Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice.

Abstract

Manganese superoxide dismutase (SOD2) converts superoxide to oxygen plus hydrogen peroxide and serves as the primary defense against mitochondrial superoxide. Impaired SOD2 activity in humans has been associated with several chronic diseases, including ovarian cancer and type I diabetes, and SOD2 overexpression appears to suppress malignancy in cultured cells. We have produced a line of SOD2 knockout mice (SOD2m1BCM/SOD2m1BcM) that survive up to 3 weeks of age and exhibit several novel pathologic phenotypes including severe anemia, degeneration of neurons in the basal ganglia and brainstem, and progressive motor disturbances characterized by weakness, rapid fatigue, and circling behavior. In addition, SOD2m1BCM/SOD2m1BCM mice older than 7 days exhibit extensive mitochondrial injury within degenerating neurons and cardiac myocytes. Approximately 10% of SOD2m1BCM/SOD2m1BCM mice exhibit markedly enlarged and dilated hearts. These observations indicate that SOD2 deficiency causes increased susceptibility to oxidative mitochondrial injury in central nervous system neurons, cardiac myocytes, and other metabolically active tissues after postnatal exposure to ambient oxygen concentrations. Our SOD2-deficient mice differ from a recently described model in which homozygotes die within the first 5 days of life with severe cardiomyopathy and do not exhibit motor disturbances, central nervous system injury, or ultrastructural evidence of mitochondrial injury.Superoxide radicals produced as by-products of metabolic oxidation can cause extensive cellular injury, and several different superoxide dismutases (SODs) have evolved to inactivate both intracellular and extracellular superoxide (1-7). Two closely related SODs containing either manganese or iron as cofactors are produced in most bacterial species, whereas most eukaryotic species contain at least two different intracellular SODs: (i) manganese superoxide (Mn SOD/SOD2) localized within the mitochondrial matrix and (ii) copper-and zinc-containing SOD1 (Cu/Zn SOD1/SOD1) localized predominantly in cytoplasmic and nuclear compartments (8).Another copper-and zinc-containing SOD found predominantly in extracellular compartments (EC SOD/SOD3) has recently been described (9). Although Mn SOD is located within the mitochondrial matrix, the SOD2 gene encoding Mn SOD is located within nuclear chromosomal DNA (10).Yeast and bacterial mutants devoid of all SOD activities exhibit hypersensitivity to oxygen and redox compounds such as paraquat, and they survive ambient oxygen by using predominantly anaerobic metabolic pathways to minimize superoxide production (2, 11-13). SODl-deficient mutants of Drosophila melanogaster are viable, but exhibit oxygen and paraquat sensitivity, decreased lifespan, and female infertility (14). Although other potent antioxidants such as glutathione, ascorbate, and tocopherols are present to varying degrees within eukaryotic and prokaryotic cells, none of these inactivates superoxide as rapidly or effectively as SODs.Several recent studies have sugg...

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…For these experiments, we compared cultured DRG neurons from adult mice with full SOD2 expression (SOD2 +/+ ) to DRG from mice heterozygous for SOD2 expression (SOD2 +/− ). Mice homozygous for SOD2 knockout (SOD2 −/ − ) could not be used as these mice die shortly after birth with severe mitochondrial abnormalities in skeletal and cardiac muscle and brain (Lebovitz et al, 1996;Li et al, 1995;Melov et al, 1999). As anticipated, under basal culture conditions, increased levels of O 2 − • and cleaved caspase-3 were present in DRG neurons from SOD2+/− mice when compared to neurons from SOD2 +/+ mice.…”

“…Our results are broadly supported by over a decade of research in SOD2 +/− and SOD2 −/ − mice. While the homozygous SOD2 −/ − mice die shortly after birth (Lebovitz et al, 1996;Li et al, 1995;Melov et al, 1999), the heterozygous SOD2 +/− mice develop normally, but have increased susceptibility to toxic injury and prooxidant stress. For example, while the mitochondrial toxin 3-nitropropionic acid increases striatal excitotoxicity and oxidative stress in mouse models of Huntington's disease, these effects are amplified in Huntington SOD2 +/− transgenic mice (Kim and Chan, 2002).…”

“…C. 02). The mitochondrial form of the enzyme, Mn + SOD or SOD2 is essential for cellular development and survival, since homozygous knockout of this gene is perinatally lethal (Lebovitz et al, 1996). Heterozygous expression of SOD2 leads to depletion of mitochondrial glutathione and increased oxidative stress in mice (Williams et al, 1998).…”

Models of reactive oxygen species in cancer

“…SOD2-deficient mouse models were created either by replacing exon 1 and exon 2 with a PGK-HPRT sequence, or by deleting exon 3 [30,31]. SOD2 −/− mice showed neonatal death with neurodegeneration, dilated cardiomyopathy, and metabolic acidosis.…”

Changes in Expression of Antioxidant Enzymes Affect Cell-Mediated LDL Oxidation and Oxidized LDL–Induced Apoptosis in Mouse Aortic Cells

“…The knockout mice with reduced levels of Mn-SOD (Sod2 ϩ/Ϫ ) were developed by deletion of the third exon of the Sod2 gene, 11 which resulted in a loss in enzyme activity. Lack of the Sod2 gene in the mouse germ line resulted in a lethal phenotype, and homozygous Sod2 ϩ/Ϫ mice died within 3 weeks from cardiomyopathy 11 or neurodegeneration, 12 depending on the genetic background. The heterozygous Sod2 ϩ/Ϫ mice used in the present study were obtained from Epstein's laboratory (Li et al 11 ) and were backcrossed into C57BL/6 for 18 generations.…”