A disulfide relay system in the intermembrane space of mitochondria that mediates protein import

Cell. 2005 Jul 1;121(7):1059-69. doi: 10.1016/j.cell.2005.04.011.


We describe here a pathway for the import of proteins into the intermembrane space (IMS) of mitochondria. Substrates of this pathway are proteins with conserved cysteine motifs, which are critical for import. After passage through the TOM channel, these proteins are covalently trapped by Mia40 via disulfide bridges. Mia40 contains cysteine residues, which are oxidized by the sulfhydryl oxidase Erv1. Depletion of Erv1 or conditions reducing Mia40 prevent protein import. We propose that Erv1 and Mia40 function as a disulfide relay system that catalyzes the import of proteins into the IMS by an oxidative folding mechanism. The existence of a disulfide exchange system in the IMS is unexpected in view of the free exchange of metabolites between IMS and cytosol via porin channels. We suggest that this process reflects the evolutionary origin of the IMS from the periplasmic space of the prokaryotic ancestors of mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / physiology
  • Binding Sites / physiology
  • Cation Transport Proteins / metabolism
  • Copper Transport Proteins
  • Cysteine / chemistry
  • Disulfides / metabolism*
  • Evolution, Molecular
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Molecular Chaperones
  • Oxidation-Reduction / drug effects
  • Oxidoreductases Acting on Sulfur Group Donors
  • Prokaryotic Cells / metabolism
  • Protein Binding / physiology
  • Protein Folding
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Reducing Agents / pharmacology
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*


  • COX17 protein, S cerevisiae
  • Cation Transport Proteins
  • Copper Transport Proteins
  • Disulfides
  • MIA40 protein, S cerevisiae
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Reducing Agents
  • Saccharomyces cerevisiae Proteins
  • TIM13 protein, S cerevisiae
  • Oxidoreductases Acting on Sulfur Group Donors
  • ERV1 protein, S cerevisiae
  • Cysteine