PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy
Open accessAbstract
Parkinson's disease genes PINK1 and parkin encode kinase and ubiquitin ligase, respectively. The gene products PINK1 and Parkin are implicated in mitochondrial autophagy, or mitophagy. Upon the loss of mitochondrial membrane potential (ΔΨm), cytosolic Parkin is recruited to the mitochondria by PINK1 through an uncharacterised mechanism - an initial step triggering sequential events in mitophagy. This study reports that Ser65 in the ubiquitin-like domain (Ubl) of Parkin is phosphorylated in a PINK1-dependent manner upon depolarisation of ΔΨm. The introduction of mutations at Ser65 suggests that phosphorylation of Ser65 is required not only for the efficient translocation of Parkin, but also for the degradation of mitochondrial proteins in mitophagy. Phosphorylation analysis of Parkin pathogenic mutants also suggests Ser65 phosphorylation is not sufficient for Parkin translocation. Our study partly uncovers the molecular mechanism underlying the PINK1-dependent mitochondrial translocation and activation of Parkin as an initial step of mitophagy.
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Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane and phosphorylates ubiquitin and PRKN at Ser65.
“Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane, where it phosphorylates ubiquitin (Ub) and PRKN at Ser65 [5–10].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [9]
The Abstract reports that PINK1 accumulates on mitochondria after membrane-potential loss and that Parkin (PRKN) is phosphorylated at Ser65 in a PINK1-dependent manner. The Discussion reports direct phosphorylation of Parkin by PINK1 in vitro but says whether this occurs directly in cells remains unresolved. Our copy does not establish phosphorylation of ubiquitin at Ser65 or specify stabilization on the outer mitochondrial membrane. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhosphorylation of ubiquitin and PRKN at Ser65 by PINK1 is required for activation of the PINK1-PRKN pathway.
“Both events are required for the activation of the pathway.”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [9]
The Abstract and Results report that PINK1-dependent phosphorylation of Parkin (PRKN) at Ser65 is important for its efficient mitochondrial translocation and mitophagy. Our copy does not establish that PINK1 phosphorylation of ubiquitin at Ser65 is also required; its references to a ubiquitin-like domain concern a domain of Parkin, not ubiquitin itself. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMitofusin 1 (Mfn1) is rapidly degraded by active Parkin in association with mitochondrial depolarization-dependent PINK1 activation.
“Mitofusin family member, Mitofusin 1 (Mfn1), is rapidly degraded by active Parkin in association with mitochondrial depolarization-dependent PINK1 activation (Shiba-Fukushima et al., 2012).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Shiba-Fukushima et al., 2012
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- Authors
- Shiba-Fukushima, K., Imai, Y., Yoshida, S., Ishihama, Y., Kanao, T., Sato, S., & Hattori, N.
- Affiliations
- Juntendo University (JP)
- Kyoto University (JP)
- Corresponding author
- Imai, Yuzuru
- Hattori, Nobutaka
- Venue
- Scientific Reports
- Published
- 2012-12-19
- Volume
- 2
- Issue
- 1
- Pages
- 1002-1002
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC3525937
- OpenAlex
- W2043276141
- Cited by
- 577
- References
- 46
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 45 · 2023: 26 · 2022: 51 · 2021: 59 · 2020: 51 · 2019: 45 · 2018: 43 · 2017: 39 · 2016: 48 · 2015: 54 · 2014: 45 · 2013: 26
- FWCI
- 26.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Novartis Foundation
- Ministry of Education, Culture, Sports, Science and Technology (CREST)
- Japan Society for the Promotion of Science (23111003, 24659017, 23790973)
- Core Research for Evolutional Science and Technology
- 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
- PINK1, Parkin, mitophagy, mitochondrial translocation, ubiquitin-like domain, Parkinson's disease, mitochondrial protein degradation
- MeSH terms
- PTEN-Induced Putative Kinase, Animals, Cells, Cultured, Female, Humans, Male, Mitochondria, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Mice, Knockout, Protein Transport, Ubiquitin-Protein Ligases, Mice, Membrane Potential, Mitochondrial, Mitophagy
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