Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment

Andrew W. Greene, Karl Grenier, Miguel A. Aguileta, Stephanie Muise, Rasoul Farazifard, M. Emdadul Haque, Heidi M. McBride, David S. Park, Edward A. Fon

Research output: Contribution to journalArticlepeer-review

525 Citations (Scopus)


Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1-Parkin pathway.

Original languageEnglish
Pages (from-to)378-385
Number of pages8
JournalEMBO Reports
Issue number4
Publication statusPublished - Apr 2012
Externally publishedYes


  • Parkinson's disease PINK1
  • mitochondria
  • mitophagy
  • proteases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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