Mutant SOD1-induced neuronal toxicity is mediated by increased mitochondrial superoxide levels

Matthew C. Zimmerman, Larry W. Oberley, Shawn W. Flanagan

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease in adults, is characterized by the selective degeneration and death of motor neurons leading to progressive paralysis and eventually death. Approximately 20% of familial ALS cases are associated with mutations in SOD1, the gene encoding Cu/Zn-superoxide dismutase (CuZnSOD). Previously, we reported that overexpression of the mitochondrial antioxidant manganese superoxide dismutase (MnSOD or SOD2) attenuates cytotoxicity induced by expression of the G37R-SOD1 mutant in a human neuroblastoma cell culture model of ALS. In the present study, we extended these earlier findings using several different SOD1 mutants (G93C, G85R, and I113T). Additionally, we tested the hypothesis that mutant SOD1 increases mitochondrial-produced superoxide (O2•-) levels and that SOD2 overexpression protects neurons from mutant SOD1-induced toxicity by reducing O2•- levels in mitochondria. In the present study, we demonstrate that SOD2 overexpression markedly attenuates the neuronal toxicity induced by adenovirus-mediated expression of all four SOD1 mutants (G37R, G93C, G85R, or I113T) tested. Utilizing the mitochondrial- targeted O2•--sensitive fluorogenic probe MitoSOX Red™, we observed a significant increase in mitochondrial O 2•- levels in neural cells expressing mutant SOD1. These elevated O2•- levels in mitochondria were significantly diminished by the overexpression of SOD2. These data suggest that mitochondrial-produced O2•- radicals play a critical role in mutant SOD1-mediated neuronal toxicity and implicate mitochondrial-produced free radicals as potential therapeutic targets in ALS.

Original languageEnglish (US)
Pages (from-to)609-618
Number of pages10
JournalJournal of Neurochemistry
Issue number3
StatePublished - Aug 2007
Externally publishedYes


  • Familial amyotrophic lateral sclerosis
  • Free radicals
  • Manganese superoxide dismutase
  • Neuroblastoma
  • Neuronal toxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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