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.
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Jin-Mi
JM
Heo
Nurit
N
Livnat-Levanon
Eric B
EB
Taylor
Kevin T
KT
Jones
Noah
N
Dephoure
Julia
J
Ring
Jianxin
J
Xie
Jeffrey L
JL
Brodsky
Frank
F
Madeo
Steven P
SP
Gygi
Kaveh
K
Ashrafi
Michael H
MH
Glickman
Jared
J
Rutter
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013312:Stress, Physiological / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; D006861:Hydrogen Peroxide; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D020123:Sirolimus