Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria

Hum Mol Genet. 2008 Nov 1;17(21):3303-17. doi: 10.1093/hmg/ddn226. Epub 2008 Aug 13.


The antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) is predominantly localized in the cytosol, but it is also found in mitochondria. Studies in yeast suggest that apoSOD1 is imported into mitochondria and trapped inside by folding and maturation, which is facilitated by its copper chaperone for SOD1 (CCS). Here, we show that in mammalian cells, SOD1 mitochondrial localization is dictated by its folding state, which is modulated by several interconnected factors. First, the intracellular distribution of CCS determines SOD1 partitioning in cytosol and mitochondria: CCS localization in the cytosol prevents SOD1 mitochondrial import, whereas CCS in mitochondria increases it. Second, the Mia40/Erv1 pathway for import of small intermembrane space proteins participates in CCS mitochondrial import in a respiratory chain-dependent manner. Third, CCS mitochondrial import is regulated by oxygen concentration: high (20%) oxygen prevents import, whereas physiological (6%) oxygen promotes it. Therefore, SOD1 localization responds to changes in environmental conditions following redistribution of CCS, which operates as an oxygen sensor. Fourth, all of the cysteine residues in human SOD1 are critical for its retention in mitochondria due to their involvement in intramolecular disulfide bonds and in the interaction with CCS. Mutations in SOD1 are associated with autosomal dominant familial amyotrophic lateral sclerosis. Like the wild-type protein, mutant SOD1 localizes to mitochondria, where it induces bioenergetic defects. We find that the physiological regulation of mitochondrial localization is either inefficient or absent in SOD1 pathogenic mutants. We propose misfolding and aggregation of these mutants that trap them inside mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cysteine / genetics
  • Cytochrome Reductases / metabolism
  • Frameshift Mutation
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Mammals
  • Mice
  • Mitochondria / enzymology*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Molecular Sequence Data
  • Mutation / genetics*
  • Protein Folding
  • Protein Structure, Tertiary
  • Protein Transport / genetics*
  • Superoxide Dismutase / chemistry
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1


  • Mitochondrial Membrane Transport Proteins
  • Molecular Chaperones
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Cytochrome Reductases
  • Cysteine