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Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

Izuo N, Nojiri H, Uchiyama S, Noda Y, Kawakami S, Kojima S, Sasaki T, Shirasawa T, Shimizu T - Oxid Med Cell Longev (2015)

Bottom Line: Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide.B-Sod2(-/-) showed perinatal death, along with severe growth retardation.Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba 260-8670, Japan.

ABSTRACT
Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

No MeSH data available.


Related in: MedlinePlus

Impaired mitochondrial respiratory activities. Enzymatic histochemical staining for NADHD (top panels) (a, b), SDH (middle panels) (c, d), and COX activities (bottom panels) (e, f) in sagittal sections of brain from three-week-old mice of the indicated genotypes. The scale bars indicate 1 mm. (g) Quantification of enzymatic reactivities of mitochondrial complexes I, II, and IV.
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fig4: Impaired mitochondrial respiratory activities. Enzymatic histochemical staining for NADHD (top panels) (a, b), SDH (middle panels) (c, d), and COX activities (bottom panels) (e, f) in sagittal sections of brain from three-week-old mice of the indicated genotypes. The scale bars indicate 1 mm. (g) Quantification of enzymatic reactivities of mitochondrial complexes I, II, and IV.

Mentions: To better understand the biochemical alterations involved in pathogenesis of the brain in the mice, we examined the mitochondrial respiratory functions in the brain of B-Sod2−/− and compared them with control. By an enzymatic histochemical analyses of succinate dehydrogenase (SDH), we assessed the biochemical activity of electron transport complex II in mitochondria on sagittal brain sections from three-week-old B-Sod2−/− and control. In the brains of B-Sod2−/−, mitochondrial complex II activity was hardly detected (Figure 4(c)), while strong staining indicating SDH activity was detected in the brains of control (Figure 4(d)). We also assessed the activity of mitochondrial complexes I (NADH dehydrogenase (NADHD)) and IV (cytochrome c oxidase (COX)) in the brain (Figures 4(a), 4(b), 4(e), and 4(f)) of the mice. The enzymatic activity of mitochondrial complexes I and IV in B-Sod2−/− showed strong staining that was comparable to that in the control (Figures 4(a), 4(b), 4(e), and 4(f)). These data clearly suggest the selective loss of enzymatic activity of mitochondrial complex II in the brains of B-Sod2−/−.


Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

Izuo N, Nojiri H, Uchiyama S, Noda Y, Kawakami S, Kojima S, Sasaki T, Shirasawa T, Shimizu T - Oxid Med Cell Longev (2015)

Impaired mitochondrial respiratory activities. Enzymatic histochemical staining for NADHD (top panels) (a, b), SDH (middle panels) (c, d), and COX activities (bottom panels) (e, f) in sagittal sections of brain from three-week-old mice of the indicated genotypes. The scale bars indicate 1 mm. (g) Quantification of enzymatic reactivities of mitochondrial complexes I, II, and IV.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537744&req=5

fig4: Impaired mitochondrial respiratory activities. Enzymatic histochemical staining for NADHD (top panels) (a, b), SDH (middle panels) (c, d), and COX activities (bottom panels) (e, f) in sagittal sections of brain from three-week-old mice of the indicated genotypes. The scale bars indicate 1 mm. (g) Quantification of enzymatic reactivities of mitochondrial complexes I, II, and IV.
Mentions: To better understand the biochemical alterations involved in pathogenesis of the brain in the mice, we examined the mitochondrial respiratory functions in the brain of B-Sod2−/− and compared them with control. By an enzymatic histochemical analyses of succinate dehydrogenase (SDH), we assessed the biochemical activity of electron transport complex II in mitochondria on sagittal brain sections from three-week-old B-Sod2−/− and control. In the brains of B-Sod2−/−, mitochondrial complex II activity was hardly detected (Figure 4(c)), while strong staining indicating SDH activity was detected in the brains of control (Figure 4(d)). We also assessed the activity of mitochondrial complexes I (NADH dehydrogenase (NADHD)) and IV (cytochrome c oxidase (COX)) in the brain (Figures 4(a), 4(b), 4(e), and 4(f)) of the mice. The enzymatic activity of mitochondrial complexes I and IV in B-Sod2−/− showed strong staining that was comparable to that in the control (Figures 4(a), 4(b), 4(e), and 4(f)). These data clearly suggest the selective loss of enzymatic activity of mitochondrial complex II in the brains of B-Sod2−/−.

Bottom Line: Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide.B-Sod2(-/-) showed perinatal death, along with severe growth retardation.Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba 260-8670, Japan.

ABSTRACT
Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

No MeSH data available.


Related in: MedlinePlus