å resolution, revealing a homotetrameric enzyme where each subunit has an N-terminal helical hairpin and C-terminal α/β domain contributing ligands to the catalytic Mn site; two identical 4-helix bundles formed from N-terminal helical hairpins create novel tetrameric interfaces that stabilize the active sites. X-ray crystallography Cell High 1394426
1995 Homozygous knockout of Sod2 in mice causes neonatal lethality with dilated cardiomyopathy, hepatic lipid accumulation, and metabolic acidosis; cytochemical analysis revealed severe reduction of succinate dehydrogenase (complex II) and aconitase activities in the heart, establishing that SOD2 is required to protect mitochondrial enzymes from superoxide-mediated inactivation. Homologous recombination knockout mouse, cytochemical enzyme activity assays Nature genetics High 7493016
1995 TNF receptor 1 (TNF-R1), but not TNF-R2, mediates TNF/lymphotoxin-induced induction of MnSOD expression; overexpression of MnSOD (but not CuZn-SOD or EC-SOD) enhances cellular resistance to radiation, and mitochondrial matrix targeting is required—CuZn-SOD or EC-SOD fused to the MnSOD mitochondrial signal sequence confer protection, whereas MnSOD lacking its signal sequence does not. Receptor-specific knockout/overexpression, antisense RNA suppression, mitochondrial targeting signal swap constructs, radiation survival assay Biochimica et biophysica acta High 7599209
1995 HIV-1 Tat protein (C-terminal region) suppresses MnSOD mRNA, protein, and activity in T cells and HeLa cells, reducing glutathione levels and shifting the cellular redox state toward oxidation, thereby potentiating TNF-induced NF-κB activation and cytotoxicity. Stable transfection with tat gene, Tat truncation mutants, enzyme activity assays, glutathione measurements The EMBO journal Medium 7859743
1996 A diallelic polymorphism (Ala-9Val) in the mitochondrial targeting sequence (MTS) of human MnSOD gene was identified; computational analysis predicts the Ala-9 allele forms a typical amphiphilic helix required for mitochondrial transport, while the Val-9 allele disrupts this helix, suggesting a functional polymorphism affecting mitochondrial import efficiency. Population sequencing, secondary structure prediction of MTS amphiphilic helix Biochemical and biophysical research communications Medium 8806673
1998 Peroxynitrite completely inhibits MnSOD enzymatic activity in vitro via nitration of Tyr34 (active-site residue) and Tyr45/Tyr193, and oxidative formation of dityrosine cross-links producing higher-molecular-mass species; hydrogen peroxide or nitric oxide alone had no effect, identifying peroxynitrite as the specific inactivating oxidant. In vitro enzyme inactivation assay, electrospray mass spectrometry, real-time spectral analysis, tetranitromethane and HOCl controls Biochemistry High 9484232
1998 SOD2 knockout mice treated with the SOD mimetic MnTBAP (which does not cross the blood-brain barrier) are rescued from cardiomyopathy and hepatic pathology but develop spongiform degeneration of cortex and brainstem nuclei with gliosis, demonstrating that SOD2 loss causes progressive neurodegeneration driven by mitochondrial ROS specifically within the CNS. Sod2-/- mice, pharmacological SOD mimetic rescue (MnTBAP), neuropathological analysis Nature genetics High 9462746
2000 A cis-acting element in the 3' UTR of MnSOD mRNA (MnSOD-RE) functions as a translational enhancer in vivo: insertion of MnSOD-RE downstream of a CAT reporter increased CAT activity ~400% without altering CAT mRNA levels, demonstrating post-transcriptional regulation of MnSOD at the translational level. Transient transfection of CAT-reporter constructs with/without MnSOD 3'UTR element, RNA and activity measurements Biochemical and biophysical research communications Medium 10872821
2002 FOXO3a directly transcriptionally activates MnSOD (SOD2) in quiescent cells: FOXO3a increases MnSOD mRNA and protein, reduces ROS, and protects quiescent cells from glucose-deprivation-induced apoptosis; this mechanism operates in the absence of PKB/Akt activity and was confirmed in mammalian cells, extending the C. elegans DAF-16/MnSOD longevity model. Overexpression and dominant-negative FOXO3a constructs, mRNA/protein quantification, ROS measurement, apoptosis assay, PKB inhibition Nature High 12239572
2008 Epigenetic silencing of SOD2 in human breast cancer cells is mediated by decreased dimethyl H3K4 and acetylated H3K9 histone marks at SOD2 regulatory elements, creating repressive chromatin that reduces SP-1, AP-1, and NF-κB binding; treatment with HDAC inhibitors trichostatin A or sodium butyrate reactivates SOD2 expression. Chromatin immunoprecipitation (ChIP) for histone marks and transcription factors, HDAC inhibitor treatment, gene expression assays Free radical biology & medicine Medium 18845242
2010 Nuclear SIRT1 induces MnSOD expression in cardiomyocytes; in failing hearts SIRT1 translocates to the nucleus where it upregulates MnSOD, increasing resistance to oxidative stress. Resveratrol enhances nuclear SIRT1 and MnSOD induction; MnSOD siRNA abrogates the protective effects of nuclear SIRT1, demonstrating MnSOD is a required downstream effector. Subcellular fractionation, siRNA knockdown, overexpression constructs, in vivo hamster heart failure model with resveratrol treatment The Journal of biological chemistry Medium 20089851
2011 SIRT3 directly binds, deacetylates, and activates SOD2 at Lys68; acetylation of SOD2 at K68 decreases its enzymatic activity. Elevated ROS stimulates SIRT3 transcription, leading to SOD2 deacetylation and activation. SIRT3 co-expression synergistically increases SOD2-mediated ROS reduction, while SIRT3 depletion cancels it. Co-immunoprecipitation, in vitro deacetylation assay, acetylation-mimic and deacetylation-mimic mutants, enzyme activity assay, ROS measurement, SIRT3 overexpression/depletion EMBO reports High 21566644
2011 SOD2 protein stability is regulated by the deubiquitinating enzyme USP36: endogenous USP36 interacts with SOD2 (co-immunoprecipitation, yeast two-hybrid), SOD2 undergoes K48-linked polyubiquitination and proteasomal degradation, and USP36 reduces SOD2 ubiquitination and extends its half-life. 2-DE/MALDI-TOF/MS proteomics, co-immunoprecipitation, yeast two-hybrid, ubiquitination assay, cycloheximide chase Journal of cellular biochemistry Medium 21268071
2013 SOD2 is exclusively localized to mitochondria and is absent from peroxisomes in mammalian cells and tissues; established by double-immunofluorescence on frozen/paraffin sections, post-embedding immunoelectron microscopy on LR White and ultrathin cryo-sections, and Western blot of biochemically purified peroxisomal fractions from mouse liver. Multiple immunofluorescence modalities, immunoelectron microscopy with multiple gold techniques, subcellular fractionation/Western blot Histochemistry and cell biology High 23744526
2013 Cyclin D1/CDK4 translocates to mitochondria in response to low-dose ionizing radiation (LDIR) and directly phosphorylates MnSOD at serine-106 (S106), enhancing its enzymatic activity and mitochondrial respiration. A mitochondria-targeted dominant-negative CDK4 or MnSOD-S106A mutant abolishes LDIR-induced mitochondrial enhancement and adaptive radioprotection. Mitochondrial fractionation, in vitro kinase assay with site-directed mutagenesis (S106A), mitochondria-targeted dominant-negative CDK4, enzymatic activity assay, in vivo mouse LDIR model Free radical biology & medicine High 25578653
2015 SOD2 upregulation in cancer cells establishes a steady-state mitochondrial H2O2 flux that activates AMPK and drives metabolic reprogramming to aerobic glycolysis (Warburg effect); restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch, establishing a MnSOD→H2O2→AMPK→glycolysis axis. siRNA knockdown, AMPK inhibition, metabolic flux assays, cell viability assay, in vitro transformation assays, clinical specimen analysis Nature communications High 25651975
2015 CRISPR/Cas9-generated SOD2-null human cells (HEK293T) are completely devoid of MnSOD protein and activity, exhibiting impaired clonogenic survival, disrupted mitochondrial ultrastructure, preferential glycolysis over oxidative phosphorylation, and significantly impaired activities of mitochondrial complex I and II (containing Fe/S centers susceptible to superoxide), rescuable by pharmacological SOD mimetic GC4419 or hypoxia. CRISPR/Cas9 biallelic gene disruption, enzyme activity assays (complex I, II, MnSOD), Seahorse metabolic profiling, electron microscopy, pharmacological rescue Free radical biology & medicine High 26208779
2017 Sirt3 impairment in hypertension leads to SOD2 hyperacetylation and reduced SOD2 activity; angiotensin II induces Sirt3 S-glutathionylation, which inactivates Sirt3 and causes SOD2 acetylation. Mitochondria-targeted H2O2 scavenging prevents Sirt3 S-glutathionylation and SOD2 acetylation. SOD2 acetylation inversely correlates with SOD2 activity and directly correlates with hypertension severity in both mouse models and human essential hypertension. Sirt3-/- and SOD2+/- mouse models, angiotensin II infusion, S-glutathionylation assay, acetylation/activity measurements, mCAT transgenic mice, human patient samples Circulation research High 28684630
2017 During osteoblast differentiation, SIRT3 increases SOD2 activity through deacetylation specifically at K68; SIRT3 and SOD2 knockdown both suppress osteoblast differentiation, and SOD2 overexpression rescues differentiation in SIRT3-deficient osteoblasts, placing SIRT3→SOD2(K68 deacetylation) as required for eliminating mitochondrial superoxide during osteoblast differentiation and bone formation. siRNA knockdown, overexpression, SIRT3-/- mouse model, mitochondrial superoxide measurement, deacetylation at K68, osteoblast differentiation assays Cell death and differentiation High 28914882
2019 Acetylation of SOD2 at lysine 68 (K68Ac) converts the enzyme from a homotetrameric superoxide dismutase to a monomeric peroxidase; the K68Q acetylation-mimic mutant behaves as a tumor promoter (not suppressor) in transformation and xenograft assays, cells expressing K68Q or physically K68-acetylated SOD2 exhibit resistance to tamoxifen, and cells selected for tamoxifen resistance show increased K68-Ac and monomeric MnSOD. In vitro transformation and xenograft assays, biochemical stoichiometry analysis, acetylation-mimic (K68Q) and physical K68-Ac protein, peroxidase activity assay, size-exclusion chromatography (monomer vs. tetramer), tamoxifen resistance selection Nature communications High 31160585
2019 Acetylation of SOD2 at K68 promotes a functional switch: K68Ac stabilizes HIF2α via increased mitochondrial ROS, which in turn drives transcription of stemness genes (Oct4, Sox2, Nanog) in breast cancer cells, linking mitochondrial SOD2 acetylation state to cancer stem cell reprogramming. K68 acetylation-mimic expression, HIF2α protein stabilization assay, stemness gene expression, ROS measurement, siRNA knockdown of HIF2α Proceedings of the National Academy of Sciences of the United States of America Medium 31591207
2019 A homozygous missense variant in SOD2 (c.542G>T, p.Gly181Val) causes lethal neonatal dilated cardiomyopathy in a human patient; patient fibroblasts show significantly elevated superoxide levels and reduced SOD2 catalytic activity; lentiviral complementation with wild-type SOD2 completely restores mitochondrial SOD2 activity. Exome sequencing, hydroethidine oxidation assay (superoxide measurement), enzyme activity assay in patient fibroblasts and muscle, lentiviral complementation with wild-type SOD2 Journal of medical genetics High 31494578
2019 SOD2 mRNA translation is rapidly induced within 30 min of matrix detachment via the RNA-binding protein HuR/ELAVL1: anchorage-independence triggers cytosolic HuR accumulation, HuR binds SOD2 mRNA 3'UTR, and HuR siRNA knockdown abolishes the increase in SOD2 mRNA association with heavy polyribosomes and nascent SOD2 protein synthesis. p38 MAPK activation is required upstream of HuR-SOD2 mRNA interaction. Polyribosome profiling, RNA immunoprecipitation, HuR siRNA knockdown, p38 inhibition, nascent protein synthesis assay Redox biology Medium 35594792
2021 Propionylation of Sod2 at lysine 132 (K132) suppresses Sod2 enzymatic activity in zebrafish intestine; global lysine propionylation analysis identified K132 as the modified site, and biochemical assays confirmed K132 propionylation reduces activity. Sirt3 can remove the propionyl group (de-propionylation), restoring Sod2 activity. Global lysine propionylation proteomics, site-specific biochemical activity assay, Sirt3 de-propionylation assay, zebrafish intestinal model iScience Medium 34142031
2021 MnSOD K68 acetylation (K68Ac) causes monomeric SOD2 to incorporate iron (instead of manganese) at the active site, maximally inducing peroxidase activity; molecular dynamics of MnSOD-K68Ac and K68Q show significant change in charge distribution along α1 and α2 helices adjacent to the Mn2+ binding site, destabilizing the tetramer and explaining monomer enrichment and altered metal incorporation. Amber codon suppression to generate physically K68-Ac protein, peroxidase activity assay, metal analysis, molecular dynamics simulation, acetylation-mimic (K68Q) expression International journal of biological sciences Medium 33867840
2006 C/EBPβ is required for TNF-induced MnSOD expression and protection against TNF-induced apoptosis: C/EBPβ-deficient fibroblasts fail to induce MnSOD upon TNF stimulation and undergo apoptosis; ectopic C/EBPβ rescues MnSOD induction; MnSOD expression alone in C/EBPβ-deficient cells bypasses the requirement for C/EBPβ in survival. Mechanistically, C/EBPβ is required for NF-κB p65 binding to the intronic TNF-response element of MnSOD and for histone acetylation at that element. C/EBPβ-deficient fibroblasts, ectopic expression rescue, ChIP for NF-κB p65 and histone acetylation at MnSOD intronic element, MnSOD stable transfection Apoptosis Medium 16850160

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free radical biology & medicine 1562 12126755
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1995 Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nature genetics 1395 7493016
2002 Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 1334 12239572
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO reports 473 21566644
1998 Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 444 9484232
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2007 A common coding variant in CASP8 is associated with breast cancer risk. Nature genetics 431 17293864
1996 Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease. Biochemical and biophysical research communications 410 8806673
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
1998 A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase. Nature genetics 384 9462746
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
1992 The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles. Cell 370 1394426
2004 Vascular protection: superoxide dismutase isoforms in the vessel wall. Arteriosclerosis, thrombosis, and vascular biology 367 15166009
1995 HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. The EMBO journal 358 7859743
2016 LncRNA GClnc1 Promotes Gastric Carcinogenesis and May Act as a Modular Scaffold of WDR5 and KAT2A Complexes to Specify the Histone Modification Pattern. Cancer discovery 334 27147598
2015 SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 308 26120888
2010 Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. The Journal of biological chemistry 305 20089851
2013 SOD2 in mitochondrial dysfunction and neurodegeneration. Free radical biology & medicine 302 23727323
2001 Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proceedings of the National Academy of Sciences of the United States of America 300 11752456
2017 Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circulation research 256 28684630
2008 Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free radical biology & medicine 244 18930811
2017 SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell death and differentiation 239 28914882
2013 MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx. Antioxidants & redox signaling 234 23581847
2015 MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nature communications 218 25651975
2001 Association between manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk. Carcinogenesis 196 11323405
2005 Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 184 15862707
2013 Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxidants & redox signaling 165 23886445
1995 Protective roles of cytokines against radiation: induction of mitochondrial MnSOD. Biochimica et biophysica acta 152 7599209
2017 Insights into the Dichotomous Regulation of SOD2 in Cancer. Antioxidants (Basel, Switzerland) 138 29099803
2015 Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Scientific reports 138 26108578
1992 SOD2: a new type of tumor-suppressor gene? International journal of cancer 135 1592538
2011 Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti-cancer agents in medicinal chemistry 134 21434856
2011 Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging 124 21386137
2011 Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a new genetically tractable model for human cancer associated fibroblasts. Cancer biology & therapy 99 21150282
2007 SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy. Experimental neurology 92 17927981
2008 Dietary resveratrol administration increases MnSOD expression and activity in mouse brain. Biochemical and biophysical research communications 86 18486604
2010 Functional and behavioral restoration of vision by gene therapy in the guanylate cyclase-1 (GC1) knockout mouse. PloS one 81 20593011
2007 Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arteriosclerosis, thrombosis, and vascular biology 76 17556650
2008 The p53-p66shc-Manganese Superoxide Dismutase (MnSOD) network: a mitochondrial intrigue to generate reactive oxygen species. The international journal of biochemistry & cell biology 75 18992840
2005 Association between Ala-9Val polymorphism of Mn-SOD gene and schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 73 15610954
2014 SIRT3 protects cells from hypoxia via PGC-1α- and MnSOD-dependent pathways. Neuroscience 71 25433241
2008 Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk. Carcinogenesis 71 18784358
2019 LncRNA GClnc1 promotes proliferation and invasion of bladder cancer through activation of MYC. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 31298933
2008 Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells. Free radical biology & medicine 69 18845242
2014 Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. Redox biology 63 25462070
2013 A GC1 Acinetobacter baumannii isolate carrying AbaR3 and the aminoglycoside resistance transposon TnaphA6 in a conjugative plasmid. The Journal of antimicrobial chemotherapy 63 24235096
2007 Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines. British journal of cancer 63 17895890
2013 Mammalian SOD2 is exclusively located in mitochondria and not present in peroxisomes. Histochemistry and cell biology 62 23744526
2019 SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer. Proceedings of the National Academy of Sciences of the United States of America 58 31591207
2013 The MnSOD Ala16Val SNP: relevance to human diseases and interaction with environmental factors. Free radical research 56 23952573
2003 Overexpression of SOD2 increases salt tolerance of Arabidopsis. Plant physiology 55 14630955
2020 Caffeine Targets SIRT3 to Enhance SOD2 Activity in Mitochondria. Frontiers in cell and developmental biology 54 33015038
2013 MiR-146a regulates SOD2 expression in H2O2 stimulated PC12 cells. PloS one 54 23935993
2013 Sesamin ameliorates doxorubicin-induced cardiotoxicity: involvement of Sirt1 and Mn-SOD pathway. Toxicology letters 49 24211423
2021 SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells. Annals of surgical oncology 47 33393034
2011 Role of MnSOD and p66shc in mitochondrial response to p53. Antioxidants & redox signaling 47 20712406
2009 Association between manganese superoxide dismutase (MnSOD) gene polymorphism and elderly obesity. Molecular and cellular biochemistry 47 19262996
2006 Integrated molecular profiling of SOD2 expression in multiple myeloma. Blood 45 17192397
2023 Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition. BMC cancer 43 36737723
2019 Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter. Nature communications 43 31160585
2010 MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes. PloS one 43 20856861
2008 Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms. BMC structural biology 43 18237438
2016 Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis. Oncotarget 41 26543228
2011 Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator GC-1. Endocrinology 40 22067320
2005 Polymorphism in the manganese superoxide dismutase (MnSOD) gene and risk of breast cancer in young women. Journal of cancer research and clinical oncology 39 15883815
2014 Barley beta-glucan promotes MnSOD expression and enhances angiogenesis under oxidative microenvironment. Journal of cellular and molecular medicine 37 25388628
2012 Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer. Cancer 37 22517484
2004 Immunohistochemical expression of superoxide dismutase (MnSOD) anti-oxidant enzyme in invasive breast carcinoma. Histology and histopathology 37 15168344
2020 ACT001 modulates the NF-κB/MnSOD/ROS axis by targeting IKKβ to inhibit glioblastoma cell growth. Journal of molecular medicine (Berlin, Germany) 36 31901951
2010 Changes in TNFα, NFκB and MnSOD protein in the vestibular nuclei after unilateral vestibular deafferentation. Journal of neuroinflammation 36 21143912
2016 Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis. Oncology reports 35 27748853
2015 CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection. Free radical biology & medicine 35 25578653
2019 FTO Knockout Causes Chromosome Instability and G2/M Arrest in Mouse GC-1 Cells. Frontiers in genetics 33 30719031
2011 Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36. Journal of cellular biochemistry 33 21268071
2022 Osteoblast lineage Sod2 deficiency leads to an osteoporosis-like phenotype in mice. Disease models & mechanisms 31 35394023
2020 Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK-mediated energy metabolism. Molecular carcinogenesis 31 32149414
2019 Decoding the role of SOD2 in sickle cell disease. Blood advances 31 31506286
2018 Integrated phosphorescence-based photonic biosensor (iPOB) for monitoring oxygen levels in 3D cell culture systems. Biosensors & bioelectronics 31 30060990
2016 Characterization of the aodA, dnmA, mnSOD and pimA genes in Aspergillus nidulans. Scientific reports 31 26846452
2021 SP1-induced lncRNA ZFPM2 antisense RNA 1 (ZFPM2-AS1) aggravates glioma progression via the miR-515-5p/Superoxide dismutase 2 (SOD2) axis. Bioengineered 30 34077295
2019 Telomerase Does Not Improve DNA Repair in Mitochondria upon Stress but Increases MnSOD Protein under Serum-Free Conditions. International journal of molecular sciences 29 31861522
2017 Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression. Oncogenesis 28 28394354
2012 A manganese superoxide dismutase (SOD2)-mediated adaptive response. Radiation research 28 23237540
2024 The Thyroid Hormone Analog GC-1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 39373388
2023 Angelica sinensis polysaccharide improves mitochondrial metabolism of osteoarthritis chondrocytes through PPARγ/SOD2/ROS pathways. Phytotherapy research : PTR 27 37632225
2007 Selenium supplementation increases liver MnSOD expression: molecular mechanism for hepato-protection. Journal of inorganic biochemistry 27 17804075
2021 Regulation of Anti-Apoptotic SOD2 and BIRC3 in Periodontal Cells and Tissues. International journal of molecular sciences 26 33435582
2015 SOD2 targeted gene editing by CRISPR/Cas9 yields Human cells devoid of MnSOD. Free radical biology & medicine 26 26208779
2005 Adipocyte differentiation in Sod2(-/-) and Sod2(+/+) murine bone marrow stromal cells is associated with low antioxidant pools. Experimental hematology 25 16219542
2021 Propionate induces intestinal oxidative stress via Sod2 propionylation in zebrafish. iScience 24 34142031
2019 Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells. Archives of biochemistry and biophysics 24 31812668
2015 ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells. Molecular nutrition & food research 24 26443543
2014 SOD2 gene polymorphism and muscle damage markers in elite athletes. Free radical research 24 24865797
2011 Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer. Journal of gynecologic oncology 24 21860737
2018 Alterations in Sod2-Induced Oxidative Stress Affect Endocrine Cancer Progression. The Journal of clinical endocrinology and metabolism 23 30165401
2010 Cloning and expression of the Mn-SOD gene from Phascolosoma esculenta. Fish & shellfish immunology 23 20654721
2000 Mechanisms of sod2 gene amplification in Schizosaccharomyces pombe. Molecular biology of the cell 23 10712506
2022 Transcription factor Nrf2 binds to circRNAPIBF1 to regulate SOD2 in lung adenocarcinoma progression. Molecular carcinogenesis 22 36193777
2022 CREBH alleviates mitochondrial oxidative stress through SIRT3 mediating deacetylation of MnSOD and suppression of Nlrp3 inflammasome in NASH. Free radical biology & medicine 21 35926687
2020 The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway. Cell death and differentiation 21 32424140
2010 Modulation of MnSOD in Cancer:Epidemiological and Experimental Evidence. Toxicological research 21 24278510
1998 Manganese superoxide dismutase (MnSOD) and autoantibodies against MnSOD in acute viral infections. Journal of medical virology 21 9598938
2019 Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy. Journal of medical genetics 20 31494578
2017 TWEAK/Fn14 promotes oxidative stress through AMPK/PGC‑1α/MnSOD signaling pathway in endothelial cells. Molecular medicine reports 20 29257217
2006 C/EBPbeta regulates TNF induced MnSOD expression and protection against apoptosis. Apoptosis : an international journal on programmed cell death 20 16850160
2022 HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence. Redox biology 19 35594792
2021 PARK7 Protects Against Chronic Kidney Injury and Renal Fibrosis by Inducing SOD2 to Reduce Oxidative Stress. Frontiers in immunology 19 34093596
2022 The structure-function relationships and physiological roles of MnSOD mutants. Bioscience reports 18 35662317
2020 Association between SOD2 V16A variant and urological cancer risk. Aging 18 31929112
2019 Roles of the Two-MnSOD System of Stenotrophomonas maltophilia in the Alleviation of Superoxide Stress. International journal of molecular sciences 18 30974814
2000 A region in the 3' UTR of MnSOD RNA enhances translation of a heterologous RNA. Biochemical and biophysical research communications 18 10872821
2021 MnSOD Lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism. International journal of biological sciences 17 33867840
2017 Radiation-induced SOD2 overexpression sensitizes colorectal cancer to radiation while protecting normal tissue. Oncotarget 17 27999194
2023 Oroxylin A relieves intrauterine adhesion in mice through inhibiting macrophage pyroptosis via SIRT3-SOD2-ROS pathway. International immunopharmacology 16 36934562
2019 The inflammatory mediators TNFα and nitric oxide arrest spermatogonia GC-1 cell cycle. Reproductive biology 16 31757605
2012 The Ala16Val MnSOD gene polymorphism modulates oxidative response to exercise. Clinical biochemistry 16 23219743