Abstract
Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (ΔΨm). We identified a negatively charged amino acid cluster motif that is evolutionarily conserved just C-terminal to the PINK1 transmembrane. PINK1 that fails to accumulate at the outer mitochondrial membrane, either by mutagenesis of this negatively charged motif or by deletion of Tom7, is imported into depolarized mitochondria and cleaved by the OMA1 protease. Some PD patient mutations also are defective in import arrest and are rescued by the suppression of OMA1, providing a new potential druggable target for PD. These results suggest that ΔΨm loss-dependent PINK1 import arrest does not result solely from Tim23 inactivation but also through an actively regulated "tug of war" between Tom7 and OMA1.
Keywords:
OMA1; TIM23 complex; TOM complex; mitochondrial protease; mitophagy.
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Motifs
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Antiparkinson Agents / pharmacology
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Biological Transport
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Drug Design
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Enzyme Activation
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HeLa Cells
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Humans
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Membrane Potential, Mitochondrial
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism*
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Mitochondria / drug effects
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Mitochondria / enzymology*
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Mitochondria / genetics
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Mitochondrial Membrane Transport Proteins / genetics
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Membranes / drug effects
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Mitochondrial Membranes / enzymology*
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Mitochondrial Precursor Protein Import Complex Proteins
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Parkinson Disease / drug therapy
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Parkinson Disease / enzymology*
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Parkinson Disease / genetics
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Protein Interaction Domains and Motifs
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Proteolysis
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Signal Transduction
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Antiparkinson Agents
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Membrane Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Precursor Protein Import Complex Proteins
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Mitochondrial Proteins
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TIMM23 protein, human
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TOMM7 protein, human
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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PTEN-induced putative kinase
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Metalloendopeptidases
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molecule metalloprotease-related protein-1, human