ABSTRACT

All aerobic organisms possess superoxide dismutases (SODs) (1). All eukaryotes have a mitochondrial form of SOD with manganese at the catalytic site and a cytosolic form with Cu and Zn at the catalytic site. In addition, mammals have an extracellular form that also contains Cu and Zn (2). The toxicity of superoxide was initially inferred by the nearly ubiquitous distribution of the enzymes (1), but was not really demonstrated until it was determined that the elimination of the Fe-and Mn-containing SODs of Escherichia coli resulted in an organism with marked sensitivity to growth in oxygen, and that this phenotype could be reversed if the mutant organism were supplied with the ability to produce the human Cu,Zn-SOD (3). In mammals, the picture is somewhat more complicated, but great insight has been provided recently with the production of knockout mice deficient in each of the three mammalian SODs. The results have been rather surprising. Mice unable to produce the cytosolic Cu,Zn-SOD appear quite normal and do not even show increased sensitivity to hyperoxia (4). Mice unable

to produce the extracellular SOD also appear quite normal, but do show some increased sensitivity to hyperoxia (5). Mice unable to produce mitochondrial SOD have a serious cardiomyopathy and neurodegeneration, and die within days of their birth (6,7). Thus, in the mammalian organism, which has much more compartmentalization than simple prokaryotes, we see that the mitochondrial protec­ tion against superoxide radical is supremely important for development, function, and survival of the organism. In sharp contrast, loss of protection for the cytosolic or extracellular compartments causes hardly any observable deficit, at least under normal (nonstressed) conditions.