CoChat
Sign Up
Cited by 392Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyNuclear Receptors and Signaling

Parkin and PINK1: much more than mitophagy

Open access
Scarffe, Leslie A., Stevens, Daniel A., Dawson, Valina L., Dawson, Ted M.·2014·Trends in Neurosciences
DOI 10.1016/j.tins.2014.03.004PMC PMC4075431
Open this paper in CoChat — free account

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease that causes a debilitating movement disorder. Although most cases of PD appear to be sporadic, rare Mendelian forms have provided tremendous insight into disease pathogenesis. Accumulating evidence suggests that impaired mitochondria underpin PD pathology. In support of this theory, data from multiple PD models have linked Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin, two recessive PD genes, in a common pathway impacting mitochondrial health, prompting a flurry of research to identify their mitochondrial targets. Recent work has focused on the role of PINK1 and parkin in mediating mitochondrial autophagy (mitophagy); however, emerging evidence casts parkin and PINK1 as key players in multiple domains of mitochondrial health and quality control.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.tins.2014.03.004

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Loss of PRKN and PINK1 dysregulates mitophagy and increases mitochondria stress, leading to mito-inflammation, which is involved in PD pathology in PINK1 and PRKN deficient mice.

    “Multiple studies have revealed that loss of PRKN and PINK1 dysregulated mitophagy and increased mitochondria stress, leading to mito-inflammation,267 which was recently suggested to be involved in PD pathology in PINK1 and PRKN deficient mice.268”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [267]

    The section “PINK1 and parkin initiate the removal of mitochondrial proteins” describes their role in mitophagy in cell models, but says their role in mitophagy in patients is unestablished and that knockout mice do not accumulate abnormal damaged mitochondria. Our copy does not support the claimed progression from mitochondrial stress to mito-inflammation. The mouse PD-pathology clause is attached to a different citation (268). (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 78 · Cited by 392

Research works printed but not linked: 67

  1. [1]Dawson TM Dawson VL 2003 Molecular pathways of neurodegeneration in Parkinson’s disease Science 302 819 822 14593166
  2. [2]Exner N 2012 Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences The EMBO journal 31 3038 3062 22735187 PMC3400019
  3. [3]Schon EA Przedborski S 2011 Mitochondria: the next (neurode)generation Neuron 70 1033 1053 21689593 PMC3407575
  4. [4]Corti O 2011 What genetics tells us about the causes and mechanisms of Parkinson’s disease Physiol Rev 91 1161 1218 22013209
  5. [5]Martin I 2011 Recent advances in the genetics of Parkinson’s disease Annu Rev Genomics Hum Genet 12 301 325 21639795 PMC4120236
  6. [6]Corti O Brice A 2013 Mitochondrial quality control turns out to be the principal suspect in parkin and PINK1-related autosomal recessive Parkinson’s disease Curr Opin Neurobiol 23 100 108 23206589
  7. [7]Kitada T 1998 Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism Nature 392 605 608 9560156
  8. [8]Houlden H Singleton AB 2012 The genetics and neuropathology of Parkinson’s disease Acta Neuropathol 124 325 338 22806825 PMC3589971
  9. [9]Dawson TM Dawson VL 2013 Parkin Plays a Role in Sporadic Parkinson’s Disease Neurodegener Dis PMC3984465 24029689
  10. [10]Walden H Martinez-Torres RJ 2012 Regulation of Parkin E3 ubiquitin ligase activity Cell Mol Life Sci 69 3053 3067 22527713 PMC11115052
  11. [11]Dove KK Klevit RE 2013 Structural Biology: Parkin’s Serpentine Shape Revealed in the Year of the Snake Curr Biol 23 R691 693 23968926
  12. [12]Byrd RA Weissman AM 2013 Compact Parkin only: insights into the structure of an autoinhibited ubiquitin ligase The EMBO journal 32 2087 2089 23852447 PMC3730235
  13. [13]Imai Y 2002 CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity Mol Cell 10 55 67 12150907
  14. [15]Zhou C 2008 The kinase domain of mitochondrial PINK1 faces the cytoplasm Proc Natl Acad Sci U S A 105 12022 12027 18687899 PMC2575334
  15. [16]Becker D 2012 Pink1 kinase and its membrane potential (Deltapsi)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode The Journal of biological chemistry 287 22969 22987 22547060 PMC3391148
  16. [17]Beilina A 2005 Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability Proc Natl Acad Sci U S A 102 5703 5708 15824318 PMC556294
  17. [18]Jin SM 2010 Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL The Journal of cell biology 191 933 942 21115803 PMC2995166
  18. [19]Clark IE 2006 Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin Nature 441 1162 1166 16672981
  19. [20]Park J 2006 Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin Nature 441 1157 1161 16672980
  20. [22]Yang Y 2006 Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin Proc Natl Acad Sci U S A 103 10793 10798 16818890 PMC1502310
  21. [23]Deng H 2008 The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila Proc Natl Acad Sci U S A 105 14503 14508 18799731 PMC2567186
  22. [24]Poole AC 2008 The PINK1/Parkin pathway regulates mitochondrial morphology Proc Natl Acad Sci U S A 105 1638 1643 18230723 PMC2234197
  23. [25]Yang Y 2008 Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery Proc Natl Acad Sci U S A 105 7070 7075 18443288 PMC2383971
  24. [26]Dagda RK 2009 Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission The Journal of biological chemistry 284 13843 13855 19279012 PMC2679485
  25. [27]Lutz AK 2009 Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation The Journal of biological chemistry 284 22938 22951 19546216 PMC2755701
  26. [28]Yu W 2011 The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons Hum Mol Genet 20 3227 3240 21613270 PMC3140825
  27. [29]Akepati VR 2008 Characterization of OPA1 isoforms isolated from mouse tissues Journal of neurochemistry 106 372 383 18419770
  28. [30]Ziviani E 2010 Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin Proc Natl Acad Sci U S A 107 5018 5023 20194754 PMC2841909
  29. [31]Tondera D 2009 SLP-2 is required for stress-induced mitochondrial hyperfusion The EMBO journal 28 1589 1600 19360003 PMC2693158
  30. [33]Itoh K 2013 Mitochondrial dynamics in neurodegeneration Trends Cell Biol 23 64 71 23159640 PMC3558617
  31. [34]Wang X 2011 PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility Cell 147 893 906 22078885 PMC3261796
  32. [36]Misko A 2010 Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex J Neurosci 30 4232 4240 20335458 PMC2852190
  33. [38]Rakovic A 2011 Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts PLoS One 6 e16746 21408142 PMC3050809
  34. [39]Chen Y Dorn GW 2nd 2013 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria Science 340 471 475 23620051 PMC3774525
  35. [40]Lazarou M 2012 Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin Developmental cell 22 320 333 22280891 PMC3288275
  36. [42]Burchell VS 2013 The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy Nat Neurosci 16 1257 1265 23933751 PMC3827746
  37. [43]McCoy MK 2013 Hexokinase activity is required for recruitment of parkin to depolarized mitochondria Hum Mol Genet PMC3857951 23962723
  38. [45]Sarraf SA 2013 Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization Nature 496 372 376 23503661 PMC3641819
  39. [46]Michiorri S 2010 The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy Cell Death Differ 17 962 974 20057503
  40. [49]Grenier K 2013 Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up? Front Neurol 4 100 23882257 PMC3715719
  41. [50]Rakovic A 2013 Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1)-dependent ubiquitination of endogenous Parkin attenuates mitophagy: study in human primary fibroblasts and induced pluripotent stem cell-derived neurons The Journal of biological chemistry 288 2223 2237 23212910 PMC3554895
  42. [51]Cai Q 2012 Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons Curr Biol 22 545 552 22342752 PMC3313683
  43. [52]Van Laar VS 2011 Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization Hum Mol Genet 20 927 940 21147754 PMC3033183
  44. [53]Wang Y 2012 ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy Autophagy 8 1462 1476 22889933
  45. [54]Sterky FH 2011 Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo Proc Natl Acad Sci U S A 108 12937 12942 21768369 PMC3150929
  46. [55]Kageyama Y 2012 Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage The Journal of cell biology 197 535 551 22564413 PMC3352955
  47. [56]Palacino JJ 2004 Mitochondrial dysfunction and oxidative damage in parkin-deficient mice The Journal of biological chemistry 279 18614 18622 14985362
  48. [57]Gautier CA 2008 Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress Proc Natl Acad Sci U S A 105 11364 11369 18687901 PMC2516271
  49. [58]McLelland GL 2014 Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control The EMBO journal 33 282 295 24446486 PMC3989637
  50. [59]Muftuoglu M 2004 Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations Mov Disord 19 544 548 15133818
  51. [60]Morais VA 2009 Parkinson’s disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function EMBO Mol Med 1 99 111 20049710 PMC3378121
  52. [61]Vos M 2012 Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency Science 336 1306 1310 22582012
  53. [62]Vincow ES 2013 The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo Proc Natl Acad Sci U S A 110 6400 6405 23509287 PMC3631677
  54. [63]Kuroda Y 2006 Parkin enhances mitochondrial biogenesis in proliferating cells Hum Mol Genet 15 883 895 16449237
  55. [64]Rothfuss O 2009 Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair Hum Mol Genet 18 3832 3850 19617636
  56. [65]Lee Y 2013 Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss Nat Neurosci PMC3785563 23974709
  57. [66]Shin JH 2011 PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease Cell 144 689 702 21376232 PMC3063894
  58. [67]Zhu J 2013 After the banquet: Mitochondrial biogenesis, mitophagy and cell survival Autophagy 9 PMC4028332 23787782
  59. [68]St-Pierre J 2006 Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators Cell 127 397 408 17055439
  60. [69]Clark J 2011 Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson’s disease BMC Med Genet 12 69 21595954 PMC3112073
  61. [70]Pacelli C 2011 Mitochondrial defect and PGC-1alpha dysfunction in parkin-associated familial Parkinson’s disease Biochim Biophys Acta 1812 1041 1053 21215313
  62. [71]Zheng B 2010 PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease Sci Transl Med 2 52ra73 PMC3129986 20926834
  63. [72]Corona JC 2014 PPARgamma activation rescues mitochondrial function from inhibition of complex I and loss of PINK1 Experimental neurology 253 16 27 24374061
  64. [73]Tufi R 2014 Enhancing nucleotide metabolism protects against mitochondrial dysfunction and neurodegeneration in a PINK1 model of Parkinson’s disease Nature cell biology 16 157 166 PMC4199097 24441527
  65. [74]Vilain S 2012 The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants PLoS Genet 8 e1002456 22242018 PMC3252300
  66. [76]Alexander C 2000 OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28 Nat Genet 26 211 215 11017080
  67. [77]Delettre C 2000 Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy Nat Genet 26 207 210 11017079

Authors
Scarffe, L. A., Stevens, D. A., Dawson, V. L., & Dawson, T. M.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2014-06
Volume
37
Issue
6
Pages
315-324
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2014.03.004
PMC
PMC4075431
OpenAlex
W1993098682
Cited by
392
References
78
Citations by year
2026: 15 · 2025: 12 · 2024: 27 · 2023: 15 · 2022: 30 · 2021: 38 · 2020: 47 · 2019: 25 · 2018: 32 · 2017: 38 · 2016: 37 · 2015: 53 · 2014: 22
FWCI
6.85
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Institutes of Health Research
  • National Institute on Drug Abuse (P50DA000266)
  • National Institute of General Medical Sciences (T32GM007309)
  • National Institute of Neurological Disorders and Stroke (NS 38377, P50NS038377, R01NS067525)
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
Parkin, PINK1, Parkinson's disease, mitophagy, mitochondrial quality control, mitochondrial dysfunction
MeSH terms
PTEN-Induced Putative Kinase, Animals, Humans, Mitochondria, Parkinson Disease, Protein Kinases, Mitochondrial Diseases, Ubiquitin-Protein Ligases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review