CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria intransgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations

Cytosolic Cu/Zn superoxide dismutase (SOD1) is a ubiquitous small cytosolic metalloenzyme, which catalyses the conversion of superoxide anion to hydro gen peroxide. Mutations in the SOD1 gene cause a familial form of amyotroph ic lateral sclerosis (fALS). The mechanism by which mutant SOD1s cause the degeneration of motor neurons is not understood. Transgenic mice expressing multiple copies of fALS-mutant SOD Is develop an ALS-like motor neuron dis ease. Vacuolar degeneration of mitochondria has been identified as the main pathological feature associated with motor neuron death and paralysis in s everal lines of fALS-SOD1 mice. Using confocal and electron microscopy we s how that mutant SOD1 is present at a high concentration in vacuolated mitoc hondria, where it colocalises with cytochrome c. Mutant SOD I is also prese nt in mildly swollen mitochondria prior to the appearance of vacuoles, sugg esting that the leakage or translocation of mutant human SOD I in mitochond ria may be the primary event triggering their further degeneration. Vacuola ted mitochondria containing SOD1 also occur in transgenic mice expressing a high concentration of wildtype human SOD1. In sum, our data suggest that b oth fALS-mutant and wild-type SOD1 may cross the mitochondrial outer membra ne, and by doing so induce the de-generation of these mitochondria.