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The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover
Open accessAbstract
Recent studies have revealed a role for the ubiquitin/proteasome system in the regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Although several molecular components required for this process have been identified, the mechanism of proteasome-dependent degradation of OMM-associated proteins is currently unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, revealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confirming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway.
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“p97 provides the driving force to extract Mfn1, Mfn2, and the anti-apoptotic protein MCL1 from the OMM and chaperone them to the proteasome [49, 50].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [50]
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“p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) [47] and mitochondrial proteins ( MAD) [49, 50].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [50]
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Mengus, C., Neutzner, M., Bento, A. C. P. F., Bippes, C. C., Kohler, C., Decembrini, S., Häusel, J., Hemion, C., Sironi, L., Frank, S., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1922982 · Cited by 41
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Self-citationCdc48p/p97-mediated regulation of mitochondrial morphology is Vms1p-independent
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Intramolecular interactions control Vms1 translocation to damaged mitochondria
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“Following ubiquitination, mitofusin is retrotranslocated from the OMM by the AAA+ ATPase VCP/p97 followed by proteasomal degradation in a process known as OMMAD (outer mitochondrial membrane protein associated degradation) (Kim et al., 2013; Tanaka et al., 2010; Xu et al., 2011).”
Degradation of the Deubiquitinating Enzyme USP33 Is Mediated by p97 and the Ubiquitin Ligase HERC2
Chan, N. C., den Besten, W., Sweredoski, M. J., Hess, S. Y., Deshaies, R. J., & Chan, D. C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.569392 · Cited by 31
Quality control of oxidatively damaged mitochondrial proteins is mediated by p97 and the proteasome
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The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria
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“Additionally, the UPS regulates cell death pathways, with VCP/p97 controlling the retrotranslocation and proteasomal degradation of the anti-apoptotic protein MCL1, while Parkin ubiquitinates the pro-apoptotic protein BAX, targeting it for proteasomal degradation [43, 45].”
Stoll, S., Xi, J., Ma, B., Leimena, C., Behringer, E. J., Qin, G., & Qiu, H. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz164 · Cited by 29
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“ARF1 and Cdc48 have previously been shown to interact, whether directly or not, and represent key regulators in the removing of misfolded proteins from mitochondria and subsequent degradation by the proteasome (Xu et al. 2011; Ackema et al. 2014).”
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“Cdc48/p97dependent proteasomal degradation of ubiquitylated mitofusins facilitates mitochondrial fragmentation, which in turn promotes the clearance of affected mitochondria by mitophagy [30], [36] (Figure 1).”
Song, Y., Xu, Y., Liu, Y., Gao, J., Feng, L., Zhang, Y., Shi, L., Zhang, M., Guo, D., Qi, B., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/3960773 · Cited by 27
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“Furthermore, treatment with mitochondrial-targeted donor AP39 can transfer mitochondrial fission to fusion by increasing OPA1 and MFN1 levels and decreasing Fis1 levels in early-onset AD model APP/PS1 neurons and transgenic mice (Cassidy-Stone et al., 2008; Park et al., 2011; Grohm et al., 2012).”
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Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover
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“Along with mitofusins, the anti-apoptotic BCL-2 family member protein MCL-1 is extracted from the OMM for UPS dependent degradation by VCP/p97 once ubiquitylated [66].”
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Morgado-Cáceres, P., Liabeuf, G., Calle, X., Briones, L., Riquelme, J. A., Bravo, R., & Parra, V. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.946678 · Cited by 29
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“Cdc48 recognizes ubiquitylated forms of this topomer, dependent on Doa1, and facilitates its degradation, thereby preventing apoptosis (left). p97 and its cofactor UBXD1 facilitate proteasomal turnover of the antiapoptotic protein Mcl1, ubiquitylated by the E3 ligases HUWE1, SCFFBW7 or MARCH5, thereby inducing apoptos…”
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“It has recently been shown that Cdc48p is also involved in degradation of proteins of the mitochondrial outer membrane (MOM), such as Mcl1, an anti-apoptotic protein of the Bcl2 family, and Fzo1p/mitofusin, which is required for mitochondrial tethering before mitochondrial fusion (Heo et al., 2010; Tanaka et al., 2010…”
BackgroundInterplay between the Ubiquitin Proteasome System and Mitochondria for Protein Homeostasis
Escobar‐Henriques, M., Altin, S., & den Brave, F. (2019) · Current Issues in Molecular Biology · doi:10.21775/cimb.035.035 · Cited by 21
“In mammals, p97 was also required for the extraction and proteasomal turnover of outer membrane proteins, under damaging conditions, including mitofusins and Mcl-1 (Neutzner et al., 2007; Tanaka et al., 2010; Xu et al., 2011).”
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Transmembrane dislocases: a second chance for protein targeting
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Discovery of Irreversible p97 Inhibitors
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Structural and functional deviations in disease-associated p97 mutants
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“The ATP hydrolyzing ability of p97 is indispensible for its function (Dalal et al., 2004; DeLaBarre et al., 2006; Kobayashi et al., 2002; Xu et al., 2011; Ye et al., 2003).”
BackgroundCulling sick mitochondria from the herd
Pallanck, L. J. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201011068 · Cited by 20
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Sorting out how Msp1 maintains mitochondrial membrane proteostasis
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“In addition, VCP has also been reported to promote degradation of key apoptotic proteins, such as Mcl1 and DIAP1 [24, 25], and thereby regulates cell proliferation and survival.”
BackgroundShanbhag, R., Shi, G., Rujiviphat, J., & McQuibban, G. A. (2012) · Parkinson s Disease · doi:10.1155/2012/382175 · Cited by 17
Mammalian Cell-Free System Recapitulates the Early Events of Post-Fertilization Sperm Mitophagy
Song, W., Zuidema, D., Yi, Y., Zigo, M., Zhang, Z., Sutovsky, M., & Šutovský, P. (2021) · Cells · doi:10.3390/cells10092450 · Cited by 12
“Acting as a protein dislocase, VCP extracts ubiquitinated mitochondrial membrane proteins and presents them to the 26S proteasome for degradation during organelle renewal mitophagy in somatic cells [35].”
BackgroundOuter mitochondrial membrane E3 Ub ligase MARCH5 controls de novo peroxisome biogenesis
Verhoeven, N. A., Oshima, Y., Cartier, E. A., Bippes, C. C., Neutzner, A., Boyman, L., & Karbowski, M. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.09.010 · Cited by 16
Self-citationTwo Cdc48 cofactors Ubp3 and Ubx2 regulate mitochondrial morphology and protein turnover
Chowdhury, A., Ogura, T., & Esaki, M. (2018) · The Journal of Biochemistry · doi:10.1093/jb/mvy057 · Cited by 17
Proteasome-mediated quality control of S-nitrosylated mitochondrial proteins
Benischke, A., Hemion, C., Flammer, J., & Neutzner, A. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.04.001 · Cited by 16
“OMMAD-mediated degradation of mitochondrial proteins was recently shown to depend on the AAA-ATPase p97 involved in protein retrotranslocation (Xu et al., 2011).”
BackgroundMitoBlue as a tool to analyze the mitochondria-lysosome communication
Sánchez, M. I., Vida, Y., Pérez‐Inestrosa, E., Mascarenas, J. L., Vázquez, M. E., Sugiura, A., & Martı́nez-Costas, J. (2020) · Scientific Reports · doi:10.1038/s41598-020-60573-7 · Cited by 15
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E2F1 interacts with BCL‐xL and regulates its subcellular localization dynamics to trigger cell death
Vuillier, C., Lohard, S., Fétiveau, A., Allègre, J., Kayaci, C., King, L. E., Braun, F., Barillé‐Nion, S., Gautier, F., Dubrez, L., et al. (2017) · EMBO Reports · doi:10.15252/embr.201744046 · Cited by 14
“The reported effect of E2F1 might extend to retrotranslocation of the other inhibitor of BAK, MCL-1 [30].”
Dual role of a GTPase conformational switch for membrane fusion by mitofusin ubiquitylation
Schuster, R., Anton, V., Simões, T., Altin, S., den Brave, F., Hermanns, T., Hospenthal, M. K., Komander, D., Dittmar, G., Dohmen, R. J., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900476 · Cited by 14
“Moreover, the ubiquitin-specific AAA chaperone Cdc48/p97/VCP (Tanaka et al, 2010; Xu et al, 2011; Bodnar & Rapoport, 2017; Chowdhury et al, 2018; Simoes et al, 2018) was shown to be a major regulator of mitofusins (Tanaka et al, 2010; Xu et al, 2011; Bodnar & Rapoport, 2017; Chowdhury et al, 2018;…”
BackgroundNabhan, J. F., Gooch, R. L., Chekler, E. L. P., Pierce, B. S., & Bulawa, C. (2015) · Scientific Reports · doi:10.1038/srep18251 · Cited by 14
Molecular pathways of mitochondrial outer membrane protein degradation
Zheng, J., Li, L., & Jiang, H. (2019) · Biochemical Society Transactions · doi:10.1042/bst20190275 · Cited by 13
Inhibition of BAK-mediated apoptosis by the BH3-only protein BNIP5
Rühl, S., Li, Z., Srivastava, S., Mari, L., Guy, C. S., Yang, M., Moldoveanu, T., & Green, D. R. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01386-3 · Cited by 13
“Anti-apoptotic BCL-2 proteins can also function to shuttle BAX and BAK between the OMM and the cytosol by a process called ‘ retro-translocation ’ [16, 17].”
Structure and Function of the AAA+ ATPase p97, a Key Player in Protein Homeostasis
Hänzelmann, P., Galgenmüller, C., & Schindelin, H. (2019) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-030-28151-9_7 · Cited by 13
Keeping the beat against time: Mitochondrial fitness in the aging heart
Mendoza, A., & Karch, J. M. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.951417 · Cited by 13
“Once activated BNIP3 becomes upregulated and translocates to the OMM as a stabilized homodimer, anchored by its C-terminus domain (Hanna et al., 2012).”
BackgroundInfluentialValimehr, S., Sethi, A., Shukla, M., Bhattacharyya, S., Kazemi, M., & Rouiller, I. (2023) · Biomolecules · doi:10.3390/biom13050737 · Cited by 13
“Golgi cisternae [17] and for the turnover of outer mitochondrial membrane proteins [18].”
BackgroundProteasome and selective autophagy: Brothers-in-arms for organelle quality control
Clavel, M., & Dagdas, Y. (2021) · Current Opinion in Plant Biology · doi:10.1016/j.pbi.2021.102106 · Cited by 12
Mei, T., Li, Y., Dolado, A. O., Li, Z., Andersson, R., Berliocchi, L., & Rasmussen, L. J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1101216 · Cited by 12
VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation
Bailin, P. L., Cui, Y., Wei, J., Liu, C., Chen, Y., Cui, C., Li, L., Zhang, X., & Zhang, L. (2018) · The FASEB Journal · doi:10.1096/fj.201801173r · Cited by 12
Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation
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“(ERAD) [99–101], mitochondria-associated degradation (MAD) [102] and cytosolic ribosomal protein quality control (RQC) [103].”
BackgroundWang, X., Wen, T., Miao, H., Hu, W., Lei, M., & Zhu, Y. (2022) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2022.117050 · Cited by 11
Pharmacological Progress of Mitophagy Regulation
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Thermal challenge alters the transcriptional profile of the breast muscle in turkey poults
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Araújo, W. L., Nunes‐Nesi, A., & Williams, T. C. R. (2012) · Frontiers in Plant Science · doi:10.3389/fpls.2012.00210 · Cited by 9
“Based on these patterns of expression the authors propose that the protein encoded by this gene may be involved in protein repair in response to stress (Xu et al., 2011).”
Backgroundp97 Inhibitor CB-5083 Blocks ERAD in Trypanosoma brucei
Garrison, P., & Bangs, J. D. (2020) · Molecular and Biochemical Parasitology · doi:10.1016/j.molbiopara.2020.111313 · Cited by 9
Molecular Determinants of Mitochondrial Shape and Function and Their Role in Glaucoma
Khalimonchuk, O., & Becker, D. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0124 · Cited by 8
“These two factors act in concert to facilitate the removal of stalled polypeptides by UPS (Heo et al, 2010; Wu et al, 2016; Xu et al, 2011).”
Makio, T., & Simmen, T. (2024) · Contact · doi:10.1177/25152564241261228 · Cited by 8
“This ubiquitin-speci fi c chaperone controls proteasomal protein degradation at the ER (Wojcik et al., 2006), and mitochondria (Xu et al., 2011).”
The many faces of p97/Cdc48 in mitochondrial homeostasis
Ram, J., & Glickman, M. H. (2025) · Essays in Biochemistry · doi:10.1042/ebc20253045 · Cited by 7
“In one study [53], p97 was shown to facilitate the retro-translocation of the anti-apoptotic protein MCL1 from isolated mitochondria by in vitro recapitulation.”
Metadata
- Authors
- Xu, S., Peng, G., Wang, Y., Fang, S., & Karbowski, M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Karbowski, Mariusz
- Venue
- Molecular Biology of the Cell
- Published
- 2011-02
- Volume
- 22
- Issue
- 3
- Pages
- 291-300
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC3031461
- OpenAlex
- W2082069715
- Cited by
- 243
- References
- 46
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 14 · 2022: 12 · 2021: 16 · 2020: 21 · 2019: 16 · 2018: 17 · 2017: 15 · 2016: 23 · 2015: 15 · 2014: 23 · 2013: 19 · 2012: 16
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM083131)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- VCP, AAA+ ATPase, mitochondrial outer membrane, protein turnover, proteasomal degradation, Mcl-1, Mfn1, retrotranslocation, ubiquitin-proteasome system, mitochondrial protein degradation, ATPase domain
- MeSH terms
- Adenosine Triphosphatases, Cytosol, HeLa Cells, Humans, Nuclear Proteins, Recombinant Fusion Proteins, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, GTP Phosphohydrolases, Protein Transport, Mitochondrial Proteins, Membrane Transport Proteins, Mitochondrial Membrane Transport Proteins, Proteasome Endopeptidase Complex, Green Fluorescent Proteins, Mitochondrial Membranes, Protein Stability, Myeloid Cell Leukemia Sequence 1 Protein
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