title: 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.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. lebovitz@bcm.tmc.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Lebovitz
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Vogel
authors.forename: J
authors.initials: J
authors.lastname: Cartwright
authors.forename: L
authors.initials: L
authors.lastname: Dionne
authors.forename: N
authors.initials: N
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Huang
authors.forename: M M
authors.initials: MM
authors.lastname: Matzuk
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology*; D009026:Mortality; D009206:Myocardium / Q000473:pathology; D009422:Nervous System Diseases / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015183:Restriction Mapping; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D013482:Superoxide Dismutase