Loss Of Manganese Superoxide Dismutase Research Articles

Mitochondrial Dysfunction Due to Lack of Manganese Superoxide Dismutase Promotes Hepatocarcinogenesis.

Aims: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice. Results: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced β-catenin and hypoxia-inducible factor-1α levels. Innovation: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/β-catenin and hypoxia signaling pathway. Conclusion: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/β-catenin and hypoxia pathway may be crucial elements. Antioxid. Redox Signal. 23, 1059–1075.

Manganese superoxide dismutase is dispensable for post-natal development and lactation in the murine mammary gland

Mammary gland development is a multistage process requiring tightly regulated spatial and temporal signalling pathways. Many of these pathways have been shown to be sensitive to oxidative stress. Understanding that the loss of manganese superoxide dismutase (Sod2) leads to increased cellular oxidative stress, and that the loss or silencing of this enzyme has been implicated in numerous pathologies including those of the mammary gland, we sought to examine the role of Sod2 in mammary gland development and function in situ in the mouse mammary gland. Using Cre-recombination driven by the mouse mammary tumor virus (MMTV) promoter, we created a mammary-specific post-natal conditional Sod2 knock-out mouse model. Surprisingly, while substantial decreases in Sod2 were noted throughout both virgin and lactating adult mammary glands, no significant changes in developmental structures either pre- or post-pregnancy were observed histologically. Moreover, mothers lacking mammary gland expression of Sod2 were able to sustain equal numbers of litters, equal pups per litter, and equal pup weights as were control animals. Overall, our results demonstrate that loss of Sod2 expression is not universally toxic to all cell types and that excess mitochondrial superoxide can apparently be tolerated during the development and function of post-natal mammary glands.

Molecular changes in the esophageal epithelium after a subchronic exposure to cigarette smoke in the presence of bile-acid reflux

Background: Gastroesophageal reflux of bile acids plays an important role in the development of Barrett’s esophagus (BE)–associated esophageal adenocarcinoma (EAC). Cigarette smoke has been demonstrated to exacerbate the effects of reflux and thus the initial stages of EAC carcinogenesis. To date, no in vivo studies have been conducted to look at the concomitant effects of cigarette smoke and bile acids on EAC incidence.Methods: In this pilot study, rats that underwent esophagoduodenal anastomosis (EDA) surgery to induce reflux were exposed to whole-body cigarette smoke 3 weeks after surgery. Smoke exposure (135 mg/m3/day) was done for 4 h/day for 5 consecutive days and animals were euthanized after a 48-h recovery period.Results: Exposure to EDA-smoke accelerated the development of BE when compared to EDA-air. The presence of reflux caused a significant 3.5-fold increase in nuclear factor-κB-inducing kinase (NIK) staining (1.47 ± 0.6; p = 0.01). Animals with both reflux and smoking had the highest (10-fold; 4 ± 0.9) induction of cyclooxygenase-2 (COX-2) expression (p < 0.05). Similarly, there was a 10-fold increase in 4-aminobiphenyl (4-ABP) protein adducts identified in all smoke-exposed animals (p < 0.01).Conclusion: Cigarette smoke aggravates reflux-induced BE and potentially accelerates the progression of BE to EAC through the loss of manganese superoxide dismutase (MnSOD), and overexpression of NF-κB- and COX-2-mediated factors.

Loss of manganese superoxide dismutase leads to abnormal growth and signal transduction in mouse embryonic fibroblasts

Manganese superoxide dismutase (MnSOD) in the mitochondria plays an important role in cellular defense against oxidative damage. Homozygous MnSOD knockout ( Sod2 −/−) mice are neonatal lethal, indicating the essential role of MnSOD in early development. To investigate the potential cellular abnormalities underlying the aborted development of Sod2 −/− mice, we examined the growth of isolated mouse embryonic fibroblasts (MEFs) from Sod2 −/− mice. We found that the proliferation of Sod2 −/− MEFs was significantly decreased compared with wild-type MEFs despite the absence of morphological differences. The Sod2 −/− MEFs produced less cellular ATP, had lower O 2 consumption, generated more superoxide, and expressed less Prdx3 protein. Furthermore, the loss of MnSOD dramatically altered several markers involved in cell proliferation and growth, including decreased growth stimulatory function of mTOR signaling and enhanced growth inhibitory function of GSK-3β signaling. Interestingly, the G-protein-coupled receptor-mediated intracellular Ca 2+ signal transduction was also severely suppressed in Sod2 −/− MEFs. Finally, the ratio of microtubule-associated protein light chain 3 (LC3)-II/LC3-I, an index of autophagic activity, was increased in Sod2 −/− MEFs, consistent with a reduction in mTOR signal transduction. These data demonstrate that MnSOD deficiency results in alterations in several key signaling pathways, which may contribute to the lethal phenotype of Sod2 −/− mice.

Deficiency of MnSOD in Hematopoietic Stem Cells Causes a Sideroblastic Anemia-Like Phenotype.

Abstract 1991Poster Board I-1013 Introduction:Sideroblastic anemia is caused by an inappropriate incorporation of iron into hemoglobin, and as such a phenotype demonstrating ringed sideroblasts, improper iron deposition, and malignancy is observed. The only known hereditary cause of this disease is a mutation in delta-aminolevulinate synthase 2 (ALAS2), which is a mitochondrially located enzyme that catalyzes the first step in heme synthesis, while the causes of the acquired or idiopathic forms remain unknown. With the knowledge that the free radical superoxide (O2•-) is able to displace iron from heme-containing proteins, it is hypothesized that the loss of the mitochondrial anti-oxidant enzyme manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, may cause disruption of proper heme synthesis and as such may contribute to a sideroblastic anemia-like phenotype. Methods: Due to the early lethality of the constitutive MnSOD knock-out mouse, a floxed (flanked by loxP) MnSOD mouse was created. Homozygous hematopoietic stem cell specific SOD2 knock-outs were generated by breeding the floxed MnSOD mice with mice expressing Cre-recombinase under the control of the hematopoietic stem cell specific promoter Vav. Results: Mice harboring the hematopoietic knock-out of MnSOD are born viable, and are able to live to maturity. Complete blood count (CBC) analysis of knock-out mice demonstrated a decrease in red blood cells (RBC), thymic white blood cells, and splenic white blood cells. The knock-outs additionally showed a decrease in hemoglobin to 5 g/dL compared to 11 g/dL in controls, a reduction in hematocrit to 32% versus 43.5% in controls, and a reticulocyte count of 31.6% compared to only 7.9% in controls. CBC analysis also revealed many RBC morphology flags including hypochromasia, ansiocytosis, and hematocrit variance. These findings were visualized in blood smears (see below). Finally, electron paramagnetic resonance spectrometry of plasma from the knock-out mice showed a ∼2-fold decrease in transferrin levels compared to controls. Conclusions: The loss of MnSOD in the hematopoietic stem cell population of a mouse creates a viable organism, but with an apparent sideroblastic anemia phenotype. Additionally, the white blood cells within these organisms also may be affected due to the decrease in total cellularity, and thus could contribute to immunodeficiency and/or malignancy later in the animal's life. Overall, this phenotype is very comparable to those observed in human patients, and as such MnSOD may play an undiscovered role in acquired or idiopathic sideroblastic anemia. Future work will focus on further characterization of the animals, examination of human blood samples for MnSOD mutations, and the use of SOD mimetics to potentially reverse the observed phenotype. This work was supported by NIH grants CA73612 and CA115438 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hepatocyte-specific loss of manganese superoxide dismutase causes liver failure

Hepatocyte-specific loss of manganese superoxide dismutase causes liver failure