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PMID: 22280891 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin.

Developmental cell ·Vol. 22 ·No. 2 ·2012-02-14 ·Pages 320-33

Lazarou M, Jin SM, Kane LA, Youle RJ

Abstract

Mutations in the mitochondrial kinase PINK1 and the cytosolic E3 ligase Parkin can cause Parkinson's disease. Damaged mitochondria accumulate PINK1 on the outer membrane where, dependent on kinase activity, it recruits and activates Parkin to induce mitophagy, potentially maintaining organelle fidelity. How PINK1 recruits Parkin is unknown. We show that endogenous PINK1 forms a 700 kDa complex with the translocase of the outer membrane (TOM) selectively on depolarized mitochondria whereas PINK1 ectopically targeted to the outer membrane retains association with TOM on polarized mitochondria. Inducibly targeting PINK1 to peroxisomes or lysosomes, which lack a TOM complex, recruits Parkin and activates ubiquitin ligase activity on the respective organelles. Once there, Parkin induces organelle selective autophagy of peroxisomes but not lysosomes. We propose that the association of PINK1 with the TOM complex allows rapid reimport of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation.

MeSH Terms
Autophagy Carrier Proteins/metabolism Cytosol/metabolism HeLa Cells Humans Immunoenzyme Techniques Intracellular Membranes/metabolism Mitochondria/metabolism Mitochondrial Precursor Protein Import Complex Proteins Protein Binding Protein Kinases/metabolism Protein Multimerization Protein Transport Ubiquitin-Protein Ligases/metabolism
Chemicals
Carrier Proteins Mitochondrial Precursor Protein Import Complex Proteins Ubiquitin-Protein Ligases parkin protein Protein Kinases PTEN-induced putative kinase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Lazarou Michael
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Jin Seok Min
Kane Lesley A
Youle Richard J
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2011.12.014
Published
2012-02-14
Epub
2012-00-25
Pages
320-33
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC3288275
Subset
IM
Grants
Intramural NIH HHS · ZIA NS003123-01 · United States
External Links
PubMed source DOI: 10.1016/j.devcel.2011.12.014 PMC Full Text View journal details
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