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Cited by 72Parkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathwaysAutophagy in Disease and Therapy

Select E2 enzymes differentially regulate parkin activation and mitophagy

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Fiesel, Fabienne C., Moussaud-Lamodière, Elisabeth L., Ando, Maya, Springer, Wolfdieter·2014·Journal of Cell Science
DOI 10.1242/jcs.147520PMC PMC4132391
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Abstract

Loss-of-function mutations in the genes encoding PINK1 and Parkin are the most common causes of recessive Parkinson's disease (PD). Both together mediate the selective degradation of mitochondrial proteins and whole organelles via the proteasome and the autophagy/lysosome pathway (mitophagy). The mitochondrial kinase PINK1 activates and recruits the E3 ubiquitin (Ub) ligase Parkin to de-energized mitochondria. However, Parkin's cognate E2 co-enzymes in this Ub-dependent pathway have not been investigated. Here, we discovered in total four E2s that either positively or negatively regulate Parkin's activation, translocation and enzymatic functions during mitochondrial quality control. UBE2D family members and UBE2L3 redundantly charge the RING/HECT hybrid ligase Parkin with Ub, resulting in its initial activation and translocation to mitochondria. UBE2N however primarily operates through a different mechanism to mediate the proper clustering of mitochondria a prerequisite for degradation. Strikingly, in contrast to UBE2D, UBE2L3 and UBE2N, depletion of UBE2R1 results in enhanced Parkin translocation and clustering upon mitochondrial uncoupling. Our study uncovered redundant, cooperative or antagonistic functions of distinct E2 enzymes in the regulation of Parkin and mitophagy may suggest a putative role in PD pathogenesis.

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  • The study used an established stable HeLa cell model with homogenous expression of GFP-PRKN.

    “we used an established stable HeLa cell model with homogenous expression of GFP-PRKN [19].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [19]

  • The machine-learning classifier had excellent agreement with the established GFP-PRKN ratio algorithm and a combined Z' score of 0.79.

    “There was excellent agreement between the new classifier and the established ‘GFP-PRKN ratio’ algorithm [19, 20, 25, 30] (Fig. 1C, Table S4) but the new classifier was more robust in this screening setting and had a combined Z’ score of 0.79.”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [19]

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Authors
Fiesel, F. C., Moussaud-Lamodière, E. L., Ando, M., & Springer, W.
Affiliations
Mayo Clinic (US)
Corresponding author
Springer, Wolfdieter
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2014-01-01
Volume
127
Issue
Pt 16
Pages
3488-504
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.147520
PMC
PMC4132391
OpenAlex
W2129750781
Cited by
72
References
65
Citations by year
2026: 1 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 7 · 2019: 2 · 2018: 4 · 2017: 9 · 2016: 11 · 2015: 13 · 2014: 4
FWCI
8.04
Type
journal article
Language
en
Open access
Locations
  • Journal of Cell Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS085070)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Parkin, PINK1, mitophagy, E2 ubiquitin-conjugating enzyme, UBE2L3, UBE2N, Parkinson's disease, mitochondrial quality control, ubiquitination, mitochondrial clustering, mitochondrial uncoupling
MeSH terms
Multigene Family, HeLa Cells, Humans, Mitochondria, Parkinson Disease, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Mitophagy

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