Oligomerization of mutant SOD1 in mitochondria of motoneuronal cells drives mitochondrial damage and cell toxicity

Mauro Cozzolino, Maria Grazia Pesaresi, Ilaria Amori, Claudia Crosio, Alberto Ferri, Monica Nencini, Maria Teresa Carrì

Research output: Contribution to journalArticlepeer-review


Increasing evidence indicates that the accumulation and aggregation of mutant Cu,Zn superoxide dismutase (mutSOD1) in spinal cord mitochondria is implicated in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). Although the mechanisms underlying this effect are only partially understood, a deficit in the import mechanism of mutSOD1 and/or in its folding and maturation inside mitochondria is likely involved. To investigate this issue, we overexpressed mitochondria-targeted wild-type and mutSOD1s in neuronal cell lines. Mitochondria-targeted G93A mutSOD1 induces a significant impairment of mitochondrial morphology and metabolism, resulting in caspase-3 activation and cell death. These effects are paralleled by the formation of disulfide-linked, insoluble oligomers of mutSOD1 inside mitochondria. Overexpression of the copper chaperone for SOD1 (CCS) improves the solubility of cytosolic mutSOD1s, but has no effect or even worsens the insolubility of mitochondria-targeted G93A mutSOD1, indicating that CCS may increase the availability of an aggregating form of mutSOD1. Interestingly, prevention of the formation of such aggregates by removal of disulfide-bonded cysteines counteracts the effects produced by mutSOD1 accumulated inside mitochondria. Overall, our results demonstrate for the first time that aggregation of mutSOD1s into mitochondria is important for mutSOD1 to induce damage, although other forms of misfolded SOD1s might be involved. Antioxid. Redox Signal. 11, 1547-1558.

Original languageEnglish
Pages (from-to)1547-1558
Number of pages12
JournalAntioxidants and Redox Signaling
Issue number7
Publication statusPublished - Jul 1 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry


Dive into the research topics of 'Oligomerization of mutant SOD1 in mitochondria of motoneuronal cells drives mitochondrial damage and cell toxicity'. Together they form a unique fingerprint.

Cite this