A Stress-Responsive System for Mitochondrial Protein Degradation
Open accessAbstract
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.
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p97/VCP and cofactor Npl4 pull out ubiquitinated proteins from the OMM and retrotranslocate them to the cytosol.
“These are the AAA ATPase p97, also referred to as valosin-containing protein (VCP), and the cofactor Npl4, both involved in the process of pulling out ubiquitinated proteins from the OMM and retrotranslocation to the cytosol [48].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [48]
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- Authors
- Heo, J.-M., Livnat-Levanon, N., Taylor, E. B., Jones, K. T., Dephoure, N., Ring, J., Xie, J., Brodsky, J. L., Madeo, F., Gygi, S. P., Ashrafi, K., Glickman, M. H., & Rutter, J.
- Affiliations
- University of Utah (US)
- University of California, San Francisco (US)
- Harvard University (US)
- University of Graz (AT)
- Cell Signaling Technology (United States) (US)
- University of Pittsburgh (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Rutter, Jared
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 40
- Issue
- 3
- Pages
- 465-480
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2998070
- OpenAlex
- W2078644413
- Cited by
- 304
- References
- 52
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 9 · 2021: 14 · 2020: 28 · 2019: 20 · 2018: 19 · 2017: 23 · 2016: 16 · 2015: 17 · 2014: 31 · 2013: 25 · 2012: 24
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01dk071962-05a1)
- National Institute of General Medical Sciences (R01GM087346, R01GM067945, GM75061, R01GM075061, GM087346)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070149, DK071962, R01 DK-071962, DK070149, R56DK071962)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K99AR059190)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial protein degradation, mitochondrial stress, oxidative stress, ubiquitin-proteasome system, mitochondrial localization, chronological lifespan, mitochondrial respiratory function, ER-associated degradation, protein quality control, yeast, mammalian homologs
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Amino Acid Sequence, Animals, Humans, Hydrogen Peroxide, Longevity, Mitochondria, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Saccharomyces cerevisiae, Stress, Physiological, Caenorhabditis elegans, Gene Deletion, Cell Cycle Proteins, Sirolimus, Protein Transport, Mitochondrial Proteins, Ubiquitin, Saccharomyces cerevisiae Proteins, Caenorhabditis elegans Proteins, Microbial Viability, Mice
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