A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently

Fabienne Fiesel, Elisabeth L. Moussaud-Lamodière, Maya Ando, Wolfdieter Springer

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Loss-of-function mutations in the genes encoding PINK1 and Parkin (also known as PARK2) are the most common causes of recessive Parkinson's disease. 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 ligase Parkin to de-energized mitochondria. However, the cognate E2 co-enzymes of Parkin in this ubiquitin-dependent pathway have not been investigated. Here, we discovered a total of four E2s that either positively or negatively regulate the activation, translocation and enzymatic functions of Parkin during mitochondrial quality control. UBE2D family members and UBE2L3 redundantly charged the RING-HECT hybrid ligase Parkin with ubiquitin, resulting in its initial activation and translocation to mitochondria. UBE2N, however, primarily operated through a different mechanism in order to mediate the proper clustering of mitochondria, a prerequisite for degradation. Strikingly, in contrast to UBE2D, UBE2L3 and UBE2N, depletion of UBE2R1 resulted 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 that might suggest a putative role in Parkinson's disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)3488-3504
Number of pages17
JournalJournal of Cell Science
Volume127
Issue number16
DOIs
StatePublished - 2014

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Mitochondrial Degradation
Ubiquitin-Conjugating Enzymes
Mitochondria
Ubiquitin
Cluster Analysis
Parkinson Disease
Ubiquitin-Protein Ligases
Mitochondrial Proteins
Autophagy
Proteasome Endopeptidase Complex
Enzymes
Ligases
Lysosomes
Quality Control
Organelles
Phosphotransferases
Mutation
Genes

Keywords

  • Autophagy
  • E2 enzymes
  • Mitochondria
  • Mitophagy
  • Parkin
  • PINK1
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Cell Biology

Cite this

A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. / Fiesel, Fabienne; Moussaud-Lamodière, Elisabeth L.; Ando, Maya; Springer, Wolfdieter.

In: Journal of Cell Science, Vol. 127, No. 16, 2014, p. 3488-3504.

Research output: Contribution to journalArticle

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