Mutant SOD1 localization and aggregation in the IMS might cause the mitochondrial abnormalities observed in familial ALS and could play a significant role in disease pathogenesis.
Our findings demonstrate that mutant SOD1 localized in the IMS is sufficient to determine mitochondrial abnormalities and neuronal toxicity, and contributes to ALS pathogenesis.
Furthermore, in transgenic mice expressing mutant Cu,Zn-superoxide dismutase (SOD1), the antioxidant enzyme associated with familial ALS (FALS), mitochondrial abnormalities precede the disease onset, suggesting that mitochondrial dysfunction is causally involved in the pathogenesis of SOD1-FALS.
The aims of the study were to: (i) investigate whether morphological mitochondrial abnormalities occur at expression levels of mutant SOD1 close to physiological levels; and (ii) determine whether the presence of mutant SOD1 causes abnormalities of mitochondrial respiratory chain function and changes in cellular bioenergetic parameters in motor neuronal cells.