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Open Access

Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

Gian‐Luca McLelland, Vincent Soubannier, Carol X Chen, Heidi M McBride, Edward A Fon

Author Affiliations

  1. Gian‐Luca McLelland1,
  2. Vincent Soubannier2,
  3. Carol X Chen1,
  4. Heidi M McBride*,2 and
  5. Edward A Fon*,1
  1. 1McGill Parkinson Program Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital McGill University, Montreal, QC, Canada
  2. 2Neuromuscular Group Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital McGill University, Montreal, QC, Canada
  1. * Corresponding author. Tel: +514 398 8398; Fax: +514 398 5214; E‐mail: ted.fon{at}mcgill.ca

    Corresponding author. Tel: +514 398 1808; Fax: +514 398 1509; E‐mail: heidi.mcbride{at}mcgill.ca

  1. GLM, VS, HMM and EAF conceived and planned the experiments, and interpreted the data. GLM, VS and CXC acquired and analyzed the data. GLM carried out the quantification and statistical analyses. GLM and EAF wrote the manuscript.

Abstract

Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild‐type but not PD‐linked mutant parkin supports the biogenesis of a population of mitochondria‐derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin‐ and PINK1‐dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD.

Synopsis

Embedded Image

Rapid lysosomal targeting of oxidized mitochondrial proteins via mitochondria‐derived vesicles constitutes an additional, mitophagy‐independent quality control role for Parkin and PINK1, two proteins responsible for familial forms of Parkinson's disease.

  • In response to mitochondrial oxidative stress, parkin induces the PINK1‐dependent formation of mitochondrial vesicles, which are enriched for specific mitochondrial proteins.

  • These vesicles form independently of fission factor Drp1, and they target to lysosomes for degradation in an autophagy‐independent manner.

  • Induction of these vesicles is a ROS‐dependent process and can occur with endogenous levels of parkin across a variety of cell types, but not in presence of disease‐associated mutant parkin.

  • The formation and turnover of parkin‐/PINK1‐dependent mitochondrial vesicles precedes mitophagy and is not induced by depolarizing agents.

  • This vesicular trafficking pathway is a “rapid response” to mitochondrial stress, shuttling oxidized cargo to lysosomes in order to preserve the integrity of the organelle.

Footnotes

  • The authors declare that they have no conflict of interest.

  • Received June 5, 2013.
  • Revision received October 24, 2013.
  • Accepted December 5, 2013.

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