Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins

EMBO J. 2014 Jul 17;33(14):1548-64. doi: 10.15252/embj.201487943. Epub 2014 May 19.


The majority of ER-targeted tail-anchored (TA) proteins are inserted into membranes by the Guided Entry of Tail-anchored protein (GET) system. Disruption of this system causes a subset of TA proteins to mislocalize to mitochondria. We show that the AAA+ ATPase Msp1 limits the accumulation of mislocalized TA proteins on mitochondria. Deletion of MSP1 causes the Pex15 and Gos1 TA proteins to accumulate on mitochondria when the GET system is impaired. Likely as a result of failing to extract mislocalized TA proteins, yeast with combined mutation of the MSP1 gene and the GET system exhibit strong synergistic growth defects and severe mitochondrial damage, including loss of mitochondrial DNA and protein and aberrant mitochondrial morphology. Like yeast Msp1, human ATAD1 limits the mitochondrial mislocalization of PEX26 and GOS28, orthologs of Pex15 and Gos1, respectively. GOS28 protein level is also increased in ATAD1(-/-) mouse tissues. Therefore, we propose that yeast Msp1 and mammalian ATAD1 are conserved members of the mitochondrial protein quality control system that might promote the extraction and degradation of mislocalized TA proteins to maintain mitochondrial integrity.

Keywords: AAA+ ATPase; Guided Entry of Tail‐anchored protein; mitochondrial protein quality control; tail‐anchored proteins.

Publication types

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

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Hep G2 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lipid-Linked Proteins / metabolism*
  • Mass Spectrometry
  • Membrane Proteins / metabolism
  • Mice
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • Mitochondria / physiology*
  • Oxygen Consumption / physiology
  • Phosphoproteins / metabolism
  • Plasmids / genetics
  • Protein Transport
  • Proteolysis*
  • RNA, Small Interfering / genetics
  • SNARE Proteins / metabolism
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism*


  • GOS1 protein, S cerevisiae
  • Lipid-Linked Proteins
  • Membrane Proteins
  • PEX15 protein, S cerevisiae
  • Phosphoproteins
  • RNA, Small Interfering
  • SNARE Proteins
  • Saccharomyces cerevisiae Proteins
  • Adenosine Triphosphatases
  • MSP1 protein, S cerevisiae
  • ATAD1 protein, mouse
  • ATPases Associated with Diverse Cellular Activities