Stress-dependent PINK1 import regulation

Identification: Sekine, Shiori


Description

Stress-dependent PINK1 import regulation
 
Shiori Sekine1 and Richard J. Youle1*
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
*Corresponding Author
 
PINK1/Parkin-mediated mitophagy, that helps maintain a healthy mitochondrial network, is initiated by the activation of the PINK1 kinase specifically on the damaged mitochondria. Mitochondrial stress-dependent PINK1 activation is exerted by regulated import of PINK1 into different mitochondrial compartments. PINK1 is imported into mitochondria through mitochondrial targeting sequence (MTS) that is currently annotated to N-terminal 34 a.a. After import, PINK1 is rapidly cleaved by PARL in its transmembrane (TM) domain (94-110 a.a.) and retrotranslocated into the cytosol, where it is constitutively degraded through the proteasome. Upon mitochondrial depolarization, PINK1 import arrest promotes the formation of a PINK1 high molecular weight complex with the TOM complex, which leads to PINK1 kinase activation through autophosphorylation. Thus, the stable accumulation of PINK1 on the TOM complex plays an important role for PINK1 activation and the subsequent process of mitophagy. However, it is not well known how this stable OMM accumulation of PINK1 is achieved in response to mitochondrial depolarization. We previously identified that Tom7, a small accessary molecule of the TOM complex, is critical for PINK1 OMM accumulation. It is reported that PINK1 has an unique domain for OMM targeting, the so-called outer mitochondrial membrane localization signal (OMS) (around 70-95 a.a.). In addition to these, we recently identified another important sequence among PINK1 for its OMM accumulation. This sequence is located in a small region just after TM domain of PINK1 (111-117 a.a.). Especially, evolutionarily-conserved clustered negative charged amino acid residues in this region are important for proper behavior of PINK1 during its import. Our findings provide a clue to uncover the detailed molecular mechanisms of stress-dependent PINK1 import regulation.

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