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Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL
Seok Min Jin1, Michael Lazarou, Chunxin Wang
1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Cell Biology
|December 1, 2010
Summary
Presenilin-associated rhomboid-like protein (PARL) regulates PTEN-induced kinase 1 (PINK1) localization and stability. PARL cleavage controls PINK1
Area of Science:
- Mitochondrial biology
- Neurodegenerative disease research
- Cellular signaling pathways
Background:
- Mutations in PTEN-induced kinase 1 (PINK1) are linked to familial Parkinson's disease.
- PINK1 functions with E3 ligase Parkin in maintaining neuronal health and mitophagy.
- PINK1's precise cellular localization and regulation are unclear due to rapid degradation.
Purpose of the Study:
- To investigate the role of presenilin-associated rhomboid-like protein (PARL) in PINK1 regulation.
- To determine how mitochondrial membrane potential affects PINK1 localization and stability.
- To elucidate the mechanism controlling PINK1's function in mitophagy.
Main Methods:
- Utilized mammalian cell models to study PINK1 and PARL interactions.
- Assessed protein localization using cell imaging techniques.
- Manipulated mitochondrial membrane potential to observe PINK1 dynamics.
- Investigated PINK1 cleavage by PARL in vitro and in vivo.
Main Results:
- Identified PARL as a mitochondrial inner membrane protease that cleaves PINK1.
- Demonstrated that PARL-mediated cleavage of PINK1 is dependent on mitochondrial membrane potential.
- Showed that inhibiting PARL stabilizes a 60-kD form of PINK1 within mitochondria.
- Observed accumulation of full-length 63-kD PINK1 on the outer mitochondrial membrane upon dissipation of membrane potential.
Conclusions:
- PARL-dependent cleavage regulates PINK1 stability and mitochondrial localization.
- Differential localization of PINK1 to inner and outer mitochondrial membranes controls its function.
- Mitochondrial membrane potential is a key regulator of PINK1's role in mitophagy and Parkinson's disease pathogenesis.
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