The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Parkin Interacts with Ambra1 to Induce Mitophagy
Open accessAbstract
Mutations in the gene encoding Parkin are a major cause of recessive Parkinson's disease. Recent work has shown that Parkin translocates from the cytosol to depolarized mitochondria and induces their autophagic removal (mitophagy). However, the molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we investigated whether Parkin interacts with autophagy-regulating proteins. We purified Parkin and associated proteins from HEK293 cells using tandem affinity purification and identified the Parkin interactors using mass spectrometry. We identified the autophagy-promoting protein Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 activates autophagy in the CNS by stimulating the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex that is essential for the formation of new phagophores. We found Ambra1, like Parkin, to be widely expressed in adult mouse brain, including midbrain dopaminergic neurons. Endogenous Parkin and Ambra1 coimmunoprecipitated from HEK293 cells, SH-SY5Y cells, and adult mouse brain. We found no evidence for ubiquitination of Ambra1 by Parkin. The interaction of endogenous Parkin and Ambra1 strongly increased during prolonged mitochondrial depolarization. Ambra1 was not required for Parkin translocation to depolarized mitochondria but was critically important for subsequent mitochondrial clearance. In particular, Ambra1 was recruited to perinuclear clusters of depolarized mitochondria and activated class III PI3K in their immediate vicinity. These data identify interaction of Parkin with Ambra1 as a key mechanism for induction of the final clearance step of Parkin-mediated mitophagy.
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“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [56]
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Cites
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809125 · Cited by 4,026
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., Cookson, M. R., & Youle, R. J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000298 · Cited by 2,944
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000) · Nature Genetics · doi:10.1038/77060 · Cited by 2,024 · cited 2×
“Because Parkin is an E3 ubiquitin ligase (Shimura et al., 2000), we asked whether Ambra1 might be a substrate for Parkinmediated ubiquitination.”
BackgroundMatsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910140 · Cited by 1,969
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M. (2006) · Nature · doi:10.1038/nature04779 · Cited by 1,788
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., Bae, E., Kim, J., Shong, M., Kim, J.-M., et al. (2006) · Nature · doi:10.1038/nature04788 · Cited by 1,705
Network organization of the human autophagy system
Behrends, C., Sowa, M. E., Gygi, S. P., & Harper, J. W. (2010) · Nature · doi:10.1038/nature09204 · Cited by 1,554
Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants
Greene, J. C., Whitworth, A. J., Kuo, I., Andrews, L. A., Feany, M. B., & Pallanck, L. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737556100 · Cited by 1,203
p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria
Okatsu, K., Saisho, K., Shimanuki, M., Nakada, K., Shitara, H., Sou, Y., Kimura, M., Sato, S., Hattori, N., Komatsu, M., et al. (2010) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01426.x · Cited by 397
Research works printed but not linked: 1
- Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for au- tophagosome biogenesis during starvation. Cell 141:656 -667.
Cited by
Sorted by citations
The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
Pickrell, A. M., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.007 · Cited by 2,310
“Affinity-binding studies indicate that AMBRA1, a protein involved in autophagy, binds to Parkin and promotes mitophagy (Van Humbeeck et al., 2011).”
BackgroundThe pathways of mitophagy for quality control and clearance of mitochondria
Ashrafi, G., & Schwarz, T. L. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2012.81 · Cited by 1,900
“Recent studies suggests that both PINK1 and Parkin can directly interact with the Beclin-1 PI3K complex.(82,83) Parkindependent recruitment of Ambra1, an activator of the Beclin1 complex, to mitochondria upon depolarization could lead to activation of the Beclin-1 complex and nucleation of pre-autophagosomal membranes…”
BackgroundMitophagy: mechanisms, pathophysiological roles, and analysis
Ding, W.-X., & Yin, X.-M. (2012) · bchm · doi:10.1515/hsz-2012-0119 · Cited by 1,032
“In addition to the ubiquitination of mitochondrial proteins, in the vertebrate central nervous system, Parkin also interacts with Ambra1 (activating molecule in Beclin 1-regulated autophagy), a protein that promotes general autophagy by activating the class III phosphatidylinositol 3-kinase complex (Fimia et al. , 200…”
BackgroundInfluentialMitochondrial dynamics and mitochondrial quality control
Ni, H.-M., Williams, J. A., & Ding, W.-X. (2015) · Redox Biology · doi:10.1016/j.redox.2014.11.006 · Cited by 931
“However, AMBRA1 also binds directly with LC3 via its LIR and induces LC3-dependent but Parkin and p62-independent mitophagy [85].”
BackgroundThe mitophagy pathway and its implications in human diseases
Wang, S., Long, H., Hou, L., Feng, B., Ma, Z., Wu, Y., Zeng, Y., Cai, J., Zhang, D., & Zhao, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01503-7 · Cited by 991
“AMBRA1 is rapidly recruited to the OMM during mitochondrial depolarization and then interacts with the ATAD3A complex to promote PINK1 stability.(135,136) Accumulation of PINK1 facilitates PINK1Parkin-mediated mitophagy to clear damaged mitochondria efficiently.”
Background
Metadata
- Authors
- Van Humbeeck, C., Cornelissen, T., Hofkens, H., Mandemakers, W., Gevaert, K., De Strooper, B., & Vandenberghe, W.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Universitair Ziekenhuis Leuven (BE)
- Corresponding author
- Vandenberghe, W.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-07-13
- Volume
- 31
- Issue
- 28
- Pages
- 10249-10261
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623066
- OpenAlex
- W2069519643
- Cited by
- 287
- References
- 0
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 23 · 2023: 15 · 2022: 11 · 2021: 22 · 2020: 19 · 2019: 20 · 2018: 11 · 2017: 21 · 2016: 22 · 2015: 33 · 2014: 26 · 2013: 21 · 2012: 22
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek
- KU Leuven (P6/28)
- Universiteit Gent
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkin, AMBRA1, mitophagy, Parkinson's disease, mitochondrial depolarization, class III PI3K, Beclin-1, autophagy, dopaminergic neurons, protein-protein interaction, mitochondrial clearance, ubiquitination
- MeSH terms
- Animals, Autophagy, Brain, Cells, Cultured, Humans, Mitochondria, Neurons, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Mice, Ubiquitination, HEK293 Cells
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