The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations

Sven Geisler, Kira M. Holmström, Angela Treis, Diana Skujat, Stephanie S. Weber, Fabienne C. Fiesel, Philipp J. Kahle, Wolfdieter Springer

Research output: Contribution to journalArticle

180 Scopus citations

Abstract

Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)871-878
Number of pages8
JournalAutophagy
Volume6
Issue number7
DOIs
StatePublished - Oct 1 2010

Keywords

  • Autophagy
  • Mitochondria
  • Mitophagy
  • PINK1
  • Parkin
  • Parkinson disease
  • Ubiquitin
  • VDAC1
  • p62/SQSTM1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W. (2010). The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy, 6(7), 871-878. https://doi.org/10.4161/auto.6.7.13286