BECN1 is involved in the initiation of mitophagy: it facilitates PARK2 translocation to mitochondria

Autophagy. 2014 Jun;10(6):1105-19. doi: 10.4161/auto.28615.

Abstract

The autophagy protein BECN1/Beclin 1 is known to play a central role in autophagosome formation and maturation. The results presented here demonstrate that BECN1 interacts with the Parkinson disease-related protein PARK2. This interaction does not require PARK2 translocation to mitochondria and occurs mostly in cytosol. However, our results suggest that BECN1 is involved in PARK2 translocation to mitochondria because loss of BECN1 inhibits CCCP- or PINK1 overexpression-induced PARK2 translocation. Our results also demonstrate that the observed PARK2-BECN1 interaction is functionally important. Measurements of the level of MFN2 (mitofusin 2), a PARK2 substrate, demonstrate that depletion of BECN1 prevents PARK2 translocation-induced MFN2 ubiquitination and loss. BECN1 depletion also rescues the MFN2 loss-induced suppression of mitochondrial fusion. In sum, our results demonstrate that BECN1 interacts with PARK2 and regulates PARK2 translocation to mitochondria as well as PARK2-induced mitophagy prior to autophagosome formation.

Keywords: BECN1; MFN2; PARK2 translocation; mitochondrial dynamics; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy
  • Beclin-1
  • Biological Transport, Active
  • Cells, Cultured
  • GTP Phosphohydrolases
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitophagy / physiology*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • PC12 Cells
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, rat
  • Membrane Proteins
  • Mitochondrial Proteins
  • Mutant Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • GTP Phosphohydrolases
  • Mfn2 protein, rat