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A stress-responsive system for mitochondrial protein degradation.

We show that Ydr049 (renamed VCP/Cdc48-associated mitochondrial stress-responsive--Vms1), a member of an unstudied pan-eukaryotic protein family, translocates from the cytosol to mitochondria upon mitochondrial stress. Cells lacking Vms1 show progressive mitochondrial failure, hypersensitivity to oxidative stress, and decreased chronological life span. Both yeast and mammalian Vms1 stably interact with Cdc48/VCP/p97, a component of the ubiquitin/proteasome system with a well-defined role in endoplasmic reticulum-associated protein degradation (ERAD), wherein misfolded ER proteins are degraded in the cytosol. We show that oxidative stress triggers mitochondrial localization of Cdc48 and this is dependent on Vms1. When this system is impaired by mutation of Vms1, ubiquitin-dependent mitochondrial protein degradation, mitochondrial respiratory function, and cell viability are compromised. We demonstrate that Vms1 is a required component of an evolutionarily conserved system for mitochondrial protein degradation, which is necessary to maintain mitochondrial, cellular, and organismal viability.

Pubmed ID: 21070972


  • Heo JM
  • Livnat-Levanon N
  • Taylor EB
  • Jones KT
  • Dephoure N
  • Ring J
  • Xie J
  • Brodsky JL
  • Madeo F
  • Gygi SP
  • Ashrafi K
  • Glickman MH
  • Rutter J


Molecular cell

Publication Data

November 12, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK070149
  • Agency: NIDDK NIH HHS, Id: DK071962
  • Agency: NIGMS NIH HHS, Id: GM087346
  • Agency: NIGMS NIH HHS, Id: GM75061
  • Agency: NIAMS NIH HHS, Id: K99 AR059190
  • Agency: NIGMS NIH HHS, Id: R01 GM067945
  • Agency: NIGMS NIH HHS, Id: R01 GM087346
  • Agency: NIGMS NIH HHS, Id: R01 GM087346-03

Mesh Terms

  • Adenosine Triphosphatases
  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • Gene Deletion
  • Humans
  • Hydrogen Peroxide
  • Longevity
  • Mice
  • Microbial Viability
  • Mitochondria
  • Mitochondrial Proteins
  • Molecular Sequence Data
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Transport
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sirolimus
  • Stress, Physiological
  • Ubiquitin