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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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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.”
BackgroundKubli, D. A., & Gustafsson, Å. B. (2012) · Circulation Research · doi:10.1161/circresaha.112.265819 · Cited by 825
“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.”
BackgroundTo Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate
Green, D. R., & Levine, B. (2014) · Cell · doi:10.1016/j.cell.2014.02.049 · Cited by 698
“Moreover, AMBRA1 (a positive regulator of the Beclin 1/ Class III PI3K initiation complex) binds to Parkin during mitophagy (Van Humbeeck et al., 2011), and several autophagy proteins , including ULK1, ATG14, ATG16L, and ATG9, are recruited to depolarized mitochondria in Parkin-expressing cells…”
Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors
Johansen, T., & Lamark, T. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.07.016 · Cited by 736
Exner, N., Lutz, A. K., Haass, C., & Winklhofer, K. F. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.170 · Cited by 677
“Ambra1 (activating molecule in Beclin-regulated autophagy) was recently identified as a parkin-interacting protein that promotes autophagic clearance of mitochondria by activating class III PI3K, which is essential for the formation of phagophores (Van Humbeeck et al , 2011).”
Kubli, D. A., Zhang, X., Lee, Y., Hanna, R. A., Quinsay, M. N., Nguyen, C. K., Jimenez, R., Petrosyan, S., Murphy, A. N., & Gustafsson, Å. B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.411363 · Cited by 476
“Interestingly, mitochondria provide an assembly site and lipid source for the nascent autophagosome (42), and it was recently reported that Parkin interacts with the autophagy-promoting protein Ambra1 at mitochondria (43).”
BackgroundIntegration of cellular bioenergetics with mitochondrial quality control and autophagy
Hill, B. G., Benavides, G. A., Lancaster, J. R., Ballinger, S. W., Dell’Italia, L., Zhang, J., & Darley-Usmar, V. M. (2012) · Biological Chemistry · doi:10.1515/hsz-2012-0198 · Cited by 495
“Parkin also interacts with Ambra1; this is important for Ambra1 to activate class III PI3K which is needed for subsequent mitochondrial clearance (Van Humbeeck et al. , 2011 ).”
Selective autophagy of intracellular organelles: Recent research advances
Li, W., He, P., Huang, Y., Li, Y.-F., Lu, J., Li, M., Kurihara, H., Luo, Z., Meng, T., Onishi, M., et al. (2020) · Theranostics · doi:10.7150/thno.49860 · Cited by 523
“Mechanismly, recruitment of Ambra1 induced by Parkin activates class III PI3K around depolarized mitochondria [110].”
BackgroundSIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage
Tseng, A. H.-H., Shieh, S.-S., & Wang, D. L. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.05.002 · Cited by 458
“Immunofluorescence of Lamp1 and Tom20 was used as a marker of lysosomes and mitochondria, respectively; colocalization of LC3 puncta and Lamp1 indicates the formation of autolysosomes [36].”
MethodYao, R.-Q., Ren, C., Xia, Z.-F., & Yao, Y.-M. (2021) · Autophagy · doi:10.1080/15548627.2020.1725377 · Cited by 441
“Types Locations Receptors Function Refs Mitophagy Outer mitochondrial membrane VDAC Mediating degradation of mitochondria in PINK1- and PRKN-dependent signaling pathway [29,30] RHOT1 MFN1/2 BNIP3L Mediating ubiquitin-independent degradation of mitochondria by directly interacting with MAP1LC3B [40,45,49] FUNDC1 [39,44…”
BackgroundInfluentialMechanisms of Selective Autophagy
Lamark, T., & Johansen, T. (2021) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120219-035530 · Cited by 429
Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease
Li, A., Gao, M. Q., Liu, B., Qin, Y. H., Chen, L., Liu, H., Wu, H., & Gong, G. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04906-6 · Cited by 478
“AMBRA1 as a Parkin interactor can localize to OMM to enhance mitochondrial clearance via binding to Lc3 through its LIR motif [45].”
BackgroundMitochondrial homeostasis: The interplay between mitophagy and mitochondrial biogenesis
Palikaras, K., & Tavernarakis, N. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.021 · Cited by 447
“Ambra1 is identified as a Parkin interactor, however there is no evidence for Parkin-mediated ubiquitination (Van Humbeeck et al., 2011) In turn, Ambra1 triggers autophagy and mitochondrial removal by stimulating the formation of new phagophore (Fimia et al., 2007).”
BackgroundLou, G., Palikaras, K., Lautrup, S., Scheibye‐Knudsen, M., Tavernarakis, N., & Fang, E. F. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.07.002 · Cited by 455
AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1
Strappazzon, F., Nazio, F., Corrado, M., Cianfanelli, V, Romagnoli, A., Fimia, G. M., Campello, S., Nardacci, R., Piacentini, M., Campanella, M., et al. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.139 · Cited by 399
“We confirm that AMBRA1 potentiates PARKIN-mediated mitophagy, in line with previous work.(16) We show that AMBRA1–ActA promotes PARKIN translocation to depolarized mitochondria in HEK293 cells, where PARKIN is present.”
InfluentialParkin and PINK1: much more than mitophagy
Scarffe, L. A., Stevens, D. A., Dawson, V. L., & Dawson, T. M. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.03.004 · Cited by 392
Mitochondrial dysfunction in the pathophysiology of renal diseases
Che, R., Yuan, Y., Huang, S., & Zhang, A. (2013) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00571.2013 · Cited by 399
Hamacher‐Brady, A., & Brady, N. R. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2087-8 · Cited by 410
“In response to mitochondrial depolarization, AMBRA1 interacts with Parkin at the OMM and contributes to Parkin-mediated mitophagy via local stimulation of autophagosome formation [58, 59].”
BackgroundSalminen, A., Kaarniranta, K., Kauppinen, A., Ojala, J. O., Haapasalo, A., Soininen, H. S., & Hiltunen, M. O. (2013) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.06.002 · Cited by 371
Mitophagy in neurodegeneration and aging
Fivenson, E. M., Lautrup, S., Sun, N., Scheibye-Knudsen, M., Stevnsner, T., Nilsen, H., Bohr, V. A., & Fang, E. F. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.02.007 · Cited by 364
“Some proteins involved in Parkin-independent mitophagy pathways, such as Ambra1, Nix, and FUNDC1, also have roles in traditional Parkindependent mitophagy [43-45].”
BackgroundThe emerging, multifaceted role of mitophagy in cancer and cancer therapeutics
Panigrahi, D. P., Praharaj, P. P., Bhol, C. S., Mahapatra, K. K., Patra, S., Behera, B. P., Mishra, S. R., & Bhutia, S. K. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.015 · Cited by 379
Cai, Q., Zakaria, H. M., Simone, A., & Sheng, Z. (2012) · Current Biology · doi:10.1016/j.cub.2012.02.005 · Cited by 346
The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
Cornelissen, T., Haddad, D., Wauters, F., Van Humbeeck, C., Mandemakers, W., Koentjoro, B., Sue, C., Gevaert, K., De Strooper, B., Verstreken, P., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu244 · Cited by 327
“Immunostaining of cultured cells was performed as described (17).”
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Dodson, M. B., Darley-Usmar, V. M., & Zhang, J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.05.014 · Cited by 333
Hale, A. N., Ledbetter, D., Gawriluk, T. R., & Rucker, E. B. (2013) · Autophagy · doi:10.4161/auto.24273 · Cited by 343
Ubiquitin signaling and autophagy
Grumati, P., & Đikić, I. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000117 · Cited by 336
“The nature and the meaning of this interaction is not completely clear as yet (80, 81).”
BackgroundMitochondrial degradation: Mitophagy and beyond
Uoselis, L., Nguyen, T. N., & Lazarou, M. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.08.021 · Cited by 270
Mitochondrial morphology in mitophagy and macroautophagy
Gomes, L. C., & Scorrano, L. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.02.012 · Cited by 259
Role and Mechanisms of Mitophagy in Liver Diseases
Ma, X., McKeen, T., Zhang, J., & Ding, W. (2020) · Cells · doi:10.3390/cells9040837 · Cited by 288
“Parkin also interacts with autophagy/beclin-1 regulator-1 (Ambra1) upon mitochondrial depolarization, and Ambra1 then further activates class III PI3K for autophagosome formation surrounding these mitochondrial clusters for their clearance [47].”
BackgroundMitophagy in Cancer: A Tale of Adaptation
Vara‐Pérez, M., Felipe‐Abrio, B., & Agostinis, P. (2019) · Cells · doi:10.3390/cells8050493 · Cited by 264
“Another mitophagy receptor is Autophagy And Beclin 1 Regulator 1 (AMBRA1), a Parkin interactor [76] that directly binds LC3 and triggers mitophagy [77] to protect the cells from apoptotic cell death caused by oxidative stress [78].”
BackgroundTruban, D., Hou, X., Caulfield, T. R., Fiesel, F. C., & Springer, W. (2016) · Journal of Parkinson’s Disease · doi:10.3233/jpd-160989 · Cited by 237
Regulation of PRKN-independent mitophagy
Terešak, P., Lapão, A., Subic, N., Boya, P., Elazar, Z., & Simonsen, A. (2021) · Autophagy · doi:10.1080/15548627.2021.1888244 · Cited by 256
“It was demonstrated that AMBRA1 plays a role in mitophagy when it is recruited to damaged mitochondria to locally activate the PtdIns3K complex, leading to phagophore formation in the proximity of perinuclear mitochondrial clusters [118].”
BackgroundMechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218
Parkinson’s disease as a result of aging
Rodriguez, M., Rodriguez‐Sabate, C., Morales, I., Sanchez, A., & Sabate, M. (2015) · Aging Cell · doi:10.1111/acel.12312 · Cited by 214
“Studies with MnSOD, catalase, and thioredoxin knockout mice have provided inconclusive data to support the oxidative stress theory of aging (Muller et al., 2007; Jang & Van Remmen, 2009; Sohal & Orr, 2012).”
BackgroundInfluentialNo Parkin Zone: Mitophagy without Parkin
Villa, E., Marchetti, S., & Ricci, J. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.07.004 · Cited by 229
Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations
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“AMBRA1 may also act as a mitophagy receptor by binding to LC3 in PRKN/PARK2-dependent and -independent manners [65,66].”
BackgroundEvolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process
Gustafsson, Å. B., & Dorn, G. W. (2018) · Physiological Reviews · doi:10.1152/physrev.00005.2018 · Cited by 235
Barazzuol, L., Giamogante, F., Brini, M., & Calí, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051772 · Cited by 246
“Moreover, Parkin interacts with Ambra1 [74], a positive regulator of Beclin-1-dependent autophagy.”
BackgroundMitophagy in Parkinson’s Disease: From Pathogenesis to Treatment
Liu, J., Liu, W., Li, R., & Yang, H. (2019) · Cells · doi:10.3390/cells8070712 · Cited by 225
“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].”
BackgroundMechanisms and roles of mitophagy in neurodegenerative diseases
Wang, Y., Liu, N., & Lu, B. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13140 · Cited by 217
Wauters, F., Cornelissen, T., Imberechts, D., Martin, S., Koentjoro, B., Sue, C. M., Vangheluwe, P., & Vandenberghe, W. (2019) · Autophagy · doi:10.1080/15548627.2019.1603548 · Cited by 200
“Western blot, mitochondrial isolation and co-ip Western blot was performed as described [12,22].”
MethodSelf-citationFueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets
Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18050933 · Cited by 207
“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].”
BackgroundA guide to the regulation of selective autophagy receptors
Gubaš, A., & Đikić, I. (2021) · FEBS Journal · doi:10.1111/febs.15824 · Cited by 229
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.11.004 · Cited by 173
Beclin 1, an Essential Component and Master Regulator of PI3K-III in Health and Disease
McKnight, N. C., & Yue, Z. (2013) · Current Pathobiology Reports · doi:10.1007/s40139-013-0028-5 · Cited by 168
The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway
Szargel, R., Shani, V., Elghani, F. A., Mekies, L. N., Liani, E., Rott, R., & Engelender, S. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw189 · Cited by 174
“In another example, ambra1 promotes PINK1–parkin-dependent and PINK1– parkin-independent, mitophagy (35,36).”
BackgroundCarroll, R. G., Hollville, É., & Martin, S. J. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.046 · Cited by 152
“…: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).”
BackgroundKim, J., Fiesel, F. C., Belmonte, K. C., Hudec, R., Wang, W.-X., Kim, C., Nelson, P. T., Springer, W., & Kim, J. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0121-4 · Cited by 163
“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
BackgroundLaar, V. S. V., & Berman, S. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.05.015 · Cited by 137
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 156
“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 168
“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.”
BackgroundMethodSelf-citationMitochondrial quality control as a key determinant of cell survival
Sedlackova, L., & Korolchuk, V. I. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.12.012 · Cited by 187
Autophagy in Cell Life and Cell Death
Anding, A. L., & Baehrecke, E. H. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.07.012 · Cited by 164
New method to assess mitophagy flux by flow cytometry
Mauro-Lizcano, M., Esteban-Martínez, L., Seco, E., Serrano-Puebla, A., Garcia-Ledo, L., Figueiredo-Pereira, C., Vieira, H. L. A., & Boya, P. (2015) · Autophagy · doi:10.1080/15548627.2015.1034403 · Cited by 140
Mitophagy mechanisms and role in human diseases
Redmann, M., Dodson, M. B., Boyer‐Guittaut, M., Darley-Usmar, V. M., & Zhang, J. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.05.010 · Cited by 138
Zhang, J. (2015) · Redox Biology · doi:10.1016/j.redox.2015.01.003 · Cited by 141
Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Grenier, K., McLelland, G., & Fon, E. A. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00100 · Cited by 124
“(UPS) (48), VDAC1, 2, and 3 (89), Ambra1 (90), NIX (63) NIX N/A”
Seabright, A. P., Fine, N. H. F., Barlow, J. P., Lord, S. O., Musa, I., Gray, A., Bryant, J. A., Banzhaf, M., Lavery, G. G., Hardie, D. G., et al. (2020) · The FASEB Journal · doi:10.1096/fj.201903051r · Cited by 176
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Feng, S., Wang, Z., Yuan, Y., Wang, X., Sun, H., Chen, N., & Zhang, Y. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104553 · Cited by 146
Mitophagy: Link to cancer development and therapy
Kulikov, A. V., Luchkina, E. A., Gogvadze, V. G., & Zhivotovsky, B. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.10.088 · Cited by 132
Selective Autophagy: Talking with the UPS
Park, C., & Cuervo, A. M. (2013) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-013-9623-7 · Cited by 118
Pilsl, A., & Winklhofer, K. F. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0902-3 · Cited by 131
Mitophagy-driven metabolic switch reprograms stem cell fate
Naik, P. P., Birbrair, A., & Bhutia, S. K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2922-9 · Cited by 134
Mitochondrial quality control: Easy come, easy go
Stotland, A. B., & Gottlieb, R. A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.12.041 · Cited by 123
Mending a broken heart: the role of mitophagy in cardioprotection
Moyzis, A. G., Sadoshima, J., & Gustafsson, Å. B. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00708.2014 · Cited by 114
Defending the mitochondria: The pathways of mitophagy and mitochondrial-derived vesicles
Roberts, R. F., Tang, M. Y. H., Fon, E. A., & Durcan, T. M. (2016) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2016.07.020 · Cited by 121
“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
Xu, L., Lin, D., Yin, D., & Koeffler, H. P. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1107-0 · Cited by 114
Regulation and function of mitophagy in development and cancer
Lu, H., Li, G., Liu, L., Feng, L., Wang, X., & Jin, H. (2013) · Autophagy · doi:10.4161/auto.26550 · Cited by 107
“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 117
“In addition to BECN1 itself, several BECN1 binding proteins also interact with PARK2.(22,39) We demonstrate here that another component of the autophagy core complex, PIK3C3, coimmunoprecipitates with PARK2.”
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Unravelling the genetic basis of schizophrenia and bipolar disorder with GWAS: A systematic review
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Haddad, D., Vilain, S., Vos, M. H., Esposito, G., Matta, S., Kalscheuer, V. M., Craessaerts, K., Leyssen, M., Nascimento, R. M. P., Vianna‐Morgante, A. M., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.04.012 · Cited by 90
“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
Wang, Q., Sun, Y., Li, T. Y., & Auwerx, J. (2026) · Cell Research · doi:10.1038/s41422-025-01203-7 · Cited by 103
“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
Kaufman, B. A., Li, C., & Soleimanpour, S. A. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.01.004 · Cited by 107
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript including sequestosome 1 (p62) and histone deacetylase 6 (HDAC6) (Geisler et al., 2010; Lee et al., 2010). p62 and HDAC6 interaction with autophagosomal proteins, including Beclin and Ambra1, ultimately leads to turnover of Parkin-bound mi…”
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 105
“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 132
“(2021) 296 100209 Furthermore, mitochondrial depolarization promotes a direct interaction between AMBRA1 and Parkin, activating proximal Class III PI3K, contributing to new phagophore formation (89).”
BackgroundAutophagy in neuronal cells: general principles and physiological and pathological functions
Daμμe, M., Suntio, T., Säftig, P., & Eskelinen, E. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1361-4 · Cited by 109
Wohlgemuth, S. E., Calvani, R., & Marzetti, E. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.03.007 · Cited by 97
“[85] provided evidence that Ambra is also essential for mitochondrial clearance.”
BackgroundThe beclin 1 interactome: Modification and roles in the pathology of autophagy-related disorders
Kaur, S., & Changotra, H. (2020) · Biochimie · doi:10.1016/j.biochi.2020.04.025 · Cited by 116
How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways
Zimmermann, M., & Reichert, A. S. (2017) · Biological Chemistry · doi:10.1515/hsz-2017-0206 · Cited by 104
Ambra1 at the crossroad between autophagy and cell death
Fimia, G. M., Corazzari, M., Antonioli, M., & Piacentini, M. (2012) · Oncogene · doi:10.1038/onc.2012.455 · Cited by 96
Mitophagy in neurodegenerative diseases
Rodolfo, C., Campello, S., & Cecconi, F. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.08.004 · Cited by 104
Abrahamsen, H., Stenmark, H., & Platta, H. W. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.04.046 · Cited by 92
“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
Campello, S., Strappazzon, F., & Cecconi, F. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2013.11.010 · Cited by 88
AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability
Rienzo, M. D., Romagnoli, A., Ciccosanti, F., Refolo, G., Consalvi, V., Arena, G., Valente, E. M., Piacentini, M., & Fimia, G. M. (2021) · Autophagy · doi:10.1080/15548627.2021.1997052 · Cited by 92
“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
Moráles, I., Sánchez, A., Puertas‐Avendaño, R., Rodriguez‐Sabate, C., Perez‐Barreto, A., & Rodrı́guez, M. (2020) · Glia · doi:10.1002/glia.23839 · Cited by 95
Hammerling, B. C., & Gustafsson, Å. B. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.07.013 · Cited by 86
“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
Ke, P. (2020) · Cells · doi:10.3390/cells9040831 · Cited by 91
“The Parkin-interacting protein AMBRA1 was shown to induce mitophagy by prolonging mitochondrial depolarization and triggering mitochondrial clearance—not by recruiting Parkin to damaged mitochondria [345].”
BackgroundMechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights
Williams, J. A. R., & Ding, W. (2017) · Biological Chemistry · doi:10.1515/hsz-2017-0228 · Cited by 92
“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).”
BackgroundBloemberg, D., & Quadrilatero, J. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00261.2018 · Cited by 100
Amadoro, G., Corsetti, V., Florenzano, F., Atlante, A., Bobba, A., Nicolin, V., Nori, S. L., & Calissano, P. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00018 · Cited by 77
Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics
Guan, Y., Wang, Y., Li, B., Shen, K., Li, Q., Ni, Y.-Y., & Huang, L. H. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02065-w · Cited by 97
“Ambra1 can also be recruited by Parkin during mitochondrial depolarization and activates class III PI3K to form autophagosomes around mitochondria [40].”
Corti, O., & Brice, A. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.11.002 · Cited by 79
“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
Li, S., Zhang, J., Liu, C., Wang, Q., Yan, J., Hui, L., Jia, Q., Shan, H., Tao, L., & Zhang, M. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6617256 · Cited by 76
“AMBRA1-mediated mitophagy is dependent on Parkin, and the overexpression of AMBRA1 in Parkin-/cells fails to restore mitophagy levels [99].”
BackgroundRita, A. D., D’Acunzo, P., Simula, L., Campello, S., Strappazzon, F., & Cecconi, F. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00092 · Cited by 83
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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