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

Abstract

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.

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Figure 1: HtrA2 binds PINK1.
Figure 2: HtrA2 is phosphorylated on MEKK3 activation.
Figure 3: PINK1 is necessary for HtrA2 phosphorylation.
Figure 4: Phosphorylation of HtrA2 increases its proteolytic activity.
Figure 5: Depletion of PINK1 affects wild-type but not HtrA2 knockout MEFs.

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Acknowledgements

We thank D. Hancock for valuable advice, N. Totty for mass spectrometric analysis, V. Dawson, NWW, RJH and ED were supported by the MRC SG0400000 grant and the PDS NWW was supported by the W-T-CRF. G. Schiavo, A. Schulze and K. Dimmer for materials, S. Loh for help with the Cellomics KSR microscopy system, and A. Borg and T. Simmonds for assistance in the preparation of recombinant HtrA2. K.K. was funded by a PhD studentship from Boehringer Ingelheim Fonds. This work was supported by Cancer Research UK.

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Correspondence to L. Miguel Martins or Julian Downward.

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Supplementary Figures 1, 2, 3, 4, 5, Supplementary Materials and Methods (PDF 1947 kb)

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Plun-Favreau, H., Klupsch, K., Moisoi, N. et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol 9, 1243–1252 (2007). https://doi.org/10.1038/ncb1644

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