Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA415919 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Superoxide radical anion and other Reactive Oxygen Species are constantly produced during respiration. In mitochondria, the dismutation of the superoxide radical anion is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. We show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.
2017-12-05 | GSE106206 | GEO
Project description:Enterocyte Superoxide Dismutase 2 Deletion Drives Hyperinsulinemia and Obesity
| PRJNA664402 | ENA
Project description:Superoxide radical anion (O2⋅‒) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O2⋅‒ is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. Here we show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H2O2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells and in vivo. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells and in vivo. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.
| S-EPMC5910218 | biostudies-literature
Project description:Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity, inflammation and insulin resistance via phospholipase A2 (PLA2) activation and increased synthesis of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese and hyperinsulinemic phenotype was rescued when fed an essential fatty acid deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal SOD2 mRNA levels and obesity features, such as body mass index and omega-6/omega-3 fatty acid ratio, appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal SOD2 levels, PLA2 activity and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.
2021-12-31 | GSE158237 | GEO
Project description:Manganese is considered essential for animal growth. Manganese ions serve as cofactors to three mitochondrial enzymes: superoxide dismutase (Sod2), arginase and glutamine synthase. In Drosophila melanogaster, manganese has also been implicated in the formation of ceramide phosphoethanolamine, the insect’s sphingomyelin analogue, a structural component of membranes. Manganese overload leads to neurodegeneration and toxicity in both humans and Drosophila. Here, we describe a Drosophila model of manganese deficiency. Due to the lack of manganese-specific chelators, we used chemically defined media to grow the flies and deplete them of the metal. Dietary manganese depletion reduces Sod2 activity. We then examined gene and protein expression changes in the intestines of manganese depleted flies. We found adaptive responses to the lack of the known manganese-dependent enzymatic activities and alterations in genes/enzymes of carbohydrate metabolism and glycosylations, similar to earlier reports of manganese deficiency in vertebrate animals.
2020-02-24 | PXD015543 | Pride
Project description:We explored the in vitro activities of the dinuclear Mn2L2Ac and Mn2L2 complexes (where HL=2-{[di(2-pyridyl)- methylamino]-methyl}phenol), possessing dual superoxide dismutase(SOD) and catalase (CAT) activity, both individually and in conjunction with various Pt(II)-complexes, either as mixtures or as the Mn2-Pt adducts. Our findings revealed a notable up to 50% enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50% in breast cancer cells upon combined treatments with Mn2 SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self-assembled Mn2-Pt adducts (isolated Mn2L2Pt and in situ Mn2L2Pt’), linking Mn2L2-core with the carboxylate group of PtDAPCl2 (dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn2L2Pt adduct (kSOD=1.7×107 M-1 s-1) remained intact. We elucidated key mechanisms underlying the observed biological effects. We demonstrated that Mn2-containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H2S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways.
2024-08-28 | PXD051376 | Pride
Project description:Proliferating cells consume more glucose to cope with the bioenergetics and biosynthetic demands of rapidly dividing cells as well as to counter a shift in cellular redox environment. This study investigates the hypothesis that manganese superoxide dismutase (MnSOD) regulates cellular redox flux and glucose consumption during the cell cycle. A direct correlation was observed between glucose consumption and percentage of S-phase cells in MnSOD wild-type fibroblasts, which was absent in MnSOD homozygous knockout fibroblasts. Results from electron paramagnetic resonance spectroscopy and flow cytometric assays showed a significant increase in cellular superoxide levels in S-phase cells, which was associated with an increase in glucose and oxygen consumption, and a decrease in MnSOD activity. Mass spectrometry results showed a complex pattern of MnSOD-methylation at both lysine (68, 89, 122, and 202) and arginine (197 and 216) residues. MnSOD protein carrying a K89A mutation had significantly lower activity compared with wild-type MnSOD. Computational-based simulations indicate that lysine and arginine methylation of MnSOD during quiescence would allow greater accessibility to the enzyme active site as well as increase the positive electrostatic potential around and within the active site. Methylation-dependent changes in the MnSOD conformation and subsequent changes in the electrostatic potential around the active site during quiescence versus proliferation could increase the accessibility of superoxide, a negatively charged substrate. These results support the hypothesis that MnSOD regulates a "metabolic switch" during progression from quiescent through the proliferative cycle. We propose MnSOD as a new molecular player contributing to the Warburg effect.
| S-EPMC3429130 | biostudies-literature
Project description:Growth of L. cremoris NCDO712 was not altered when manganese is omitted from its defined medium. This study was conducted in order to compare protein requirements of Lactococcus cremoris NCDO712 to grow in the presence or absence of manganese in defined medium (1% lactose). The majority of protein adaptation involves upregulation of Mn transporters and to a lesser extent various NADH-dependent proteins. Such adaptation is highly relevant for starter culture in dairy fermentation where manganese is limited and NADH homeostasis determines the formation of volatiles during long-term incubation e.g. cheese ripening.
2022-05-16 | PXD030123 | Pride
Project description:Manganese superoxide dismutase is an important antioxidant defense metalloenzyme that protects cells from damage by the toxic oxygen metabolite, superoxide free radical, formed as an unavoidable by-product of aerobic metabolism. Many years of research have gone into understanding how the metal cofactor interacts with small molecules in its catalytic role. In contrast, very little is presently known about how the protein acquires its metal cofactor, an important step in the maturation of the protein and one that is absolutely required for its biological function. Recent work is beginning to provide insight into the mechanisms of metal delivery to manganese superoxide dismutase in vivo and in vitro.
| S-EPMC2818121 | biostudies-literature