PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1

Emory University, Atlanta, Georgia, United States
PLoS Biology (Impact Factor: 9.34). 07/2007; 5(7):e172. DOI: 10.1371/journal.pbio.0050172
Source: PubMed


Author Summary

Parkinson disease (PD) is characterized by the selective loss of midbrain dopaminergic neurons. Although the cause of PD is unknown, pathological analyses have suggested the involvement of oxidative stress and mitochondrial dysfunction. Recently, an inherited form of early-onset PD has been linked to mutations in both copies of the gene encoding the mitochondrial protein PINK1. Furthermore, increasing evidence indicates that single-copy mutations in PINK1 are a significant risk factor in the development of later-onset PD. Here we show that PINK1 is a protein kinase that phosphorylates the mitochondrial molecular chaperone TRAP1 to promote cell survival. We find that PINK1 normally protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria. The PINK1 mutations linked to PD impair the ability of PINK1 to phosphorylate TRAP1 and promote cell survival. Our findings reveal a novel anti-apoptotic signaling pathway that is disrupted by mutations in PINK1. We suggest that this pathway has a role in PD pathogenesis and may be a target for therapeutic intervention.

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Available from: Julia Pridgeon, Jun 20, 2014
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    • "The accumulation of misfolded proteins is sensed by PINK1 (Jin and Youle 2013). PINK1 interacts with several proteins involved with the MT-UPR and MT quality control including TRAP1 (Pridgeon et al. 2007), HSP60 (Rakovic et al. 2011) and HTRA2/OMI (Plun-Favreau et al. 2007). "
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    • "For example TRAP1 was identified in such a screen (Butler et al., 2012). TRAP1 is a mitochondrial chaperone that already had been implicated to be phosphorylated by another PD-protein Pink1 (Costa et al., 2013; Pridgeon et al., 2007; Zhang et al., 2013). Hence, such interaction screens start to elucidate common pathways that span several of the PD-relevant genes. "
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