Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice
R M Lebovitz1, H Zhang, H Vogel
1Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. lebovitz@bcm.tmc.edu
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.
Insights
Manganese superoxide dismutase (SOD2) deficiency in mice leads to severe anemia, neurodegeneration, and motor deficits. This highlights SOD2
Area of Science:
- Mitochondrial biochemistry
- Neuroscience
- Cardiovascular research
Background:
- Manganese superoxide dismutase (SOD2) is crucial for neutralizing mitochondrial superoxide radicals.
- Impaired SOD2 function is linked to chronic diseases like ovarian cancer and type I diabetes.
- SOD2 overexpression shows potential in suppressing cancer cell malignancy.
Purpose of the Study:
- To investigate the in vivo effects of SOD2 deficiency using a novel knockout mouse model.
- To characterize the pathological phenotypes associated with SOD2 loss.
Main Methods:
- Generation of SOD2 knockout mice (SOD2m1BCM/SOD2m1BCM).
- Phenotypic analysis including survival, neurological assessment, and histopathology.
- Mitochondrial injury assessment in affected tissues.
Main Results:
- SOD2 knockout mice survive up to 3 weeks, displaying severe anemia and neurodegeneration in the basal ganglia and brainstem.
- Mice exhibit progressive motor disturbances, including weakness, fatigue, and circling behavior.
- Extensive mitochondrial injury observed in neurons and cardiac myocytes, with some mice showing dilated hearts.
Conclusions:
- SOD2 deficiency results in increased susceptibility to oxidative mitochondrial injury in metabolically active tissues.
- This mouse model reveals novel phenotypes distinct from previously described SOD2-deficient models.
- SOD2 is essential for protecting against oxidative stress in the central nervous system and heart postnatally.
