Phosphatase and Tensin Homolog (PTEN)-induced Putative Kinase 1 (PINK1)-dependent Ubiquitination of Endogenous Parkin Attenuates Mitophagy
Open accessAbstract
Mutations in the E3 ubiquitin ligase Parkin and the mitochondrial PTEN-induced putative kinase 1 (PINK1) have been identified to cause autosomal recessive forms of familial Parkinson disease, with PINK1 functioning upstream of Parkin in a pathway important for the maintenance of mitochondrial function and morphology. Upon the loss of the mitochondrial membrane potential, Parkin translocates to mitochondria in a PINK1-dependent manner to ubiquitinate mitochondrial proteins. Parkin-mediated polyubiquitination of outer mitochondrial membrane (OMM) proteins recruits the ubiquitin- and LC3-binding adaptor protein p62 to mitochondria and induces mitophagy. Although previous studies examined mitophagy in established cell lines through overexpression approaches, there is an imperative to study the role of endogenous Parkin and PINK1 in human-derived and biologically relevant cell models. Here, we demonstrate in human primary fibroblasts and induced pluripotent stem-derived neurons from controls and PINK1 mutation carriers that endogenous levels of Parkin are not sufficient to initiate mitophagy upon loss of the mitochondrial membrane potential, caused by its (self-)ubiquitination, followed by degradation via the ubiquitin proteasome system. Next, we showed differential PINK1-dependent, Parkin-mediated ubiquitination of OMM proteins, which is Parkin dose-dependent and affects primarily OMM proteins of higher molecular mass. In contrast to the situation fibroblasts, we did not detect mitophagy in induced pluripotent stem-derived neurons even upon overexpression of Parkin. Taken together, our data demonstrate that mitophagy differs between human non-neuronal and neuronal cells and between "endogenous" and "Parkin-overexpressing" cellular models. Background: The Parkinson disease-related proteins PINK1 and Parkin initiate mitophagy of damaged mitochondria. Results: Endogenous Parkin is not sufficient to induce mitophagy due to PINK1-dependent ubiquitination of Parkin. Conclusion: Mitophagy is detectable only with supraphysiological levels of Parkin and differs between fibroblasts and iPS-derived neurons. Significance: Stresses the importance of future studies in Parkinson disease-relevant tissue, i.e. , dopaminergic neurons.
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Proteasomal degradation of parkin occurs during mitophagy due to autoubiquitination, halting its activity.
“Proteasomal degradation of parkin was demonstrated during mitophagy due to autoubiquitination, halting its activity28,29,33,34.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [29]
The Discussion (page not provided) says endogenous Parkin becomes self-ubiquitinated during mitochondrial depolarization and is likely degraded through the ubiquitin–proteasome system. It proposes that this reduces the Parkin available to translocate to mitochondria, attenuating further mitophagy; it does not demonstrate that Parkin’s activity halts. (LLM, conf=0.87)
Experimental — accuracy not yet measuredParkin labels mitochondria for mitophagy by ubiquitinating specific mitochondrial proteins; parkin is then degraded by the proteasome/lysosome due to autoubiquitination.
“Parkin labels mitochondria for mitophagy by ubiquitinating specific mitochondrial proteins; parkin is then degraded by the proteasome/lysosome due to autoubiquitination26–29.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [29]
The Discussion reports Parkin-mediated ubiquitination of multiple outer mitochondrial membrane proteins and says endogenous Parkin is self-ubiquitinated and likely degraded through the ubiquitin–proteasome system. It does not support lysosomal degradation of Parkin, and describes proteasomal degradation as likely rather than established. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 astrocytes exhibit increased parkin levels.
“increased parkin levels (targets mitochondria for mitophagy, followed by proteasomal/lysosomal degradation26–29)”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [29]
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- Authors
- Rakovic, A., Shurkewitsch, K., Seibler, P., Grünewald, A., Zanon, A., Hagenah, J., Krainc, D., & Klein, C.
- Affiliations
- University of Lübeck (DE)
- Eurac Research (IT)
- Harvard University (US)
- Corresponding author
- Klein, Christine
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 4
- Pages
- 2223-2237
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3554895
- OpenAlex
- W2053071811
- Cited by
- 218
- References
- 6
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 4 · 2022: 13 · 2021: 12 · 2020: 23 · 2019: 11 · 2018: 23 · 2017: 25 · 2016: 18 · 2015: 25 · 2014: 22 · 2013: 17
- FWCI
- 12.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Funders
- Hermann und Lilly Schilling-Stiftung für Medizinische Forschung
- Fritz Thyssen Stiftung
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkin, PINK1, mitophagy, ubiquitination, Parkinson's disease, mitochondrial membrane potential, mitochondrial outer membrane proteins, p62, ubiquitin-proteasome system, human fibroblasts, familial Parkinson's disease, E3 ubiquitin ligase
- MeSH terms
- PTEN-Induced Putative Kinase, Cell Line, Dose-Response Relationship, Drug, Fibroblasts, Homozygote, Humans, Lung, Microscopy, Fluorescence, Mitochondria, Models, Biological, Mutation, Neurons, Parkinson Disease, Protein Kinases, Stem Cells, Mutation, Missense, Ubiquitin, Ubiquitin-Protein Ligases, Induced Pluripotent Stem Cells, Mitophagy
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