Oligomerization of Mutant SOD1 in Mitochondria of Motoneuronal Cells Drives Mitochondrial Damage and Cell Toxicity

摘要: Increasing evidence indicates that the accumulation and aggregation of mutant Cu,Zn superoxide dismutase (mutSOD1) in spinal cord mitochondria is implicated pathogenesis familial amyotrophic lateral sclerosis (FALS). Although mechanisms underlying this effect are only partially understood, a deficit import mechanism mutSOD1 and/or its folding maturation inside likely involved. To investigate issue, we overexpressed mitochondria-targeted wild-type mutSOD1s neuronal cell lines. Mitochondria-targeted G93A induces significant impairment mitochondrial morphology metabolism, resulting caspase-3 activation death. These effects paralleled by formation disulfide-linked, insoluble oligomers mitochondria. Overexpression copper chaperone for SOD1 (CCS) improves solubility cytosolic mutSOD1s, but has no or even worsens insolubility mutSOD1, indicating CCS may increase availability an aggregating form mutSOD1. Interestingly, prevention such aggregates removal disulfide-bonded cysteines counteracts produced accumulated Overall, our results demonstrate first time into important to induce damage, although other forms misfolded SOD1s might be