The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy
Open accessAbstract
Damaged mitochondria are detrimental to cellular homeostasis. One mechanism for removal of damaged mitochondria involves the PINK1-PARKIN pathway, which poly-ubiquitylates damaged mitochondria to promote mitophagy. We report that assembly of ubiquitin chains on mitochondria triggers autophagy adaptor recruitment concomitantly with activation of the TBK1 kinase, which physically associates with OPTN, NDP52, and SQSTM1. TBK1 activation in HeLa cells requires OPTN and NDP52 and OPTN ubiquitin chain binding. In addition to the known role of S177 phosphorylation in OPTN on ATG8 recruitment, TBK1-dependent phosphorylation on S473 and S513 promotes ubiquitin chain binding in vitro as well as TBK1 activation, OPTN mitochondrial retention, and efficient mitophagy in vivo. These data reveal a self-reinforcing positive feedback mechanism that coordinates TBK1-dependent autophagy adaptor phosphorylation with the assembly of ubiquitin chains on mitochondria to facilitate efficient mitophagy, and mechanistically links genes mutated in Parkinson's disease and amyotrophic lateral sclerosis in a common selective autophagy pathway.
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pUbS65 accumulates with mitochondrial stress, age, and disease and serves as a specific signal for recognition by autophagy receptors.
“Moreover, pUbS65 has been suggested to accumulate with mitochondrial stress, age, and disease [19] and to serve as a specific signal for recognition by autophagy receptors [20, 21].”
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 [20]
The citation to this paper concerns pUbS65 as a specific signal for autophagy-receptor recognition; the accumulation claim is attached to [19]. In the Results ("Focal localization of p-TBK1S172 with OPTN on depolarized mitochondria"), the authors conclude that p-S65 UB alone does not specify sites of adaptor recruitment. The Discussion likewise says p-S65 UB does not exclusively dictate those sites. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredATG9A has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy.
“has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy [12, 34, 35].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [35]
The Discussion reports that PARKIN-mediated mitochondrial ubiquitylation recruits autophagy adaptors, including OPTN, and promotes mitophagy. That supports OPTN’s role in PINK1-PARKIN mitophagy, but the passages retrieved for ATG9A and OPTN do not establish a link between those two proteins. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTBK1 amplifies mitophagy signaling by phosphorylating OPTN and SQSTM1, enhancing their binding to ubiquitin and LC3, and promoting TBK1 autophosphorylation in a positive-feedback manner.
“Additionally, TBK1 amplifies the signaling cascade for mitophagy by phosphorylating OPTN and SQSTM1 (which enhances binding to ubiquitin and LC3) and promoting TBK1 autophosphorylation in a positive-feedback manner [58,59].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [58]
Through phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52, TBK1 regulates macroautophagy, xenophagy and mitophagy.
“Through its phosphorylation of the autophagy receptors OPTN, SQSTM1, and CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2) [58,59,194], TBK1 regulates several aspects of autophagy, including macroautophagy, xenophagy and mitophagy [59,90,148,194–196].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [58]
Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1, TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner.
“Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1 (nucleosome assembly protein 1), TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner [58,200,201].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [58]
Mitophagy can also occur through Parkin-independent pathways.
“Mitophagy can also occur through Parkin-independent pathways.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [142]
Mitochondrial protein ubiquitination promotes mitochondrial recruitment of autophagy regulators and receptors such as TBK1 and optineurin.
“Mitochondrial protein ubiquitination promotes mitochondrial recruitment of autophagy regulators and receptors such as TBK1 and optineurin (Heo et al., 2015, Matsumoto et al., 2015, Richter et al., 2016).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Heo et al., 2015
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Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
IKKε and TBK1 are essential components of the IRF3 signaling pathway
Fitzgerald, K. A., McWhirter, S. M., Faia, K. L., Rowe, D. C., Latz, E., Golenbock, D. T., Coyle, A. J., Liao, S.-M., & Maniatis, T. (2003) · Nature Immunology · doi:10.1038/ni921 · Cited by 2,680 · see citing works
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630 · see citing works
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 · see citing works
Ubiquitin is phosphorylated by PINK1 to activate parkin
Koyano, F., Okatsu, K., Kosako, H., Tamura, Y., Go, E., Kimura, M., Kimura, Y., Tsuchiya, H., Yoshihara, H., Hirokawa, T., et al. (2014) · Nature · doi:10.1038/nature13392 · Cited by 1,477 · see citing works
Phosphorylation of the Autophagy Receptor Optineurin Restricts <i>Salmonella</i> Growth
Wild, P., Farhan, H., McEwan, D. G., Wagner, S., Rogov, V. V., Brady, N. R., Richter, B., Korac, J., Waidmann, O., Choudhary, C., et al. (2011) · Science · doi:10.1126/science.1205405 · Cited by 1,298 · see citing works
PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity
Kane, L. A., Lazarou, M., Fogel, A. I., Li, Y., Yamano, K., Sarraf, S. A., Banerjee, S., & Youle, R. J. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201402104 · Cited by 1,298 · see citing works
Mutations of optineurin in amyotrophic lateral sclerosis
Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., Kinoshita, Y., Kamada, M., Nodera, H., Suzuki, H., et al. (2010) · Nature · doi:10.1038/nature08971 · Cited by 1,265 · see citing works
Cargo recognition and trafficking in selective autophagy
Stolz, A., Ernst, A., & Dikic, I. (2014) · Nature Cell Biology · doi:10.1038/ncb2979 · Cited by 1,207 · see citing works
Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization
Sarraf, S. A., Raman, M., Guarani, V., Sowa, M. E., Huttlin, E. L., Gygi, S. P., & Harper, J. W. (2013) · Nature · doi:10.1038/nature12043 · Cited by 1,020 · see citing works
Self-citationExome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways
Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y.-F., Wang, Q., Krueger, B. J., et al. (2015) · Science · doi:10.1126/science.aaa3650 · Cited by 966 · see citing works
Self-citationKondapalli, C., Kazlauskaite, A., Zhang, N., Woodroof, H. I., Campbell, D. G., Gourlay, R., Burchell, L., Walden, H., Macartney, T. J., Deak, M., et al. (2012) · Open Biology · doi:10.1098/rsob.120080 · Cited by 940 · see citing works
Thurston, T. L. M., Ryzhakov, G., Bloor, S., von Muhlinen, N., & Randow, F. (2009) · Nature Immunology · doi:10.1038/ni.1800 · Cited by 872 · see citing works
Wong, Y. C., & Holzbaur, E. L. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405752111 · Cited by 812 · see citing works
Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65
Kazlauskaite, A., Kondapalli, C., Gourlay, R., Campbell, D. G., Ritorto, M. S., Hofmann, K., Alessi, D. R., Knebel, A., Trost, M., & Muqit, M. M. K. (2014) · Biochemical Journal · doi:10.1042/bj20140334 · Cited by 806 · see citing works
Narendra, D. P., Kane, L. A., Hauser, D. N., Fearnley, I. M., & Youle, R. J. (2010) · Autophagy · doi:10.4161/auto.6.8.13426 · Cited by 789 · see citing works
Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
Freischmidt, A., Wieland, T., Richter, B., Ruf, W., Schaeffer, V., Müller, K., Marroquin, N., Nordin, F., Hübers, A., Weydt, P., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4000 · Cited by 786 · see citing works
Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation
Rahighi, S., Ikeda, F., Kawasaki, M., Akutsu, M., Suzuki, N., Kato, R., Kensche, T., Uejima, T., Bloor, S., Komander, D., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.007 · Cited by 745 · see citing works
Ordureau, A., Sarraf, S. A., Duda, D. M., Heo, J., Jedrychowski, M. P., Sviderskiy, V. O., Olszewski, J. L., Koerber, J. T., Xie, T., Beausoleil, S. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.007 · Cited by 693 · see citing works
Self-citationMatsumoto, G., Wada, K., Okuno, M., Kurosawa, M., & Nukina, N. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.07.039 · Cited by 692 · see citing works
Fecto, F. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.250 · Cited by 650 · see citing works
Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-κB activation
Wu, C.-J., Conze, D. B., Li, T., Srinivasula, S. M., & Ashwell, J. D. (2006) · Nature Cell Biology · doi:10.1038/ncb1384 · Cited by 607 · see citing works
Clark, K., Plater, L., Peggie, M. W., & Cohen, P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.000414 · Cited by 389 · see citing works
von Muhlinen, N., Akutsu, M., Ravenhill, B. J., Foeglein, Á., Bloor, S., Rutherford, T. J., Freund, S. M. V., Komander, D., & Randow, F. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.024 · Cited by 332 · see citing works
USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria
Cunningham, C. N., Baughman, J. M., Phu, L., Tea, J. S., Yu, C., Coons, M. M., Kirkpatrick, D. S., Bingol, B., & Corn, J. E. (2015) · Nature Cell Biology · doi:10.1038/ncb3097 · Cited by 329 · see citing works
Novel cross-talk within the IKK family controls innate immunity
Clark, K., Peggie, M., Plater, L., Sorcek, R. J., Young, E. R. R., Madwed, J. B., Hough, J., McIver, E. G., & Cohen, P. (2011) · Biochemical Journal · doi:10.1042/bj20101701 · Cited by 326 · see citing works
Matsumoto, G., Shimogori, T., Hattori, N., & Nukina, N. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv179 · Cited by 317 · see citing works
The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations
Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W. (2010) · Autophagy · doi:10.4161/auto.6.7.13286 · Cited by 311 · cited 2× · see citing works
“Early studies suggested that SQSTM1 is responsible for directing damaged mitochondria to the autophagosome (Geisler et al., 2010), but subsequent work revealed that SQSTM1 is required for aggregation of damaged mitochondria but not for mitophagy itself (Narendra et al., 2010).”
BackgroundOrdureau, A., Heo, J.-M., Duda, D. M., Paulo, J. A., Olszewski, J. L., Yanishevski, D., Rinehart, J., Schulman, B. A., & Harper, J. W. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1506593112 · Cited by 310 · see citing works
Self-citationMitochondrial Membrane Potential Is Required for MAVS-Mediated Antiviral Signaling
Koshiba, T., Yasukawa, K., Yanagi, Y., & Kawabata, S.-I. (2011) · Science Signaling · doi:10.1126/scisignal.2001147 · Cited by 257 · see citing works
Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation
Ma, X., Helgason, E., Phung, Q. T., Quan, C. L., Iyer, R. S., Lee, M. W., Bowman, K. K., Starovasnik, M. A., & Dueber, E. C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121552109 · Cited by 240 · see citing works
Laplantine, E., Fontan, E., Chiaravalli, J., Lopez, T. E., Lakisic, G., Véron, M., Agou, F., & Israël, A. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.241 · Cited by 201 · see citing works
Morton, S., Hesson, L. B., Peggie, M. W., & Cohen, P. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.02.047 · Cited by 180 · see citing works
Gleason, C. E., Ordureau, A., Gourlay, R., Arthur, J. S. C., & Cohen, P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.267567 · Cited by 173 · see citing works
Self-citationvan Wijk, S. J. L., Fiškin, E., Putyrski, M., Pampaloni, F., Hou, J., Wild, P. S., Kensche, T., Grecco, H. E., Bastiaens, P. I. H., & Đikić, I. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.017 · Cited by 155 · see citing works
TBK1 Mediates Crosstalk Between the Innate Immune Response and Autophagy
Weidberg, H., & Elazar, Z. (2011) · Science Signaling · doi:10.1126/scisignal.2002355 · Cited by 148 · see citing works
Quantifying Ubiquitin Signaling
Ordureau, A., Münch, C., & Harper, J. W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.02.020 · Cited by 147 · see citing works
Self-citationAutophagy Receptor NDP52 Regulates Pathogen-Containing Autophagosome Maturation
Verlhac, P., Grégoire, I. P., Azocar, O., Petkova, D. S., Baguet, J., Viret, C., & Faure, M. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.02.008 · Cited by 147 · see citing works
IKK-i and TBK-1 are Enzymatically Distinct from the Homologous Enzyme IKK-2
Kishore, N. N., Huynh, Q. K., Mathialagan, S., Hall, T., Rouw, S., Creely, D., Lange, G., Caroll, J., Reitz, B. A., Donnelly, A. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110474200 · Cited by 138 · see citing works
Sims, J. J., Scavone, F., Cooper, E. M., Kane, L. A., Youle, R. J., Boeke, J. D., & Cohen, R. E. (2012) · Nature Methods · doi:10.1038/nmeth.1888 · Cited by 121 · see citing works
Pirman, N. L., Barber, K. W., Aerni, H. R., Ma, N. J., Haimovich, A. D., Rogulina, S., Isaacs, F. J., & Rinehart, J. (2015) · Nature Communications · doi:10.1038/ncomms9130 · Cited by 102 · see citing works
Self-citationAnalysis of OPTN as a causative gene for amyotrophic lateral sclerosis
Belzil, V., Daoud, H., Desjarlais, A., Bouchard, J.-P., Dupré, N., Camu, W., Dion, P. A., & Rouleau, G. A. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.10.001 · Cited by 51 · see citing works
Flagged first, then by citations
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Sorted by citations
Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance
Pickles, S., Vigié, P., & Youle, R. J. (2018) · Current Biology · doi:10.1016/j.cub.2018.01.004 · Cited by 2,081 · see citing works
Molecular definitions of autophagy and related processes
Galluzzi, L., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cecconi, F., Choi, A. M., Chu, C. T., Codogno, P., Colombo, M. I., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796697 · Cited by 1,646 · see citing works
Self-citationThe increasing complexity of the ubiquitin code
Yau, R., & Rape, M. (2016) · Nature Cell Biology · doi:10.1038/ncb3358 · Cited by 1,054 · see citing works
Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms
Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., Bohr, V. A., & Fang, E. F. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.01.002 · Cited by 870 · see citing works
Richter, B., Sliter, D. A., Herhaus, L., Stolz, A., Wang, C., Beli, P., Zaffagnini, G., Wild, P., Martens, S., Wagner, S. A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523926113 · Cited by 755 · see citing works
Parkinson’s Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation
Matheoud, D., Sugiura, A., Bellemare-Pelletier, A., Laplante, A., Rondeau, C., Chemali, M., Fazel, A., Bergeron, J. J., Trudeau, L.-E., Burelle, Y., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.039 · Cited by 582 · see citing works
Autophagy balances inflammation in innate immunity
Deretic, V., & Levine, B. (2018) · Autophagy · doi:10.1080/15548627.2017.1402992 · Cited by 563 · see citing works
Autophagy in the liver: functions in health and disease
Ueno, T., & Komatsu, M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.185 · Cited by 500 · see citing works
Mitochondrial fission facilitates the selective mitophagy of protein aggregates
Burman, J. L., Pickles, S., Wang, C., Sekine, S., Vargas, J. N. S., Zhang, Z., Youle, A. M., Nezich, C. L., Wu, X., Hammer, J. A., et al. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201612106 · Cited by 479 · see citing works
Sellier, C., Campanari, M., Julie Corbier, C., Gaucherot, A., Kolb‐Cheynel, I., Oulad‐Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593350 · Cited by 414 · see citing works
Mechanisms 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 · see citing works
ALS Genetics: Gains, Losses, and Implications for Future Therapies
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R., & Gitler, A. D. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.022 · Cited by 370 · see citing works
Mitophagy: An Emerging Role in Aging and Age-Associated Diseases
Chen, G., Kroemer, G., & Kepp, O. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00200 · Cited by 359 · see citing works
Selective autophagy as a potential therapeutic target for neurodegenerative disorders
Scrivo, A., Bourdenx, M., Pampliega, O., & Cuervo, A. M. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30238-2 · Cited by 355 · see citing works
TBK1: a new player in ALS linking autophagy and neuroinflammation
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Mitochondrial 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 · see citing works
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“Moreover, it has been shown that mitochondrial ubiquitin chains can interact with optineurin (Optn) and NDP52 (Nuclear dot protein 52 kD) via its LC3 interaction region (LIR) motif to rem ve dysfunctional mitochondria [141,142].”
BackgroundMechanisms of Selective Autophagy in Normal Physiology and Cancer
Mancias, J. D., & Kimmelman, A. C. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.02.027 · Cited by 196 · see citing works
The biosynthesis, signaling, and neurological functions of bile acids
Kiriyama, Y., & Nochi, H. (2019) · Biomolecules · doi:10.3390/biom9060232 · Cited by 204 · see citing works
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
“autophosphorylation in a positive-feedback manner [58,59].”
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 · see citing works
“Moreover, pUb has been suggested to accumulate with mitochondrial stress, age, and disease [19] and to serve as a specific signal for recognition by autophagy receptors [20, 21].”
BackgroundLoss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain
Sarraf, S. A., Shah, H. V., Kanfer, G., Pickrell, A. M., Holtzclaw, L. A., Ward, M. E., & Youle, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.10.041 · Cited by 143 · see citing works
Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons
Evans, C. S., & Holzbaur, E. L. (2020) · eLife · doi:10.7554/elife.50260 · Cited by 137 · see citing works
“…to the mitochondrial surface where it interacts with ubiquitin through its ubiquitin binding in ABIN and NEMO (UBAN) domain (Gleason et al., 2011; Heo et al., 2015; Lazarou et al., 2015; Moore and Holzbaur, 2016; Rogov et al., 2014; Wild et al., 2011; Wong and Holzbaur, 2014a; Zhu et al., 2007).”
BackgroundInfluentialHou, X., Fiesel, F. C., Truban, D., Castanedes Casey, M., Lin, W.-L., Soto, A. I., Tacik, P., Rousseau, L. G., Diehl, N. N., Heckman, M. G., et al. (2018) · Autophagy · doi:10.1080/15548627.2018.1461294 · Cited by 147 · see citing works
Lu, X., Altshuler-Keylin, S., Wang, Q., Chen, Y., Henrique Sponton, C., Ikeda, K., Maretich, P., Yoneshiro, T., & Kajimura, S. (2018) · Science Signaling · doi:10.1126/scisignal.aap8526 · Cited by 143 · see citing works
Béland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125 · see citing works
Mitophagy and cGAS–STING crosstalk in neuroinflammation
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Gerbino, V., Kaunga, E., Ye, J., Canzio, D., O’Keeffe, S., Rudnick, N. D., Guarnieri, P., Lutz, C. M., & Maniatis, T. (2020) · Neuron · doi:10.1016/j.neuron.2020.03.005 · Cited by 102 · see citing works
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Zhou, R., Zhang, Q., & Xu, P. (2020) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmaa051 · Cited by 104 · see citing works
Potting, C., Crochemore, C., Moretti, F., Nigsch, F., Schmidt, I., Manneville, C., Carbone, W., Knehr, J., DeJesus, R., Lindeman, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711023115 · Cited by 93 · see citing works
Selective Autophagy Receptors in Neuronal Health and Disease
Conway, O., Akpinar, H. A., Rogov, V. V., & Kirkin, V. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.10.013 · Cited by 75 · see citing works
Liu, J., Wang, X., Lu, Y., Duan, C., Gao, G., Lu, L., & Yang, H. (2017) · Cell Death & Disease · doi:10.1038/cddis.2017.427 · Cited by 75 · see citing works
The lifecycle of skeletal muscle mitochondria in obesity
Pileggi, C. A., Parmar, G., & Harper, M. (2021) · Obesity Reviews · doi:10.1111/obr.13164 · Cited by 61 · see citing works
Novel Insights into the Anti-Aging Role of Mitophagy
(2018) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2018.05.005 · Cited by 56 · see citing works
A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling
Shiba-Fukushima, K., Inoshita, T., Sano, O., Iwata, H., Ishikawa, K.-I., Okano, H., Akamatsu, W., Imai, Y., & Hattori, N. (2020) · iScience · doi:10.1016/j.isci.2020.101048 · Cited by 37 · see citing works
miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00029-w
- Authors
- Heo, J.-M., Ordureau, A., Paulo, J. A., Rinehart, J., & Harper, J. W.
- Affiliations
- Harvard University (US)
- Yale University (US)
- Corresponding author
- Harper, J. Wade
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 60
- Issue
- 1
- Pages
- 7-20
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4592482
- OpenAlex
- W2149200223
- Cited by
- 906
- References
- 43
- Citations by year
- 2026: 81 · 2025: 99 · 2024: 84 · 2023: 64 · 2022: 87 · 2021: 111 · 2020: 87 · 2019: 70 · 2018: 74 · 2017: 78 · 2016: 67 · 2015: 3
- FWCI
- 58.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM095567, GM095567)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK098285)
- National Institute of Neurological Disorders and Stroke (R37NS083524)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PINK1/Parkin pathway, mitophagy, optineurin, NDP52, p62, TBK1 phosphorylation, Parkinson's disease, amyotrophic lateral sclerosis, selective autophagy, positive feedback loop
- MeSH terms
- Sequestosome-1 Protein, PTEN-Induced Putative Kinase, HeLa Cells, Humans, Mitochondria, Nuclear Proteins, Phosphorylation, Protein Kinases, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Membrane Transport Proteins, Transcription Factor TFIIIA, Proteomics, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Ubiquitination, Mitophagy
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