This study investigates the effects of SOD2 deficiency in mice, revealing significant neurological and cardiac abnormalities. SOD2 knockout mice (SOD2^m1BCM/SOD2^m1BCM) survive up to 3 weeks, exhibiting severe anemia, neuronal degeneration in the basal ganglia and brainstem, and progressive motor impairments. These mice also show extensive mitochondrial injury in neurons and cardiac myocytes, with approximately 10% displaying enlarged, dilated hearts. Unlike a previously described model where homozygous mice die within 5 days with severe cardiomyopathy, these mice show no motor disturbances or central nervous system injury. Superoxide radicals, produced as by-products of metabolic oxidation, can cause extensive cellular damage. SOD2, a manganese-dependent superoxide dismutase, is crucial for mitochondrial defense against superoxide. SOD2 deficiency leads to increased susceptibility to oxidative mitochondrial injury in neurons, cardiac myocytes, and other metabolically active tissues after postnatal exposure to ambient oxygen. The SOD2^m1BCM/SOD2^m1BCM mice show reduced growth rates and a striking reduction in adipose and skeletal muscle mass. Histological analysis reveals hypocellular bone marrow, atypical glycogen deposition, and abundant intracellular lipid vacuoles in hepatocytes. Electron microscopy shows degenerative injury to large CNS neurons, particularly in the basal ganglia and brainstem, with extensive mitochondrial damage, loss of polysomes, and cytoplasmic clearing. Cardiac abnormalities include marked dilatation in approximately 10% of mice, with widespread cellular injury and death characterized by mitochondrial swelling and fragmentation. These findings suggest that SOD2 deficiency causes selective mitochondrial injury in cells with high oxidative metabolism, including cardiac myocytes, neurons, and hepatocytes. The apparent normal embryonic development of these mice suggests protection by low oxygen tension and low oxidative metabolism. The study highlights the critical role of SOD2 in maintaining mitochondrial function and preventing oxidative damage in metabolically active tissues.This study investigates the effects of SOD2 deficiency in mice, revealing significant neurological and cardiac abnormalities. SOD2 knockout mice (SOD2^m1BCM/SOD2^m1BCM) survive up to 3 weeks, exhibiting severe anemia, neuronal degeneration in the basal ganglia and brainstem, and progressive motor impairments. These mice also show extensive mitochondrial injury in neurons and cardiac myocytes, with approximately 10% displaying enlarged, dilated hearts. Unlike a previously described model where homozygous mice die within 5 days with severe cardiomyopathy, these mice show no motor disturbances or central nervous system injury. Superoxide radicals, produced as by-products of metabolic oxidation, can cause extensive cellular damage. SOD2, a manganese-dependent superoxide dismutase, is crucial for mitochondrial defense against superoxide. SOD2 deficiency leads to increased susceptibility to oxidative mitochondrial injury in neurons, cardiac myocytes, and other metabolically active tissues after postnatal exposure to ambient oxygen. The SOD2^m1BCM/SOD2^m1BCM mice show reduced growth rates and a striking reduction in adipose and skeletal muscle mass. Histological analysis reveals hypocellular bone marrow, atypical glycogen deposition, and abundant intracellular lipid vacuoles in hepatocytes. Electron microscopy shows degenerative injury to large CNS neurons, particularly in the basal ganglia and brainstem, with extensive mitochondrial damage, loss of polysomes, and cytoplasmic clearing. Cardiac abnormalities include marked dilatation in approximately 10% of mice, with widespread cellular injury and death characterized by mitochondrial swelling and fragmentation. These findings suggest that SOD2 deficiency causes selective mitochondrial injury in cells with high oxidative metabolism, including cardiac myocytes, neurons, and hepatocytes. The apparent normal embryonic development of these mice suggests protection by low oxygen tension and low oxidative metabolism. The study highlights the critical role of SOD2 in maintaining mitochondrial function and preventing oxidative damage in metabolically active tissues.