The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1.
In mice, targeted deletion of the serine protease HtrA2 (also known as Omi) causes mitochondrial dysfunction leading to a neurodegenerative disorder with parkinsonian features. In humans, point mutations in HtrA2 are a susceptibility factor for Parkinson's disease (PARK13 locus). Mutations in PINK1, a putative mitochondrial protein kinase, are associated with ... the PARK6 autosomal recessive locus for susceptibility to early-onset Parkinson's disease. Here we determine that HtrA2 interacts with PINK1 and that both are components of the same stress-sensing pathway. HtrA2 is phosphorylated on activation of the p38 pathway, occurring in a PINK1-dependent manner at a residue adjacent to a position found mutated in patients with Parkinson's disease. HtrA2 phosphorylation is decreased in brains of patients with Parkinson's disease carrying mutations in PINK1. We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.
Mesh Terms:
Animals, Binding Sites, Brain, Cell Line, Enzyme Activation, Humans, MAP Kinase Kinase Kinase 3, Mice, Mitochondrial Proteins, Models, Biological, Mutagenesis, Site-Directed, Mutation, Parkinson Disease, Phosphorylation, Protein Kinases, Serine Endopeptidases, Signal Transduction
Animals, Binding Sites, Brain, Cell Line, Enzyme Activation, Humans, MAP Kinase Kinase Kinase 3, Mice, Mitochondrial Proteins, Models, Biological, Mutagenesis, Site-Directed, Mutation, Parkinson Disease, Phosphorylation, Protein Kinases, Serine Endopeptidases, Signal Transduction
Nat. Cell Biol.
Date: Nov. 01, 2007
PubMed ID: 17906618
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