Mitochondrial protein translocation-associated degradation

Nature. 2019 May;569(7758):679-683. doi: 10.1038/s41586-019-1227-y. Epub 2019 May 22.


Mitochondrial biogenesis and functions depend on the import of precursor proteins via the 'translocase of the outer membrane' (TOM complex). Defects in protein import lead to an accumulation of mitochondrial precursor proteins that induces a range of cellular stress responses. However, constitutive quality-control mechanisms that clear trapped precursor proteins from the TOM channel under non-stress conditions have remained unknown. Here we report that in Saccharomyces cerevisiae Ubx2, which functions in endoplasmic reticulum-associated degradation, is crucial for this quality-control process. A pool of Ubx2 binds to the TOM complex to recruit the AAA ATPase Cdc48 for removal of arrested precursor proteins from the TOM channel. This mitochondrial protein translocation-associated degradation (mitoTAD) pathway continuously monitors the TOM complex under non-stress conditions to prevent clogging of the TOM channel with precursor proteins. The mitoTAD pathway ensures that mitochondria maintain their full protein-import capacity, and protects cells against proteotoxic stress induced by impaired transport of proteins into mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / metabolism
  • Endoplasmic Reticulum-Associated Degradation
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins / metabolism*
  • Protein Transport
  • Proteolysis*
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Valosin Containing Protein / metabolism


  • Carrier Proteins
  • MIM1 protein, S cerevisiae
  • Membrane Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins
  • Saccharomyces cerevisiae Proteins
  • TOM70 protein, S cerevisiae
  • UBX2 protein, S cerevisiae
  • CDC48 protein, S cerevisiae
  • Valosin Containing Protein