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Nature Cell Biology 9, 1243–1252 (1 November 2007) | doi:10.1038/ncb1644

The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1

H|[eacute]|l|[egrave]|ne Plun-Favreau , Kristina Klupsch , Nicoleta Moisoi , Sonia Gandhi , Svend Kjaer , David Frith , Kirsten Harvey , Emma Deas , Robert J. Harvey , Neil McDonald , Nicholas W. Wood , L. Miguel Martins & Julian Downward

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.