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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AMBRA1 and ATG12 positively regulate mitophagy.
“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]
The Discussion (p. 10259) identifies Ambra1 as a key player in clearing depolarized mitochondria and says its activating role in mitophagy depends on Parkin. The cited paper does not establish the claim about ATG12 (searched: ATG12 and ATG12 positively regulates mitophagy). (LLM, conf=0.85)
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“PARKIN also interacts with AMBRA1 at mitochondria to promote mitochondrial clearance, and depolarization of mitochondria increases the interaction between Parkin and AMBRA1.(113) Interestingly, AMBRA1 is required for the clearance of mitochondria, but not for the translocation of Parkin.”
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Lou, G., Palikaras, K., Lautrup, S., Scheibye-Knudsen, M., Tavernarakis, N., & Fang, E. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.07.002 · Cited by 412 · see citing works
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Gustafsson, Å. B., & Dorn, G. W. (2018) · Physiological Reviews · doi:10.1152/physrev.00005.2018 · Cited by 229 · see citing works
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“Moreover, Parkin interacts with Ambra1 [74], a positive regulator of Beclin-1-dependent autophagy.”
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“Autophagy and Beclin 1 regulator 1 (AMBRA1), an upstream autophagy regulator, can interact with LC3 through an LIR motif; interestingly, AMBRA1 can trigger both Parkin-dependent and Parkin-independent mitophagy [34,35].”
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“Parkin can also interact with activating molecule in Beclin1-regulated autophagy (AMBRA1), which stimulates the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex required for phagophore formation [61].”
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Gubaš, A., & Đikić, I. (2021) · FEBS Journal · doi:10.1111/febs.15824 · Cited by 215 · see citing works
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“In another example, ambra1 promotes PINK1–parkin-dependent and PINK1– parkin-independent, mitophagy (35,36).”
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“…:Bcl-xL (ng) : 50 μm 50 μm 50 μm 50 μm 50 μm 50 μm A B (legend on next page) Cell Reports 9, 1538–1553, November 20, 2014 ª2014 The Authors 1539 which are well established to promote Parkin activation during mitophagy (Narendra et al., 2008; Vives-Bauza et al., 2010; Van Humbeeck et al., 2011).”
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“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
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The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance
Bertolin, G., Ferrando-Miguel, R., Jacoupy, M., Traver, S., Grenier, K., Greene, A. W., Dauphin, A., Waharte, F., Bayot, A., Salamero, J., et al. (2013) · Autophagy · doi:10.4161/auto.25884 · Cited by 154 · see citing works
“Of note, PINK1 was also dispensable for the degradation of whole organelles, which, in this model, was only accomplished in the presence of exogenous PARK2, as illustrated by clearance of the matrix marker PMPCB.”
BackgroundDJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy
Imberechts, D., Kinnart, I., Wauters, F., Terbeek, J., Manders, L., Wierda, K. D. B., Eggermont, K., Madeiro, R. F., Sue, C. M., Verfaillie, C. M., et al. (2022) · Brain · doi:10.1093/brain/awac313 · Cited by 161 · see citing works
“The construct encoding parkin with an N-terminal FLAG tag was described previously.(31) The mito-Keima construct (mt/mKeima/ pIND[SP1]) was a gift from Dr A.”
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Sedlackova, L., & Korolchuk, V. I. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.12.012 · Cited by 186 · see citing works
Autophagy in Cell Life and Cell Death
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New method to assess mitophagy flux by flow cytometry
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Mitophagy mechanisms and role in human diseases
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Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
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“(UPS) (48), VDAC1, 2, and 3 (89), Ambra1 (90), NIX (63) NIX N/A”
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Selective Autophagy: Talking with the UPS
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Mitophagy-driven metabolic switch reprograms stem cell fate
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Mitochondrial quality control: Easy come, easy go
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Mending a broken heart: the role of mitophagy in cardioprotection
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Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles
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“Consistent with this notion, several groups have been unable to observe mitophagy in neurons (Ashrafi et al., 2014; Bingol et al., 2014; Rakovic et al., 2013; Van Laar et al., 2011).”
An emerging role of PARK2 in cancer
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“Consequently, AMBRA1 is indispensable for the final step of PARK2triggered mitophagy rather than the translocation of PARK2 to depolarized mitochondria.(163) These findings unveil a novel mechanism by which AMBRA1 enhances PARK2-mediated mitophagy.”
BackgroundBECN1 is involved in the initiation of mitophagy
Choubey, V., Cagalinec, M., Liiv, J., Safiulina, D., Hickey, M. A., Kuum, M., Liiv, M., Anwar, T., Eskelinen, E., & Kaasik, A. (2014) · Autophagy · doi:10.4161/auto.28615 · Cited by 114 · see citing works
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Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review
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“IPs, including the protein extraction and detection, were performed by standard protocols (Van Humbeeck et al., 2011).”
MethodMitophagy in the pathogenesis and management of disease
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“153 On the OMM, AMBRA1 interacts with PINK1, increasing its stability by preventing its degradation by the mitochondrial protease LONP1, thereby enhancing PINK1 accumulation.”
Mitochondrial regulation of β-cell function: Maintaining the momentum for insulin release
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BackgroundCianfanelli, V., Zio, D. D., Bartolomeo, S. D., Nazio, F., Strappazzon, F., & Cecconi, F. (2015) · Journal of Cell Science · doi:10.1242/jcs.168153 · Cited by 104 · see citing works
“In this context, the cytosolic pool of Ambra1 interacts with PARKIN to enhance mitochondrial clearance (Van Humbeeck et al., 2011).”
BackgroundTargeting mitophagy in Parkinson's disease
Clark, E. H., de la Torre, A. V., Hoshikawa, T., & Briston, T. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.014294 · Cited by 128 · see citing works
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BackgroundAutophagy in neuronal cells: general principles and physiological and pathological functions
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“[85] provided evidence that Ambra is also essential for mitochondrial clearance.”
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Mitophagy in neurodegenerative diseases
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“At the damaged mitochindria, Parkin mediates the recruitment of AMBRA1 and thereby facilitates the localized induction of PI3K-III activity there [80].”
BackgroundMitochondrial dismissal in mammals, from protein degradation to mitophagy
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AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability
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“AMBRA1, a positive regulator of ULK1- and BECN1dependent autophagy [33], has been reported to regulate both PINK1-PRKN-dependent and independent mitophagy [34,35].”
BackgroundInfluentialNeuroglial transmitophagy and Parkinson's disease
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“Parkin has also been found to interact with Ambra1, a promoter of phagophore nucleation, independent of its ubiquitin ligase function [49].”
Mitophagy in the Pathogenesis of Liver Diseases
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BackgroundMechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights
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“Parkin interacts with Ambra1 during mitochondrial depolarization, and Ambra1 is recruited to perinuclear clusters during Parkin-mediated mitophagy to activate class III PI3K for autophagosome formation surrounding these mitochondrial clusters for their clearance (Van Humbeeck et al., 2011).”
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Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics
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“Ambra1 can also be recruited by Parkin during mitochondrial depolarization and activates class III PI3K to form autophagosomes around mitochondria [40].”
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“stimulate the nucleation of preautophagosomal isolation membranes (Figure 1), as they have been independently implicated in the recruitment of Ambra1, an activator of the class III PI3K complex [32], and in the interaction with its component Beclin 1 [33].”
The Role of Mitophagy in Regulating Cell Death
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“AMBRA1-mediated mitophagy is dependent on Parkin, and the overexpression of AMBRA1 in Parkin-/cells fails to restore mitophagy levels [99].”
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- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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