Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin

Michael Lazarou, Seok Min Jin, Lesley A. Kane, Richard J. Youle

Research output: Contribution to journalArticleResearchpeer-review

329 Citations (Scopus)

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 700kDa 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. PINK1 recruits Parkin to induce mitophagy; this quality control mechanism is defective in Parkinson's disease. Lazarou etal. find that targeting PINK1 to peroxisomes activates Parkin there, suggesting that mitochondria-specific activators are not required. PINK1 also binds mitochondrial protein import complexes, further highlighting the importance of regulating PINK1 localization.

Original languageEnglish
Pages (from-to)320-333
Number of pages14
JournalDevelopmental Cell
Volume22
Issue number2
DOIs
Publication statusPublished - 14 Feb 2012
Externally publishedYes

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