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

By M. Lazarou, S. Jin, L. A. Kane, R. Youle. Developmental Cell, 2012

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Summary 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 re-import of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/846448f4abe521915bc6d763b62d268b94c99331

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Citations in the corpus

Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria (2016, background): “By the addition of rapalog, PINK1 is targeted to mitochondria that are stably expressing FKBP12/rapamycin-binding (FRB) fused to Fis1 (FRB–Fis1) (34); this allows PINK1, in the absence of Parkin and mitochondrial membrane depolarization, to phosphorylate mitochondrial ubiquitin to recruit autophagy ”
Mitochondria ROS and mitophagy in acute kidney injury (2022, background): “PINK1 is imported as normal to the OMM of depolarized mitochondria, however the loss of ΔΨm prevents its import and subsequent cleavage in the IMM [47].”
The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “expression of PINK1 on peroxisomes recruits Parkin to induce pexophagy (Lazarou et al., 2012).”
Mitophagy: mechanisms, pathophysiological roles, and analysis (2012, background): “However, Pink1 is stabilized on the outer mitochondrial membrane and forms a large complex with the translocase of the outer membrane where it can recruit Parkin to impaired mitochondria when mitochondrial membrane potential is dissipated (Jin et al. , 2010 ; Lazarou et al. , 2012 ).”
Quantitative proteomics reveal a feed-forward model for mitochondrial PARKIN translocation and UB chain synthesis (2014, positive): “When PARKIN encounters activated PINK1 associated with the TOM complex on damaged mitochondria (Lazarou et al., 2012; Sarraf et al., 2013), it becomes phosphorylated on S65 (Figure 7E), leading to activation of its UB chain assembly function by more than 2,000-fold based on our quantitative…”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “In depolarized mitochondria, endogenous PINK1 is associated with the TOM complex, which may allow rapid reimport of PINK1 after repolarization to switch off the mitophagy pathway (Lazarou et al , 2012).”
The pathways of mitophagy for quality control and clearance of mitochondria (2012, background): “Loss of mitochondrial membrane potential may be the event that acutely activates this pathway; loss of the potential gradient precludes import of PINK1 to the inner membrane, thereby stabilizing intact PINK1 on the mitochondrial outer membrane where it interacts with the TOM complex.(74) In this man”
A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “Upon mitochondrial depolarization, the import machinery is inactivated and PINK1 becomes trapped either within the import channel or becomes anchored to the mitochondrial outer membrane near the import channel (Greene et al, 2012; Lazarou et al, 2012).”
Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control (2014, methodology): “In the time-course experiment, cells were treated with DMSO, 25 lM antimycin A, 25 lM antimycin A and 10 lM oligomycin, 25 lM antimycin A and 50 lM EUK134, and 20 lM CCCP for the indicated time prior to fixation.”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “Parkin and its partner PIKN1, a mitochondrial kinase, co-work in a pathway to control mitochondria morphology and functionality (Geisler et al., 2010; Lazarou et al., 2012).”