RGD Reference Report - Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. - Rat Genome Database

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Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment.

Authors: Greene, Andrew W  Grenier, Karl  Aguileta, Miguel A  Muise, Stephanie  Farazifard, Rasoul  Haque, M Emdadul  McBride, Heidi M  Park, David S  Fon, Edward A 
Citation: Greene AW, etal., EMBO Rep. 2012 Apr;13(4):378-85. doi: 10.1038/embor.2012.14.
RGD ID: 14995326
Pubmed: PMID:22354088   (View Abstract at PubMed)
PMCID: PMC3321149   (View Article at PubMed Central)
DOI: DOI:10.1038/embor.2012.14   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein processing involved in protein targeting to mitochondrion involved_inIDA 14995326PMID:22354088UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
metalloendopeptidase activity enablesIDA 14995326PMID:22354088UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Pmpcb  (peptidase, mitochondrial processing subunit beta)


Additional Information