RGD Reference Report - The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications. - Rat Genome Database

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The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications.

Authors: Durcan, TM  Fon, EA 
Citation: Durcan TM and Fon EA, Genes Dev. 2015 May 15;29(10):989-99. doi: 10.1101/gad.262758.115.
RGD ID: 10401790
Pubmed: PMID:25995186   (View Abstract at PubMed)
PMCID: PMC4441056   (View Article at PubMed Central)
DOI: DOI:10.1101/gad.262758.115   (Journal Full-text)

Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ub-dependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKIN-mediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control.

Objects Annotated

Genes (Rattus norvegicus)
Atxn3  (ataxin 3)
Optn  (optineurin)
Pink1  (PTEN induced kinase 1)
Prkn  (parkin RBR E3 ubiquitin protein ligase)
Sqstm1  (sequestosome 1)
Ube2l3  (ubiquitin-conjugating enzyme E2L 3)
Usp15  (ubiquitin specific peptidase 15)
Usp30  (ubiquitin specific peptidase 30)
Usp8  (ubiquitin specific peptidase 8)

Genes (Mus musculus)
Atxn3  (ataxin 3)
Optn  (optineurin)
Pink1  (PTEN induced putative kinase 1)
Prkn  (parkin RBR E3 ubiquitin protein ligase)
Sqstm1  (sequestosome 1)
Ube2l3  (ubiquitin-conjugating enzyme E2L 3)
Usp15  (ubiquitin specific peptidase 15)
Usp30  (ubiquitin specific peptidase 30)
Usp8  (ubiquitin specific peptidase 8)

Genes (Homo sapiens)
ATXN3  (ataxin 3)
OPTN  (optineurin)
PINK1  (PTEN induced kinase 1)
PRKN  (parkin RBR E3 ubiquitin protein ligase)
SQSTM1  (sequestosome 1)
UBE2L3  (ubiquitin conjugating enzyme E2 L3)
USP15  (ubiquitin specific peptidase 15)
USP30  (ubiquitin specific peptidase 30)
USP8  (ubiquitin specific peptidase 8)


Additional Information