The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations
Open accessAbstract
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
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Some neurodevelopmental disorders can present later in the teens to early adulthood, while early-onset neurodegenerative disorders can be seen in the 4th or 5th decade of life.
“For example, some “neurodevelopmental” disorders can present later in the teens to early adulthood, while early-onset “neurodegenerative” disorders can be seen in the 4th or 5th decade of life.”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [62]
The Introduction and Results discuss Parkinson disease and PINK1/Parkin-mediated mitophagy, but do not address when neurodevelopmental disorders present or specify an age of onset for neurodegenerative disorders. Searches for teen or early-adult presentation and fourth- or fifth-decade onset found no supporting passage in our copy; the References mention early-onset Parkinson disease without giving those ages. (LLM, conf=0.74)
Experimental — accuracy not yet measuredKufor-Rakeb syndrome can present in adulthood, quite late for a neurodevelopmental disorder.
“It can present in adulthood, quite late for a neurodevelopmental disorder.62,63”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [62]
The Introduction and Discussion address PINK1/Parkin-mediated mitophagy and Parkinson disease, not the age at which Kufor-Rakeb syndrome presents. Searches for Kufor-Rakeb syndrome, adult onset, and ATP13A2 found no passage addressing the claim; the paper’s references to early-onset parkinsonism concern PINK1. (LLM, conf=0.76)
Experimental — accuracy not yet measuredKufor-Rakeb syndrome is an autosomal recessive early-onset form of Parkinson's disease caused by mutations in the lysosomal ATPase protein, ATP13A2.
“A striking example of this overlap is Kufor-Rakeb syndrome, an autosomal recessive early-onset form of Parkinson’s disease caused by mutations in the lysosomal ATPase protein, ATP13A2.”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [62]
The Introduction and Discussion discuss Parkinson’s disease mutations in PINK1 and Parkin, not Kufor-Rakeb syndrome. Searches for “Kufor-Rakeb syndrome” and “ATP13A2 lysosomal ATPase” found no passage addressing the claimed syndrome, inheritance, or cause; page numbers were not available in our copy. (LLM, conf=0.76)
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MethodSelf-citationMitochondrial respiratory chain dysfunction: Implications in neurodegeneration
Morán, M., Moreno-Lastres, D., Marín-Buera, L., Arenas, J., Martín, M. A., & Ugalde, C. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.009 · Cited by 163 · see citing works
“In agreement, lower H2O2 doses induced mitochondrial hyperfusion associated with decreased Fis1 expression levels and augmented Mfn1 and Mfn2 [245].”
BackgroundInfluentialThe 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
“2A and B); surprisingly, FRET was not detected between PARK2 and VDAC1, previously reported to be ubiquitinated by PARK2 after CCCP treatment.(11) These interactions were also observed with exogenous PARK2 in COS7 cells treated with CCCP and in HeLa-T-REx-shLONP1 cells depleted of LONP1, and for the TOMM70A-PARK2 pair…”
BackgroundResultMitophagy links oxidative stress conditions and neurodegenerative diseases
Jung, J., Huh, Y., Shefa, U., Jeong, N., Song, I., Chung, H.-J., & Kim, D. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.249218 · Cited by 152 · see citing works
“Translocation of PARKIN to damaged mitochondria has been shown to weaken PINK1 function (Geisler et al., 2010).”
p62/SQSTM1 at the interface of aging, autophagy, and disease
Bitto, A., Lerner, C. A., Nacarelli, T., Crowe, E. P., Torres, C. A., & Sell, C. (2014) · AGE · doi:10.1007/s11357-014-9626-3 · Cited by 144 · see citing works
“…impaired mitochondrial dynamics and oxidative stress are among the main characteristics of the disease (Narendra et al. 2008; Buttner et al. 2008; Geisler et al. 2010b). p62/SQSTM1 aids in clearing dysfunctional mitochondria tagged for degradation by the Pink1-Parkin system, two genes involved…”
Macroautophagy in CNS health and disease
Griffey, C. J., & Yamamoto, A. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00588-3 · Cited by 144 · see citing works
Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism
Puschmann, A., Fiesel, F. C., Caulfield, T. R., Hudec, R., Ando, M., Fričová, D., Hou, X., Ogaki, K., Heckman, M. G., James, E. D., et al. (2016) · Brain · doi:10.1093/brain/aww261 · Cited by 137 · see citing works
“The proteins encoded by the PINK1 and PARK2 genes, PINK1, a mitochondrial kinase, and parkin, a cytosolic E3 ubiquitin ligase, together mediate a protective pathway that selectively eliminates damaged mitochondria from cells (Geisler et al., 2010a, b).”
BackgroundSelf-citationDegradation 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
“PINK1 recruits Parkin to phospho-ubiquitinate outer mitochondrial membrane proteins, which act as a specific cue for organelle degradation (Geisler et al., 2010; Kane et al., 2014; Kazlauskaite et al., 2014; Koyano et al., 2014; Matsuda et al., 2010; Narendra et al., 2008; Narendra et al., 2010b;…”
BackgroundMitophagy 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 136 · see citing works
Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease
Calí, T., Ottolini, D., & Brini, M. (2011) · BioFactors · doi:10.1002/biof.159 · Cited by 133 · see citing works
Mitochondrial quality control by the Pink1/Parkin system
Rüb, C., Wilkening, A., & Voos, W. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2485-8 · Cited by 132 · see citing works
“Providing an explanation for their genetic interaction, Pink1 was finally demonstrated to be responsible for Parkin translocation to depolarized mitochondria (Geisler et al. 2010b; Narendra et al. 2010; Vives-Bauza et al. 2010; Ziviani et al. 2010).”
BackgroundSiddiqui, A., Bhaumik, D., Chinta, S. J., Rane, A., Rajagopalan, S., Lieu, C. A., Lithgow, G. J., & Andersen, J. K. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0109-15.2015 · Cited by 129 · see citing works
“…A large body of work in cultured mammalian cells demonstrates that parkin via its interaction with PINK1 mediates initiation of lysosomal autophagy, particularly under conditions of damage or stress (Narendra et al., 2008; Geisler et al., 2010b; Matsuda and Tanaka, 2010; Vives-Bauza et al., 2010).”
BackgroundMethodPilsl, A., & Winklhofer, K. F. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0902-3 · Cited by 128 · see citing works
The role of mitochondria-associated membranes in cellular homeostasis and diseases
Perrone, M., Caroccia, N., Genovese, I., Missiroli, S., Modesti, L., Pedriali, G., Vezzani, B., Vitto, V. A. M., Antenori, M., Lebiedzińska, M., et al. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.11.002 · Cited by 127 · see citing works
Mitophagy in neurodegeneration and aging
Palikaras, K., & Tavernarakis, N. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00297 · Cited by 122 · see citing works
“The molecular mechanisms of mitophagy were studied in the yeast Saccharomyces cerevisiae.”
BackgroundInfluentialIP3Receptors, Mitochondria, and Ca2+Signaling: Implications for Aging
Decuypere, J.-P., Monaco, G., Missiaen, L., SMEDT, H. D., Parys, J. B., & Bultynck, G. (2011) · Journal of Aging Research · doi:10.4061/2011/920178 · Cited by 122 · see citing works
“NIX/BNIP3L [201, 202], BNIP3 [203], PARKIN [204], and PINK-1 [205–210] were proposed to be involved in mitochondrial degradation in mammalian cells.”
BackgroundAutophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity
Thellung, S., Corsaro, A., Nizzari, M., Barbieri, F., & Florio, T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20040901 · Cited by 116 · see citing works
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 120 · see citing works
“However, using an AMBRA1 construct with alanine mutations at key residues in its LIR (W1019A-L1022A), Strappazon and colleagues show that the interaction between mutant AMBRA1 and LC3 is abolished and mitophagy is not induced, indicating that the AMBRA1-LC3 interaction is crucial for this type of mitophagy to occur fo…”
InfluentialThe multifaceted role of mitochondria in autism spectrum disorder
Халиулин, И. Г., Hamoudi, W., & Amal, H. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02725-z · Cited by 122 · see citing works
“It has been suggested that this PTM of the mitochondrial proteins enables the recruitment of the autophagy adaptor p62, leading to the autophagosomal degradation of the damaged mitochondria [12, 278, 279].”
Xiong, H., Chen, S., Lai, L., Yang, H., Xu, Y., Pang, J., Su, Z., Lin, H., & Zheng, Y. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.03.013 · Cited by 116 · see citing works
Mitochondrial Dynamics: The Intersection of Form and Function
Ferree, A. W., & Shirihai, O. S. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3573-0_2 · Cited by 110 · see citing works
Geisler, S., Vollmer, S., Golombek, S., & Kahle, P. J. (2014) · Journal of Cell Science · doi:10.1242/jcs.146035 · Cited by 109 · see citing works
“…and the voltage-dependent anion-selective channel protein 1 (VDAC1), which finally results in the autophagic elimination of damaged mitochondria (Chan et al., 2011; Geisler et al., 2010a; Lazarou et al., 2013; Okatsu et al., 2012; Rakovic et al., 2013; Sarraf et al., 2013; Yoshii et al., 2011).”
BackgroundMethodInfluentialSelf-citationvan der Merwe, C., Dashti, Z. J. S., Christoffels, A. G., Loos, B., & Bardien, S. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12872 · Cited by 106 · see citing works
“…experiments have determined that parkin and PINK1 are involved in a direct interaction, whereby PINK1 phosphorylates parkin and activates its E3 ligase activity at the OMM (Kim et al., 2008; Shiba et al., 2009; Um et al., 2009; Geisler et al., 2010; Kawajiri et al., 2010; Sha et al., 2010).”
BackgroundKubli, D. A., Cortez, M. Q., Moyzis, A. G., Najor, R. H., Lee, Y., & Gustafsson, Å. B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0130707 · Cited by 102 · see citing works
“Mutations in the PINK1/Parkin pathway are associated with juvenile recessive forms of Parkinson’s disease and neuronal defects [14, 15].”
BackgroundPINK1 Triggers Autocatalytic Activation of Parkin to Specify Cell Fate Decisions
Zhang, C., Lee, S., Peng, Y., Bunker, E. N., Giaime, E., Shen, J., Zhou, Z., & Liu, X. (2014) · Current Biology · doi:10.1016/j.cub.2014.07.014 · Cited by 101 · see citing works
“A diverse set of protein substrates have been shown be ubiquitinated by Parkin [2], including several proteins localized in the mitochondrial outer membrane, such as Mfn1 and Mfn2 [10, 18, 19], Drp1 [20], voltage-dependent anion channel 1 (VDAC1) [21], and Miro [12].”
Mitochondrial Quality Control and Dynamics in Parkinson's Disease
McCoy, M. K., & Cookson, M. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4019 · Cited by 103 · see citing works
“Parkin relocalization to mitochondria is fully dependent on PINK1 kinase activity and is interrupted by some, but not all, pathogenic PINK1 and parkin mutations (40, 64, 74, 75).”
BackgroundThe Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease
Varughese, J. T., Buchanan, S. K., & Pitt, A. S. (2021) · Cells · doi:10.3390/cells10071737 · Cited by 101 · see citing works
“Pathogenesis of Parkinson’s disease can progress if the impaired mitochondria are not cleared due to defective quality control mechanisms [49,50].”
BackgroundPINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control
Zhuang, N., Li, L., Chen, S., & Wang, T. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.396 · Cited by 92 · see citing works
PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease
Mouton‐Liger, F., Jacoupy, M., Corvol, J., & Corti, O. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00120 · Cited by 97 · see citing works
“…these observations, demonstrating that PINK1 and Parkin jointly regulate the clearance of dysfunctional mitochondria by the autophagy-lysosomal pathway, a process termed mitophagy (Narendra et al., 2008, 2010; Geisler et al., 2010; Vives-Bauza and Przedborski, 2010; Pickrell and Youle, 2015).”
Hexokinase activity is required for recruitment of parkin to depolarized mitochondria
McCoy, M. K., Kaganovich, A., Rudenko, I. N., Ding, J., & Cookson, M. R. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt407 · Cited by 97 · see citing works
“Parkin has been shown to be recruited to the OMM in many studies (3,8,12,17,18,20,29,30,42,43).”
BackgroundHo, D. H., Je, A. R., Lee, H.-J., Son, I., Kweon, H., Kim, H., & Seol, W. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.3.171 · Cited by 96 · see citing works
Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity
Anand, S. K., Sharma, A., Singh, N., & Kakkar, P. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.102748 · Cited by 91 · see citing works
Liu, K., Zhao, Q., Liu, P., Cao, J., Gong, J., Wang, C., Wang, W., Li, X., Sun, H., Zhang, C., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1212786 · Cited by 92 · see citing works
Mechanisms, 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 89 · see citing works
“…for selective mitophagy in 293 cells, mouse macrophages and in pre-implantation embryos for paternal elimination of mitochondria (Ding et al., 2010b; Geisler et al., 2010b; Rojansky et al., 2016; Zhong et al., 2016), but it is dispensable for mitophagy in MEFs and HeLa cells and may play a role…”
BackgroundShedding light on mitophagy in neurons: what is the evidence for PINK1/Parkin mitophagy in vivo?
Cummins, N., & Götz, J. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2692-9 · Cited by 87 · see citing works
Monaco, A., & Fraldi, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00037 · Cited by 89 · see citing works
Wang, S.-F., Wu, M.-Y., Cai, C.-Z., Li, M., & Lu, J. (2016) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2016.10.069 · Cited by 87 · see citing works
Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson’s Disease
Madsen, D. A., Schmidt, S. I., Blaabjerg, M., & Meyer, M. (2021) · Cells · doi:10.3390/cells10020283 · Cited by 85 · see citing works
“Parkin functions as an E3-ubiquitin ligase and has a broad range of neuroprotective functions including the maintenance of mitochondrial metabolism [83] and the ubiquitin-proteasome system, where parkin plays an essential role in the ubiquitin-mediated degradation of misfolded or damaged proteins and in removal of dys…”
Lim, L., Jackson-Lewis, V. R., Wong, L. C., Shui, G., Goh, A. X., Kesavapany, S., Jenner, A. M., Fivaz, M. L., Przedborski, S., & Wenk, M. R. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.105 · Cited by 83 · see citing works
Weil, R., Laplantine, E., Curic, S., & Génin, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01243 · Cited by 80 · see citing works
“Interestingly, patient mutations in both PARK2 and PARK6 genes prevent recruitment of Parkin to mitochondria indicating that mitochondrial dysfunction may play a role in sporadic Parkinson disease (94, 96, 97, 241).”
BackgroundMolecular machinery of macroautophagy and its deregulation in diseases
Wong, A. S. L., Cheung, Z. H., & Ip, N. Y. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.07.005 · Cited by 83 · see citing works
Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases
Sádaba, M. C., Martín‐Estal, I., Puche, J. E., & Castilla‐Cortázar, I. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.03.010 · Cited by 81 · see citing works
PINK1/Parkin-mediated mitophagy alleviates chlorpyrifos-induced apoptosis in SH-SY5Y cells
Dai, H., Deng, Y., Zhang, J., Han, H., Zhao, M., Li, Y., Zhang, C., Tian, J., Bing, G., & Zhao, L. (2015) · Toxicology · doi:10.1016/j.tox.2015.06.003 · Cited by 80 · see citing works
“Once recruited, Parkin ubiquitinates various substrates to induce and promote autophagic removal of damaged mitochondria (Geisler et al., 2010; Jin et al., 2010; Jin and Youle, 2012).”
The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity
Ando, M., Fiesel, F. C., Hudec, R., Caulfield, T. R., Ogaki, K., Górka-Skoczylas, P., Koziorowski, D., Friedman, A., Chen, L., Dawson, V. L., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0174-z · Cited by 79 · see citing works
“We have just recently shown that various mutations disrupt the enzymatic and biological functions of PINK1 at different steps [24, 25].”
BackgroundSelf-citationMitochondrial quality control in AMD: does mitophagy play a pivotal role?
Hyttinen, J. M. T., Viiri, J., Kaarniranta, K., & Błasiak, J. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2843-7 · Cited by 78 · see citing works
CHIP as a therapeutic target for neurological diseases
Zhang, S., Hu, Z., Mao, C., Shi, C., & Xu, Y. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02953-5 · Cited by 72 · see citing works
Parkinson's disease and mitophagy: an emerging role for LRRK2
Singh, F., & Ganley, I. G. (2021) · Biochemical Society Transactions · doi:10.1042/bst20190236 · Cited by 75 · see citing works
Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants
Esposito, G., Vos, M. H., Vilain, S., Swerts, J., Valadas, J. S., Meensel, S. V., Schaap, O., & Verstreken, P. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003478 · Cited by 74 · see citing works
- Authors
- Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W.
- Affiliations
- Hertie Institute for Clinical Brain Research (DE)
- University of Tübingen (DE)
- Corresponding author
- Kahle, Philipp J.
- Springer, Wolfdieter
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2010-10
- Volume
- 6
- Issue
- 7
- Pages
- 871-878
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- OpenAlex
- W2088002295
- Cited by
- 311
- References
- 0
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 15 · 2023: 12 · 2022: 18 · 2021: 28 · 2020: 22 · 2019: 26 · 2018: 17 · 2017: 11 · 2016: 28 · 2015: 22 · 2014: 23 · 2013: 16 · 2012: 23
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- PINK1, Parkin, mitophagy, Parkinson's disease, PINK1 mutations, parkin mutations, mitochondrial dysfunction, selective autophagy, macroautophagy, mitochondrial depolarization, neurodegeneration
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Autophagy, HeLa Cells, Humans, Mitochondria, Mutation, Parkinson Disease, Protein Kinases, RNA, Small Interfering, Ubiquitin-Protein Ligases, HEK293 Cells
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