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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.

Pubmed ID: 17906618


  • Plun-Favreau H
  • Klupsch K
  • Moisoi N
  • Gandhi S
  • Kjaer S
  • Frith D
  • Harvey K
  • Deas E
  • Harvey RJ
  • McDonald N
  • Wood NW
  • Martins LM
  • Downward J


Nature cell biology

Publication Data

November 2, 2007

Associated Grants

  • Agency: Medical Research Council, Id: G0400000
  • Agency: Medical Research Council, Id: G0700183
  • Agency: Medical Research Council, Id: MC_U132674518

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