Affinage

SOD2

Superoxide dismutase [Mn], mitochondrial · UniProt P04179

Length
222 aa
Mass
24.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOD2 (MnSOD) is a manganese-dependent homotetramer synthesized with a cleavable mitochondrial leader peptide that targets it exclusively to the mitochondrial matrix, where it dismutates superoxide to hydrogen peroxide and thereby governs mitochondrial redox homeostasis (PMID:12126755). Its metalloenzyme function depends on ZIP8-mediated manganese delivery (PMID:31086870), and complete loss of activity disrupts Fe/S-dependent respiratory complexes I and II, shifts cells toward glycolysis, and perturbs mitochondrial ultrastructure (PMID:26208779); a homozygous p.Gly181Val variant that abolishes catalytic activity causes lethal neonatal dilated cardiomyopathy, with wild-type complementation restoring activity in patient cells (PMID:31494578). SOD2 activity is bidirectionally tuned by post-translational modification: SIRT3 deacetylates conserved lysines including K68 to activate the dismutase, and loss of SIRT3 produces hyperacetylation, elevated superoxide, and tissue dysfunction across bone, vascular, and hepatic contexts (PMID:21386137, PMID:23886445, PMID:28914882, PMID:28684630, PMID:26120888); CDK4 translocating to mitochondria under low-dose radiation phosphorylates S106 to enhance activity during adaptive stress responses (PMID:25578653); and USP36 deubiquitination stabilizes the protein and extends its half-life (PMID:21268071). Acetylation at K68 also remodels SOD2's quaternary structure, converting the dismutase tetramer into a monomeric peroxidase that promotes transformation, stemness via HIF2α stabilization, and chemoresistance (PMID:31160585, PMID:31591207, PMID:33867840). The H2O2 product is itself a signaling output: SOD2-derived H2O2 activates AMPK to drive a glycolytic (Warburg) shift (PMID:25651975, PMID:32149414), suppresses the NLRP3 inflammasome (PMID:29972711), and at high flux drives autophagic cell death (PMID:20856861), explaining SOD2's context-dependent tumor-suppressive and tumor-promoting roles. Transcriptional induction proceeds through NF-κB/C/EBPβ acting at an intronic TNF response element (PMID:16850160), ZEB2 during TGF-β-driven EMT (PMID:25659582), and SIRT1–FoxO3a signaling (PMID:25450701), while HuR/p38 MAPK provides translational control under anchorage independence (PMID:35594792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2002 High

    Established the foundational identity of SOD2 as a Mn-containing matrix homotetramer that converts superoxide to H2O2, defining the enzymatic and compartmental basis for all subsequent function.

    Evidence Molecular and biochemical characterization, gene structure analysis

    PMID:12126755

    Open questions at the time
    • Does not address regulation of activity
    • Does not connect enzyme output to downstream signaling
  2. 1995 Medium

    Resolved whether SOD2's protective function depends on its location by showing mitochondrial targeting is necessary and sufficient for radiation protection, and placed SOD2 induction downstream of TNF-R1.

    Evidence Receptor-specific overexpression and signal peptide swap with radiation survival assays

    PMID:7599209

    Open questions at the time
    • Single lab
    • Does not define the transcriptional machinery linking TNF-R1 to SOD2
  3. 2006 Medium

    Defined the transcriptional logic of TNF-induced SOD2 expression by showing C/EBPβ enables NF-κB p65 binding and histone acetylation at an intronic TNF response element.

    Evidence C/EBPβ-deficient fibroblasts with ChIP and MnSOD rescue

    PMID:16850160

    Open questions at the time
    • Single lab
    • Does not address other inducers (Nrf2, FoxO3a)
  4. 2005 Medium

    Showed that SOD2's growth-inhibitory and anti-apoptotic effects are mediated by its H2O2 product rather than superoxide removal alone, establishing the enzyme product as the functional effector.

    Evidence Adenoviral/stable overexpression with catalase and GPx co-expression, cytochrome c release and growth assays

    PMID:15817612 PMID:15862707

    Open questions at the time
    • Overexpression contexts may not reflect endogenous flux
    • Single-lab readouts
  5. 2011 High

    Identified reversible acetylation as the principal switch on SOD2 activity and named SIRT3 as the deacetylase that activates the enzyme in response to mitochondrial nutrient/redox state.

    Evidence Acetylation assays with SIRT3 gain/loss and enzymatic activity measurement

    PMID:21386137

    Open questions at the time
    • Did not pinpoint individual lysines
    • Acetyltransferase writer not identified
  6. 2011 Medium

    Established protein-stability control of SOD2 by identifying USP36 as a deubiquitinase that binds SOD2 and extends its half-life.

    Evidence MS identification, reciprocal co-IP, yeast two-hybrid, ubiquitination and half-life assays

    PMID:21268071

    Open questions at the time
    • Cognate E3 ligase not identified
    • Single lab
  7. 2013 High

    Consolidated the SIRT3–SOD2 axis by showing direct site-specific deacetylation activates dismutase activity and that SIRT3 loss creates a tumor-permissive, hyperacetylated, ROS-rich state.

    Evidence Deacetylation assays with SIRT3 knockdown/knockout and activity measurement

    PMID:23886445

    Open questions at the time
    • Acetyltransferase still unidentified
    • Tissue-specific consequences not yet mapped
  8. 2015 High

    Demonstrated a second activating modification by showing CDK4 enters mitochondria after low-dose radiation and phosphorylates S106 to boost activity and respiration during adaptive protection.

    Evidence Mitochondrial fractionation, in vitro kinase assay, S106 mutagenesis, dominant-negative CDK4, in vivo mouse skin

    PMID:25578653

    Open questions at the time
    • Phosphatase reversing S106 unknown
    • Crosstalk with acetylation not defined
  9. 2015 High

    Localized SIRT3-mediated activation to K68 and proved its physiological importance in osteoblast differentiation via in vivo rescue in SIRT3-deficient mice.

    Evidence K68 deacetylation assay, SIRT3/SOD2 knockdown, osteoblast differentiation, SIRT3-KO mouse rescue

    PMID:28914882

    Open questions at the time
    • Other regulated lysines (K122) not addressed here
    • Does not address tumor contexts
  10. 2015 High

    Defined a downstream signaling role by showing SOD2-derived H2O2 activates AMPK to drive a glycolytic Warburg shift in cancer cells.

    Evidence Reciprocal SOD2 manipulation, AMPK and metabolic flux assays, xenografts

    PMID:25651975

    Open questions at the time
    • Direct H2O2 target on the AMPK pathway not identified
    • Threshold separating protective vs pro-tumor flux unclear
  11. 2015 High

    Showed that SIRT3 deacetylase activity is mechanistically required for SOD2-dependent control of mitochondrial superoxide and stress-induced autophagy, using a catalytic-dead SIRT3 mutant.

    Evidence SIRT3-H248Y catalytic mutant, acetylation and O2·- assays, autophagy readouts in HepG2 and in vivo

    PMID:26120888

    Open questions at the time
    • Does not identify SOD2 acetylation sites in this context
    • Other SIRT3 substrates may contribute
  12. 2015 High

    Defined SOD2 as essential for mitochondrial bioenergetics by showing complete null cells lose complex I/II activity through Fe/S center disruption and default to glycolysis.

    Evidence CRISPR biallelic SOD2 knockout in HEK293T, bioenergetics, complex assays, EM, SOD-mimetic rescue

    PMID:26208779

    Open questions at the time
    • Did not test tissue-specific bioenergetic consequences
    • Link to PTM-regulated activity not examined
  13. 2016 High

    Extended the SIRT3–K68 axis to vascular and skeletal pathophysiology, establishing that SOD2 acetylation inversely tracks activity and contributes to hypertension and bone remodeling.

    Evidence Sirt3-KO and SOD2+/- mice, angiotensin II model, K68 deacetylation and activity assays, in vivo calvaria knockdown

    PMID:27540894 PMID:28684630

    Open questions at the time
    • Mechanism upstream of SIRT3 modulation tissue-specific
    • Does not address acetyltransferase identity
  14. 2019 High

    Revealed a moonlighting function by showing K68 acetylation converts the dismutase tetramer into a monomeric peroxidase that acts as a tumor promoter and confers tamoxifen resistance.

    Evidence K68Q mimic and physically acetylated protein, native PAGE/gel filtration, peroxidase and transformation/xenograft assays

    PMID:31160585

    Open questions at the time
    • Acetyltransferase driving K68-Ac in tumors unidentified
    • In vivo prevalence of the monomer not quantified
  15. 2019 Medium

    Connected the acetylated monomer to cancer stemness by showing K68-Ac raises mtROS that stabilize HIF2α and activate Oct4/Sox2/Nanog.

    Evidence K68 acetylation analysis, mtROS and HIF2α stabilization assays, stemness gene expression in breast cancer cells

    PMID:31591207

    Open questions at the time
    • Single lab
    • Direct HIF2α oxidation target not defined
  16. 2021 Medium

    Provided structural rationale for the tetramer-to-monomer switch, showing K68 acetylation destabilizes the tetramer near the Mn site, favors Fe incorporation and peroxidase activity, and underlies cisplatin/doxorubicin resistance.

    Evidence K68Q mimic, molecular dynamics, peroxidase activity, drug resistance and mitochondrial morphology assays

    PMID:33867840

    Open questions at the time
    • Computational structural model awaits experimental structure
    • Single lab
  17. 2019 High

    Linked SOD2 catalytic loss directly to human Mendelian disease, identifying p.Gly181Val as causative for lethal neonatal dilated cardiomyopathy with complementation rescue.

    Evidence Exome sequencing, O2·- and activity assays in patient fibroblasts/muscle, lentiviral WT complementation

    PMID:31494578

    Open questions at the time
    • Single family
    • Mechanism of cardiac specificity not resolved
  18. 2019 Medium

    Identified ZIP8 as the manganese supply route required for SOD2 metalloenzyme function in myoblasts.

    Evidence ZIP8 siRNA, Mn supplementation rescue, ICP-MS, SOD2 activity assay

    PMID:31086870

    Open questions at the time
    • Single lab
    • Whether ZIP8 is the sole Mn route in other tissues unknown
  19. 2019 Medium

    Placed SOD2 within mutant-p53 redox control, showing mutant p53 induces SIRT3 to deacetylate and activate SOD2 and modulate proliferation.

    Evidence Mutant p53 cell lines, SIRT3 rescue, enzyme activity and ROS assays

    PMID:31812668

    Open questions at the time
    • Single lab
    • Direct vs indirect SIRT3 induction not separated
  20. 2014 Medium

    Defined a SIRT1–FoxO3a transcriptional arm controlling SOD2 expression, with angiotensin II suppressing SIRT1 to hyperacetylate FoxO3a and lower MnSOD.

    Evidence Angiotensin II osteoblast treatment, FoxO3a acetylation, MnSOD expression, SIRT1 activator and MnTBAP rescue

    PMID:25450701

    Open questions at the time
    • Single lab
    • Direct FoxO3a occupancy at SOD2 promoter not shown here
  21. 2020 Medium

    Demonstrated pharmacological tunability of the SIRT3–SOD2 axis by showing caffeine binds SIRT3 and enhances its deacetylation of SOD2 to raise activity.

    Evidence Binding affinity measurement, SIRT3 and SOD2 activity assays, 3-TYP inhibitor control

    PMID:33015038

    Open questions at the time
    • Single lab
    • In vivo specificity of caffeine effect uncertain
  22. 2022 Medium

    Identified translational regulation of SOD2 by showing HuR binds SOD2 mRNA upon anchorage-independence and, via p38 MAPK, boosts polysome loading and protein synthesis.

    Evidence Polyribosome profiling, RIP, HuR siRNA, p38 inhibition, nascent synthesis assay

    PMID:35594792

    Open questions at the time
    • Single lab
    • HuR binding site on SOD2 mRNA not mapped
  23. 2020 Medium

    Broadened SOD2's signaling outputs to inflammasome control, steroidogenesis, EMT restraint, and stromal cell fate, showing context-dependent roles via mtROS suppression.

    Evidence CRISPR/knockdown across periodontitis cells, granulosa cells, EMT models, and MSCs with inflammasome, hormone, CD44, and PGC-1α readouts

    PMID:25659582 PMID:29972711 PMID:32717420 PMID:38310354

    Open questions at the time
    • Each context single lab
    • Mechanistic convergence on a common mtROS threshold not established
  24. 2007 High

    Established the physiological essentiality of SOD2 in vivo by showing retinal knockdown causes oxidative damage, RPE degeneration, and photoreceptor apoptosis.

    Evidence AAV-ribozyme knockdown in mouse retina, ERG, oxidative damage MS, microscopy

    PMID:17898259

    Open questions at the time
    • Does not separate enzymatic from structural contributions
    • Tissue-specific to retina
  25. 2023 Medium

    Revealed an unexpected genome-stability function for mitochondrial Sod2, showing it cooperates with the Sgs1 helicase to suppress oxidative-stress-driven nuclear chromosomal rearrangements.

    Evidence Yeast genetic epistasis (sod2Δ sgs1Δ), paraquat stress, rearrangement reporter, Rad51/Pol32/Rev1 epistasis

    PMID:37638880

    Open questions at the time
    • Yeast ortholog study
    • Human relevance of the mito-to-nucleus genome link unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • The acetyltransferase(s) that acetylate SOD2 K68 to generate the tumor-promoting peroxidase monomer remain unidentified, leaving the writer side of the activating/inactivating PTM switch unresolved.
  • No K68 acetyltransferase identified in the corpus
  • How phosphorylation, acetylation, and ubiquitination integrate is unknown
  • No experimental high-resolution structure of the acetylated monomer

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0016209 antioxidant activity 3
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3
Partners
CDK4HURSIRT3USP36ZIP8

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SOD2 (MnSOD) is a manganese-containing homotetramer that is synthesized with a mitochondrial leader peptide targeting it exclusively to the mitochondrial matrix, where it catalyzes the dismutation of superoxide anions to hydrogen peroxide. Molecular characterization, gene structure analysis, biochemical characterization Free radical biology & medicine High 12126755
1995 TNF-R1 (but not TNF-R2) mediates TNF/LT-induced MnSOD expression, and MnSOD protection against radiation requires its mitochondrial localization — insertion of the mitochondrial signal sequence into CuZn-SOD or EC-SOD confers radiation protection, whereas MnSOD lacking the mitochondrial signal does not protect. Receptor-specific overexpression, signal peptide swap experiments, radiation survival assays Biochimica et biophysica acta Medium 7599209
2005 MnSOD overexpression inhibits proline oxidase (POX)-induced apoptosis in colorectal cancer cells by dramatically reducing cytochrome c release from mitochondria; the protective effect operates through scavenging superoxide radicals generated by POX, converting them to H2O2. Adenoviral overexpression of MnSOD in DLD-1 cells with inducible POX, cytochrome c release assay, ROS measurement Carcinogenesis Medium 15817612
2005 MnSOD overexpression produces a tumor-suppressive effect mediated primarily by the hydrogen peroxide generated from superoxide dismutation, as both catalase and glutathione peroxidase modulate the growth-inhibitory effect. Overexpression studies with antioxidant enzyme co-expression, growth inhibition assays across cancer cell lines Biomedicine & pharmacotherapy Medium 15862707
2011 MnSOD enzymatic activity is regulated by reversible acetylation of specific evolutionarily conserved lysines; SIRT3 deacetylates these lysines in response to changes in mitochondrial nutrient/redox status, enhancing MnSOD activity. Acetylation assays, SIRT3 overexpression/knockdown, enzymatic activity measurements Aging High 21386137
2011 USP36 is a deubiquitinating enzyme that interacts with SOD2 (confirmed by co-IP and yeast two-hybrid), reduces its polyubiquitination, and extends its half-life, thereby regulating SOD2 protein stability through the ubiquitin-proteasomal pathway. 2-DE/MALDI-TOF/MS identification, co-immunoprecipitation, yeast two-hybrid, ubiquitination assay, half-life measurement Journal of cellular biochemistry Medium 21268071
2013 SIRT3 directly deacetylates MnSOD at specific lysine residues to activate its enzymatic dismutase activity; loss of SIRT3 function leads to MnSOD hyperacetylation and reduced ROS scavenging, creating a tumor-permissive phenotype. Deacetylation assays, SIRT3 knockdown/knockout models, enzymatic activity measurements Antioxidants & redox signaling High 23886445
2015 MnSOD upregulation in cancer cells establishes a steady mitochondrial H2O2 flow that activates AMPK and drives metabolic shift to glycolysis (Warburg effect); restricting MnSOD expression or inhibiting AMPK suppresses this metabolic switch. MnSOD overexpression/knockdown in cancer cells, AMPK activity assays, metabolic flux measurements, xenograft models Nature communications High 25651975
2015 CDK4 translocates to mitochondria under low-dose ionizing radiation and directly phosphorylates MnSOD at serine-106 (S106), enhancing its enzymatic activity and mitochondrial respiration; mitochondria-targeted dominant-negative CDK4 or MnSOD-S106 mutant reverses this adaptive protection. Mitochondrial fractionation, in vitro kinase assay, site-directed mutagenesis, dominant-negative CDK4 constructs, enzymatic activity measurements Free radical biology & medicine High 25578653
2015 SIRT3 deacetylates SOD2 at K68 to enhance its activity during osteoblast differentiation; SIRT3 expression increases during differentiation and SOD2 knockdown suppresses differentiation, while SOD2 overexpression rescues osteoblast differentiation in SIRT3-deficient mice. SIRT3/SOD2 knockdown, K68 deacetylation assay, osteoblast differentiation assays, SIRT3-knockout mouse model Cell death and differentiation High 28914882
2016 Sirt3 depletion increases SOD2 acetylation, elevates mitochondrial superoxide, and diminishes endothelial nitric oxide; angiotensin II-induced hypertension involves Sirt3 S-glutathionylation, vascular SOD2 hyperacetylation, and reduced SOD2 activity. SOD2 acetylation inversely correlates with SOD2 activity. Sirt3-knockout and SOD2+/- mouse models, angiotensin II hypertension model, acetylation assays, SOD2 activity measurements, mitochondria-targeted antioxidant rescue Circulation research High 28684630
2016 Sirt3 deacetylates K68 of SOD2 to reduce mitochondrial ROS and suppress osteoclastogenesis; Sirt3-targeted siRNA decreases SOD2 deacetylation at K68, increasing osteoclast differentiation. In vivo knockdown of SOD2 or Sirt3 in mouse calvaria decreases bone volume and increases osteoclast surface. siRNA knockdown, site-specific deacetylation assay (K68), in vivo calvaria injection, bone volume measurements Journal of bone and mineral research High 27540894
2019 Acetylation of MnSOD at lysine 68 (K68-Ac) shifts its quaternary structure from a homotetramer (superoxide dismutase activity) to a monomer that functions as a peroxidase; MnSOD-K68Q (acetylation mimic) acts as a tumor promoter in transformation assays and confers tamoxifen resistance in breast cancer cells. K68Q acetylation-mimic mutation, in vitro transformation assay, xenograft growth assay, biochemical peroxidase activity assay, gel filtration/native PAGE for oligomeric state, physically acetylated K68-Ac protein analysis Nature communications High 31160585
2019 SOD2 K68 acetylation promotes breast cancer cell stemness by increasing mitochondrial ROS (mtROS), which stabilize HIF2α, activating stemness genes (Oct4, Sox2, Nanog). K68 acetylation analysis, mtROS measurement, HIF2α stabilization assay, stemness gene expression, breast cancer cell models Proceedings of the National Academy of Sciences of the United States of America Medium 31591207
2021 MnSOD-K68 acetylation mimic (MnSOD-K68Q) leads to cisplatin and doxorubicin resistance, shifts MnSOD to monomeric form, alters mitochondrial morphology and metabolism; the monomer appears to incorporate Fe to maximally induce peroxidase activity, with conformational change adjacent to Mn2+ binding site destabilizing the tetramer. Acetylation-mimic mutation, drug resistance assays, molecular dynamics simulation, biochemical peroxidase activity, mitochondrial structural analysis International journal of biological sciences Medium 33867840
2011 MnSOD upregulation in senescent keratinocytes produces H2O2 overproduction that drives autophagic cell death; overexpression of MnSOD or exogenous H2O2 reproduces the autophagic death, which is blocked by catalase treatment or autophagy inhibitors (3-methyladenine, anti-Atg5 siRNA). MnSOD overexpression, catalase rescue, autophagy inhibition (3-MA, Atg5 siRNA), lysotracker staining, LC3 vesiculation, TEM PloS one Medium 20856861
2015 SIRT3 depletion reduces SOD2 activity by promoting acetylation, leading to elevated mitochondrial O2•- and hepatotoxicity; a catalytically inactive SIRT3 mutant (SIRT3-H248Y) loses the capacity to suppress cadmium-induced autophagy, confirming deacetylase activity is required. SIRT3 overexpression with catalytic mutant (H248Y), SOD2 acetylation assay, mitochondrial O2•- measurement, autophagy assay in HepG2 cells and in vivo Autophagy High 26120888
2006 C/EBPβ is required for TNF-induced MnSOD expression and protection against TNF-induced apoptosis; mechanistically, C/EBPβ is required for NF-κB p65 binding to MnSOD's intronic TNF response element and for histone acetylation of that element in response to TNF. C/EBPβ-deficient fibroblasts, ectopic C/EBPβ expression, MnSOD stable transfection rescue, ChIP for NF-κB binding and histone acetylation Apoptosis Medium 16850160
2012 Intact TNF signaling (via TNFR1/R2) is required for low-dose ionizing radiation to induce elevated MnSOD activity and SOD2-mediated adaptive responses; amifostine (via its thiol WR1065) can directly activate NF-κB to elevate SOD2 activity independent of TNF receptors. SOD2 siRNA completely abolishes both SOD2 activity elevation and adaptive responses. TNFR1/R2 knockout cells and mice, SOD2 siRNA, micronucleus assay, SOD2 activity measurement Radiation research Medium 23237540
2015 SOD2 knockdown in human cells (CRISPR/Cas9 complete null) impairs mitochondrial bioenergetics; SOD2-null cells prefer glycolysis over oxidative phosphorylation and show impaired mitochondrial complex I and II activities (from disruption of Fe/S centers), with perturbed mitochondrial ultrastructure. CRISPR/Cas9 biallelic SOD2 knockout in HEK293T cells, mitochondrial bioenergetics assay, complex I/II activity, electron microscopy Free radical biology & medicine High 26208779
2019 Manganese influx via ZIP8 transporter is essential for SOD2 activity in skeletal myoblasts; ZIP8 knockdown impairs Mn-dependent SOD2 activity and can be partially rescued by Mn supplementation, demonstrating that ZIP8-mediated Mn delivery is required for SOD2 metalloenzyme function. ZIP8 siRNA knockdown, Mn supplementation rescue, SOD2 activity assay, ICP-MS metal quantification, cell differentiation assays Metallomics Medium 31086870
2019 Mutant p53 induces SIRT3 expression, which deacetylates MnSOD to enhance its enzymatic activity; SIRT3 restoration reverses MnSOD activity decrease caused by mutant p53 knockdown. MnSOD knockdown further enhances mutant p53-mediated ROS increase and counteracts cell hyperproliferation. p53 mutant cell lines, qPCR, immunoblotting, enzyme activity assay, SIRT3 overexpression rescue, ROS assay after transfection Archives of biochemistry and biophysics Medium 31812668
2020 Caffeine binds SIRT3 with high affinity (KD = 6.858×10⁻⁷ M) and promotes SIRT3-substrate binding, enhancing SIRT3 deacetylase activity toward SOD2, thereby reducing SOD2 acetylation and increasing SOD2 enzymatic activity. The SIRT3 inhibitor 3-TYP reverses caffeine-induced SOD2 activation. Binding affinity assay, SIRT3 enzyme activity assay, SOD2 acetylation measurement, 3-TYP inhibitor control, in vitro and in vivo models Frontiers in cell and developmental biology Medium 33015038
2019 A homozygous missense variant (p.Gly181Val) in SOD2 causes lethal neonatal dilated cardiomyopathy; patient fibroblasts show significantly increased superoxide levels and reduced SOD2 catalytic activity; lentiviral complementation with wild-type SOD2 completely restores mitochondrial SOD2 activity. Exome sequencing, hydroethidine oxidation assay for O2•-, SOD2 activity assay in patient fibroblasts and muscle, lentiviral wild-type SOD2 complementation Journal of medical genetics High 31494578
2022 HuR (ELAVL1) RNA-binding protein accumulates in the cytosol upon anchorage-independence and binds SOD2 mRNA, promoting increased association with heavy polyribosomes and nascent SOD2 protein synthesis. p38 MAPK activation is necessary for HuR-SOD2 mRNA interactions and induction of SOD2 protein output in detached cells. Polyribosome profiling, HuR siRNA knockdown, RIP assay, p38 inhibition, nascent protein synthesis assay Redox biology Medium 35594792
2007 SOD2 knockdown in RPE cells via AAV-delivered ribozyme reduces MnSOD protein, increases superoxide, causes oxidative protein damage, progressive loss of electroretinograph response, RPE degeneration, Bruch's membrane thickening, and photoreceptor apoptosis — establishing SOD2 as essential for RPE and retinal function. AAV-delivered ribozyme knockdown of MnSOD in mouse retina, ERG, immunoblot, LC-MS/MS oxidative damage markers, light/electron microscopy Investigative ophthalmology & visual science High 17898259
2010 MnSOD overexpression in LNCaP prostate cancer cells induces neuroendocrine (NE) differentiation features including synaptophysin expression, androgen independence, Bcl-2 upregulation, and prevention of docetaxel/etoposide/TNF-induced cell death; the effects are linked to reduced superoxide and elevated H2O2 levels. Stable MnSOD-overexpressing LNCaP clones, NE marker expression (synaptophysin), androgen receptor localization, apoptosis assays with multiple chemotherapeutics, ROS measurement Free radical biology & medicine Medium 21056653
2020 SOD2 drives glycolysis via H2O2-mediated AMPK activation in colorectal cancer; proper SOD2 levels maintain mitochondrial function by superoxide disposal, while overexpression induces H2O2-mediated AMPK upregulation and glycolysis. SOD2 knockdown in CRC cell lines, mitochondrial function assays, AMPK activation measurement, glycolysis measurement, proliferation/migration/invasion assays Molecular carcinogenesis Medium 32149414
2017 SOD2 expression is transcriptionally upregulated during TGF-β-induced EMT by NF-κB and ZEB2 (but not ZEB1); SOD2-mediated antioxidant activity restricts early conversion of CD44L epithelial cells to CD44H mesenchymal cells and suppresses TGF-β-mediated ROS induction and senescence. Genetically engineered cell lines, RNAi knockdown, flow cytometry for CD44 subpopulations, TGF-β stimulation, transcription factor pathway analysis Oncogene Medium 25659582
2014 Angiotensin II inhibits SIRT1 in osteoblasts, leading to hyperacetylation of FoxO3a, which reduces expression of MnSOD and catalase, causing mitochondrial oxidative stress and mtDNA damage; SIRT1 activator (SRT3025) or MnSOD mimetic (MnTBAP) rescue these effects. Angiotensin II treatment of osteoblasts, SIRT1/SIRT3 protein level analysis, FoxO3a acetylation assay, MnSOD mRNA/protein measurement, pharmacological rescue Biochemical and biophysical research communications Medium 25450701
2020 SOD2 deficiency-induced oxidative stress in granulosa cells decreases progesterone and estradiol production by reducing StAR protein gene expression, key steroidogenic enzyme genes, and impairing cholesterol transport from cytosol to mitochondria. Sod2+/- mouse model, granulosa cell isolation, steroid hormone measurement, qRT-PCR for StAR and steroidogenic enzymes, lipid peroxidation assay Molecular and cellular endocrinology Medium 32717420
2020 SOD2 knockdown in periodontitis cells leads to increased NLRP3 inflammasome component production; SOD2 is upregulated through the NF-κB pathway and exerts a protective role by suppressing the NLRP3 inflammasome-caspase-1-IL-1β axis. CRISPR/Cas9 SOD2 knockout, immunoblot for NLRP3 components, NF-κB pathway analysis Oral diseases Medium 29972711
2020 IT (IFN-γ + TNF-α) cytokine stimulation upregulates SOD2 in MSCs, decreasing mitochondrial ROS; SOD2 knockdown leads to enhanced adipogenic differentiation but reduced immunosuppression; SOD2-dependent suppression of mtROS inhibits PGC-1α expression and mitochondrial biogenesis while promoting glycolysis. SOD2 knockdown in human adipose-MSCs, adipogenic differentiation assay, immunosuppression co-culture assay, mtROS measurement, PGC-1α expression, DSS colitis mouse model Molecular therapy Medium 38310354
2023 Mitochondrial Sod2 genetically interacts with the DNA helicase Sgs1 to suppress nuclear chromosomal rearrangements under oxidative stress; PQ-induced chromosome rearrangements in the absence of Sod2 are promoted by Rad51 recombinase and the polymerase subunit Pol32, and depend on Rev1/Pol ζ translesion synthesis. Genetic epistasis in yeast (sod2Δ sgs1Δ double mutant), paraquat-induced oxidative stress, chromosomal rearrangement reporter assay, Rad51/Pol32/Rev1 epistasis Genetics Medium 37638880

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 1581 12126755
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 336 27147598
2015 SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 312 26120888
2013 SOD2 in mitochondrial dysfunction and neurodegeneration. Free radical biology & medicine 307 23727323
2017 Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circulation research 261 28684630
2017 SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. Cell death and differentiation 243 28914882
2013 MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx. Antioxidants & redox signaling 236 23581847
2015 MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nature communications 219 25651975
2007 SOD2 knockdown mouse model of early AMD. Investigative ophthalmology & visual science 197 17898259
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 166 23886445
1995 Protective roles of cytokines against radiation: induction of mitochondrial MnSOD. Biochimica et biophysica acta 152 7599209
2015 Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Scientific reports 142 26108578
2017 Insights into the Dichotomous Regulation of SOD2 in Cancer. Antioxidants (Basel, Switzerland) 139 29099803
2011 Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti-cancer agents in medicinal chemistry 135 21434856
1992 SOD2: a new type of tumor-suppressor gene? International journal of cancer 135 1592538
2011 Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging 124 21386137
2016 SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 118 27540894
2005 MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells. Carcinogenesis 114 15817612
2000 MnSOD expression is increased in metastatic gastric cancer. The Journal of surgical research 111 10644478
2006 MnSOD deficiency increases endothelial dysfunction in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 107 16873728
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
2007 Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arteriosclerosis, thrombosis, and vascular biology 76 17556650
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 70 31298933
2015 Mitochondrial SOD2 regulates epithelial-mesenchymal transition and cell populations defined by differential CD44 expression. Oncogene 69 25659582
2007 Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines. British journal of cancer 63 17895890
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 59 31591207
2013 The MnSOD Ala16Val SNP: relevance to human diseases and interaction with environmental factors. Free radical research 57 23952573
2020 Caffeine Targets SIRT3 to Enhance SOD2 Activity in Mitochondria. Frontiers in cell and developmental biology 54 33015038
2017 SIRT3-SOD2-ROS pathway is involved in linalool-induced glioma cell apoptotic death. Acta biochimica Polonica 50 28567457
2021 SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells. Annals of surgical oncology 48 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
2023 Depletion of SOD2 enhances nasopharyngeal carcinoma cell radiosensitivity via ferroptosis induction modulated by DHODH inhibition. BMC cancer 45 36737723
2006 Integrated molecular profiling of SOD2 expression in multiple myeloma. Blood 45 17192397
2019 Lysine 68 acetylation directs MnSOD as a tetrameric detoxification complex versus a monomeric tumor promoter. Nature communications 44 31160585
2010 MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes. PloS one 44 20856861
2016 Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis. Oncotarget 41 26543228
2020 SOD2 deficiency-induced oxidative stress attenuates steroidogenesis in mouse ovarian granulosa cells. Molecular and cellular endocrinology 40 32717420
2016 SOD2 and the Mitochondrial UPR: Partners Regulating Cellular Phenotypic Transitions. Trends in biochemical sciences 40 27180143
2020 ACT001 modulates the NF-κB/MnSOD/ROS axis by targeting IKKβ to inhibit glioblastoma cell growth. Journal of molecular medicine (Berlin, Germany) 37 31901951
2014 Barley beta-glucan promotes MnSOD expression and enhances angiogenesis under oxidative microenvironment. Journal of cellular and molecular medicine 37 25388628
2013 Expression of CYP1A1, CYP1B1 and MnSOD in a panel of human cancer cell lines. Molecular and cellular biochemistry 37 23873331
2012 Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer. Cancer 37 22517484
2010 Changes in TNFα, NFκB and MnSOD protein in the vestibular nuclei after unilateral vestibular deafferentation. Journal of neuroinflammation 37 21143912
2004 Immunohistochemical expression of superoxide dismutase (MnSOD) anti-oxidant enzyme in invasive breast carcinoma. Histology and histopathology 37 15168344
2015 CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection. Free radical biology & medicine 35 25578653
2020 Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK-mediated energy metabolism. Molecular carcinogenesis 34 32149414
2019 Decoding the role of SOD2 in sickle cell disease. Blood advances 34 31506286
2011 Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36. Journal of cellular biochemistry 34 21268071
2022 Osteoblast lineage Sod2 deficiency leads to an osteoporosis-like phenotype in mice. Disease models & mechanisms 33 35394023
2022 Sirt3-Sod2-mROS-Mediated Manganese Triggered Hepatic Mitochondrial Dysfunction and Lipotoxicity in a Freshwater Teleost. Environmental science & technology 33 35653605
2020 Genistein inhibits lung cancer cell stem-like characteristics by modulating MnSOD and FoxM1 expression. Oncology letters 32 32782570
2014 Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1–FoxO3a–MnSOD pathway. Biochemical and biophysical research communications 32 25450701
2021 SP1-induced lncRNA ZFPM2 antisense RNA 1 (ZFPM2-AS1) aggravates glioma progression via the miR-515-5p/Superoxide dismutase 2 (SOD2) axis. Bioengineered 31 34077295
2018 SOD2 is upregulated in periodontitis to reduce further inflammation progression. Oral diseases 31 29972711
2010 Deregulation of manganese superoxide dismutase (SOD2) expression and lymph node metastasis in tongue squamous cell carcinoma. BMC cancer 30 20618948
2022 SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression. Molecules (Basel, Switzerland) 29 35164076
2023 Angelica sinensis polysaccharide improves mitochondrial metabolism of osteoarthritis chondrocytes through PPARγ/SOD2/ROS pathways. Phytotherapy research : PTR 28 37632225
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
2018 Association between Polymorphisms of Antioxidant Gene (MnSOD, CAT, and GPx1) and Risk of Coronary Artery Disease. BioMed research international 27 30225256
2022 Maresin 1 Alleviates Diabetic Kidney Disease via LGR6-Mediated cAMP-SOD2-ROS Pathway. Oxidative medicine and cellular longevity 26 35498124
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
2010 MnSOD drives neuroendocrine differentiation, androgen independence, and cell survival in prostate cancer cells. Free radical biology & medicine 26 21056653
2017 Hexokinase 2 enhances the metastatic potential of tongue squamous cell carcinoma via the SOD2-H2O2 pathway. Oncotarget 25 27926482
2015 SOD2 immunoexpression predicts lymph node metastasis in penile cancer. BMC clinical pathology 25 25745358
2024 SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation. Molecular therapy : the journal of the American Society of Gene Therapy 24 38310354
2021 SOD2- and NRF2-associated Gene Signature to Predict Radioresistance in Head and Neck Cancer. Cancer genomics & proteomics 24 34479919
2019 Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells. Archives of biochemistry and biophysics 24 31812668
2018 Alterations in Sod2-Induced Oxidative Stress Affect Endocrine Cancer Progression. The Journal of clinical endocrinology and metabolism 24 30165401
2015 ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells. Molecular nutrition & food research 24 26443543
2015 SOD2 Mediates Amifostine-Induced Protection against Glutamate in PC12 Cells. Oxidative medicine and cellular longevity 24 26770652
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
2022 Transcription factor Nrf2 binds to circRNAPIBF1 to regulate SOD2 in lung adenocarcinoma progression. Molecular carcinogenesis 23 36193777
2010 Cloning and expression of the Mn-SOD gene from Phascolosoma esculenta. Fish & shellfish immunology 23 20654721
2022 Ecklonia cava extracts decrease hypertension-related vascular calcification by modulating PGC-1α and SOD2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 35717781
2022 HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence. Redox biology 21 35594792
2020 The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway. Cell death and differentiation 21 32424140
2019 Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2. Metallomics : integrated biometal science 21 31086870
2010 Modulation of MnSOD in Cancer:Epidemiological and Experimental Evidence. Toxicological research 21 24278510
2019 Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy. Journal of medical genetics 20 31494578
2006 C/EBPbeta regulates TNF induced MnSOD expression and protection against apoptosis. Apoptosis : an international journal on programmed cell death 20 16850160
2014 Is SOD2 Ala16Val polymorphism associated with migraine with aura phenotype? Antioxidants & redox signaling 19 25295643
2011 SOD2 contributes to anti-oxidative capacity in rabbit corneal endothelial cells. Molecular vision 19 21976958
2006 Manganese superoxide dismutase (MnSOD: Ala-9Val) gene polymorphism and mood disorders: a preliminary study. Progress in neuro-psychopharmacology & biological psychiatry 19 16626843
2023 Mitochondrial superoxide dismutase Sod2 suppresses nuclear genome instability during oxidative stress. Genetics 18 37638880
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
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
2022 SOD2 Gene Variants (rs4880 and rs5746136) and Their Association with Breast Cancer Risk. Current issues in molecular biology 16 36354667
2020 Mechanistic study of mtROS-JNK-SOD2 signaling in bupivacaine-induced neuron oxidative stress. Aging 16 32658869
2018 HZ08 suppresses RelB-activated MnSOD expression and enhances Radiosensitivity of prostate Cancer cells. Journal of experimental & clinical cancer research : CR 16 30053873

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