Superoxide dismutase was discovered by Fridovich et al. (1975). Known for over 30 years as a copper-containing, low molecular weight cytoplasmic protein, erythrocuprein was shown in 1969 to catalyze the disproportionation of superoxide radicals to molecular oxygen and hydrogen peroxide. The name came from the fact that the reaction is a dismutation of superoxide anions. The 2 distinct forms of superoxide dismutase have different immunologic specificities. SOD1 is a copper- and zinc-containing enzyme. SOD2 is a manganese-containing enzyme. SOD1 is a dimer whereas SOD2 is a tetramer.
NCBI Summary:
This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. [provided by RefSeq, Apr 2016]
The SOD2 gene encodes an intramitochondrial free radical scavenging enzyme that is the first line of defense against superoxide produced as a byproduct of oxidative phosphorylation.
Cellular localization
Mitochondrial
Comment
GWAS123
Ovarian function
Follicle atresia, Steroid metabolism, Luteolysis
Comment
SOD2 deficiency-induced oxidative stress attenuates steroidogenesis in mouse ovarian granulosa cells. Zaidi SK et al. (2020) This study investigated the effects of SOD2 (MnSOD)-deficiency-induced excessive oxidative stress on ovarian steroidogenesis in vivo and isolated and cultured granulosa cells using WT and Sod2 ± mice. Basal and 48 h eCG-stimulated plasma progesterone levels were decreased ∼50% in female Sod2 ± mice, whereas plasma progesterone levels were decreased ∼70% in Sod2 ± mice after sequential stimulation with eCG followed by hCG. Sod2 ± deficiency caused about 50% reduction in SOD2 activity in granulosa cells. SOD2-deficiency also caused a marked reduction in progestins and estradiol in isolated granulosa cells. qRT-PCR measurements indicated that the mRNA expression levels of StAR protein and steroidogenic enzymes are decreased in the ovaries of Sod2 ± mice. Further studies showed a defect in the movement of mobilized cytosolic cholesterol to mitochondria. The ovarian membrane from Sod2 ± mice showed higher susceptibility to lipid peroxidation. These data indicates that SOD2-deficiency induced oxidative stress inhibits ovarian granulosa cell steroidogenesis primarily by interfering with cholesterol transport to mitochondria and attenuating the expression of Star protein gene and key steroidogenic enzyme genes.//////////////////
Dharmarajan et al. (1999) indicated that the gonadotropin-mediated inhibition of apoptosis in rabbit luteal cells involves enhanced expression of the oxidative stress response gene, SOD2, whose protein product may then function to protect luteal cells directly from the damaging effect of reactive oxygen species and/or indirectly by acutely down-regulating expression of Bax, a prooxidant member of the Bcl-2 protein family.
Expression regulated by
FSH, LH, Prolactin, estradiol, dexamethasone
Comment
Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations. Benayoun BA et al. FOXL2 is a Forkhead transcription factor, essential for ovarian function, whose mutations are responsible for the Blepharophimosis Syndrome, characterized by craniofacial defects, often associated with premature ovarian failure. Here, we show that cell stress upregulates FOXL2 expression in an ovarian granulosa cell model. Increased FOXL2 transcription might be mediated at least partly by self-activation. Moreover, using 2D-western blot, we show that the response of FOXL2 to stress correlates with a dramatic remodeling of its post-translational modification profile. Upon oxidative stress, we observe an increased recruitment of FOXL2 to several stress-response promoters, notably that of the mitochondrial Superoxide Dismutase (MnSOD). Using several reporter systems, we show that FOXL2 transactivation is enhanced in this context. Models predict that gene upregulation in response to a signal should eventually be counterbalanced to restore the initial steady state. In line with this, we find that FOXL2 activity is repressed by the SIRT1 deacetylase. Interestingly, we demonstrate that SIRT1 transcription is, in turn, directly upregulated by FOXL2, which closes a negative-feedback loop. The regulatory relationship between FOXL2 and SIRT1 prompted us the test action of nicotinamide, an inhibitor of sirtuins, on FoxL2 expression/activity. According to our expectations, nicotinamide treatment increases FoxL2 transcription. Finally, we show that 11 disease-causing mutations in the ORF of FOXL2 induce aberrant regulation of FOXL2 and/or regulation of the FOXL2 stress-response target gene MnSOD. Taken together, our results establish that FOXL2 is an actor of the stress response, and provide new insights into the pathogenic consequences of FOXL2 mutations.
Profiling of SOD isoenzymes in compartments of the developing bovine antral follicle. Combelles C et al. The antral follicle constitutes a complex and regulated ovarian microenvironment that influences oocyte quality. Oxidative stress is a cellular state that may play a role during folliculogenesis and oogenesis, although direct supporting evidence is currently lacking. We thus evaluated the expression of the three isoforms (SOD1, 2, 3) of the enzymatic antioxidant superoxide dismutase in all of the cellular (granulosa cells, cumulus cells, oocytes) and extracellular (follicular fluid) compartments of the follicle. Comparisons were performed in bovine ovaries across progressive stages of antral follicular development. Follicular fluid possessed increased amounts of SOD1, 2, 3 in small when compared to large antral follicles; concomitantly, total SOD activity was highest in follicular fluids from smaller diameter follicles. SOD1, 2, and 3 proteins were expressed in granulosa cells without any fluctuations with follicle sizes. All three SOD isoforms were present but distributed differently in oocytes from small, medium, or large antral follicles. Cumulus cells expressed high levels of SOD3, some SOD2, but no detectable SOD1. Our studies provide a temporal and spatial expression profile of the three SOD isoforms in the different compartments of the developing bovine antral follicles. These results lay the ground for future investigations into the potential regulation and roles of antioxidants during folliculogenesis and oogenesis.
Suzuki et al. (1999) investigated the expression of manganese (Mn) (SOD2) and copper-zinc (Cu,Zn) superoxide dismutase (SOD1) in normal cycling human ovaries throughout the menstrual cycle. They reported that, in the follicular stage, SOD2 immunoreactivity was detected in granulosa and theca interna cells of steroid-producing follicles, that is, preantral, nondominant, dominant, and atretic follicles. In the luteal stage, immunoreactivity for SOD2 and SOD1 was observed in both luteinized granulosa and theca cells of the functioning corpus luteum. In the early degenerating corpus luteum, both SOD2 and SOD1 were positive in steroid-producing luteinized theca cells. SOD2 immunoreactivity was also detected in nonsteroid-producing luteinized granulosa cells and macrophages. The results suggest that the expression of Mn-SOD and Cu,Zn-SOD closely correlates with steroidogenesis in the human ovary. Sabatini et al.(1999) reported that superoxide dismutase (SOD) activity is present in human follicular fluid and is higher than in serum. The degree of SOD activity is variable and seems to be inversely related to the fertilization of oocytes.
Sugino et al. (2000) reported that manganese SOD (Mn-SOD) activities were low in the mid-luteal phase and increased toward the regression phase of the corpus luteum. In contrast, Cu,Zn-SOD activities in the pregnant human corpus luteum were significantly higher than those in the mid-luteal phase. Changes in mRNA expression of both types of SOD were similar to changes in their activities. Lequarre AS et al 2001 reported the expression of Cu/Zn and Mn superoxide dismutases during bovine
embryo development.
Temporal pattern of expression of Cu/Zn and Mn superoxide dismutases (SODs)
was investigated in bovine oocytes and embryos produced in vitro in two
different culture conditions and in vivo after superovulation. SODs were
examined at a transcriptional level in single oocytes and embryos by reverse
transcriptase-polymerase chain reaction (RTPCR) and, at a protein level, by
Western blotting on pools of embryos. Transcripts for Mn SOD gene were
detected in most immature and in vitro matured oocytes as well as in some
zygotes and 5- to 8-cell embryos while no transcript was found at the 9- to
16-cell stage in both culture conditions.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:Matzuk et al. (1998) reported that SOD2-deficient mice die within three weeks of birth due to oxidative mitochondrial injury in central nervous system neurons and cardiac myocytes. Ovaries from postnatal SOD2-deficient mice, transplanted to the bursa of wild-type hosts, show all stages of folliculogenesis including corpora lutea and can give rise to viable offspring. These studies suggest that SOD2 is not essential for ovarian function.
Species: mouse
Mutation name: None
type: null mutation fertility: None Comment:Li et al. (1995) inactivated the SOD2 gene in transgenic mice by homologous recombination. Homozygous mutant mice died within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis. The findings suggested to Li et al. (1995) that MnSOD is required for normal biologic function of tissues by maintaining the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: A genome-wide association study of polycystic ovary syndrome identified from electronic health records. Zhang Y et al. (2020) Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. We developed a polycystic ovary syndrome phenotyping algorithm based on the Rotterdam criteria and applied it to three electronic health records-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual genome-wide association study using the Geisinger's MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1x10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed effect model was adopted for meta-analysis. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to characterize protein-protein interaction network. Using the same algorithm based on the Rotterdam criteria, we identified 2,995 patients with polycystic ovary syndrome and 53,599 population controls in total (2,742 cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). We identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8x10-8) located near SOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52,2.86], P=8.45x10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 SNPs with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, while rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using STRING to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1 which has been previously associated with polycystic ovary syndrome. Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4, and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome-gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.//////////////////