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Cited by 670Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyUbiquitin and proteasome pathways

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

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Lazarou, Michael, Jin, Seok Min, Kane, Lesley A., Youle, Richard J.·2012·Developmental Cell
DOI 10.1016/j.devcel.2011.12.014PMC PMC3288275
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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.

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  • Mitochondrial depolarization stabilizes PINK1 by arresting its import at the TOM complex, preventing turnover and allowing accumulation of full-length, dimerized PINK1 on the outer mitochondrial membrane.

    “Current models suggest that mitochondrial depolarization stabilizes PINK1 by arresting its import at the TOM complex, thereby preventing turnover and allowing accumulation of full-length, dimerized PINK1 on the outer mitochondrial membrane [59–62].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [59]

    The Results section reports that depolarization inhibits PINK1 import and degradation, allowing it to accumulate on the outer mitochondrial membrane. But the Discussion explicitly argues against the claim’s proposed mechanism of import stalling at the TOM complex; it says PINK1 can associate with TOM without impaired import. The Discussion also presents PINK1 dimerization as a possibility, not an established result. Page numbers were not available in our copy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Lazarou, M., Jin, S. M., Kane, L. A., & Youle, R. J.
Affiliations
National Institutes of Health (US)
Corresponding author
Youle, Richard J.
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2012-02
Volume
22
Issue
2
Pages
320-333
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2011.12.014
PMC
PMC3288275
OpenAlex
W2160330769
Cited by
670
References
10
Citations by year
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FWCI
32.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (ZIANS003123)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
PINK1, Parkin, TOM complex, translocase of the outer membrane, mitophagy, Parkinson's disease, mitochondrial depolarization, mitochondrial quality control, protein recruitment
MeSH terms
Mitochondrial Precursor Protein Import Complex Proteins, PTEN-Induced Putative Kinase, Autophagy, Carrier Proteins, Cytosol, HeLa Cells, Humans, Immunoenzyme Techniques, Intracellular Membranes, Mitochondria, Protein Binding, Protein Kinases, Protein Transport, Ubiquitin-Protein Ligases, Protein Multimerization

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