ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

Quan Li, Christine Vande Velde, Adrian Israelson, Jing Xie, Aaron O. Bailey, Meng Qui Dong, Seung Joo Chun, Tamal Roy, Leah Winer, John R. Yates, Roderick A. Capaldi, Don W. Cleveland, Timothy M. Miller

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


Mutations in superoxide dismutase 1 (SOD1) cause familial ALS. Mutant SOD1 preferentially associates with the cytoplasmic face of mitochondria from spinal cords of rats and mice expressing SOD1 mutations. Two-dimensional gels and multidimensional liquid chromatography, in combination with tandem mass spectrometry, revealed 33 proteins that were increased and 21 proteins that were decreased in SOD1G93A rat spinal cord mitochondria compared with SOD1WT spinal cord mitochondria. Analysis of this group of proteins revealed a higher-than-expected proportion involved in complex I and protein import pathways. Direct import assays revealed a 30% decrease in protein import only in spinal cord mitochondria, despite an increase in the mitochondrial import components TOM20, TOM22, and TOM40. Recombinant SOD1G93A or SOD1 G85R, but not SOD1WT or a Parkinson's disease-causing, misfolded α-synucleinE46K mutant, decreased protein import by >50% in nontransgenic mitochondria from spinal cord, but not from liver. Thus, altered mitochondrial protein content accompanied by selective decreases in protein import into spinal cord mitochondria comprises part of the mitochondrial damage arising from mutant SOD1.

Original languageEnglish
Pages (from-to)21146-21151
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - 7 Dec 2010
Externally publishedYes


  • Amyotrophic
  • Motor neuron disease
  • Neurodegenerative disease
  • Proteomic

ASJC Scopus subject areas

  • General


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