PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1

Abstract

Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis.

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

“…A growing body of evidence now supports the idea that TRAP1 is associated with important human diseases including cancer and neurodegeneration (37,42). However, the molecular regulatory mechanisms and signaling pathways affecting the chaperone functions are largely unknown at this point.…”

“…Post-translational modification, such as phosphorylation, is an important means to regulate the protein function in vivo. Phosphorylation of TRAP1 by PTEN induced putative kinase 1 (PINK1) is responsible for the protection of ROS mediated cell death (42). It is likely that a PINK1-TRAP1 pathway affects mitochondrial integrity by regulating the Cyp-D function, but the potential regulatory pathway has not yet been fully investigated.…”

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

“…Pink1 binds and colocalizes with TRAP1 in the mitochondria. Also, Pink1 phosphorylates TRAP1 both in vitro and in vivo 25 . Thus, we tested whether Pink1 kinase activity is also required for mitochondrial fragmentation and apoptosis pathway in cardiomyocytes.…”

“…This is in consistence with other reports that demonstrate the protective effect of Pink1 on mitochondrial integrity. For example, Pink1 is mutated in parkinsonism, and overexpression of the WT Pink1, but not the parkinsonism-associated mutant, protects cells from apoptosis in response to oxidative stress 25,33 . Inhibition of Pink1 induces fragmented mitochondria, altered cristae morphology and reduced membrane potential 34 .…”

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…Pridgeon et al (2007) report stable complex formation between PINK1 and TNF-receptor-associated protein 1 (TRAP1). TRAP1 is a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75) that modulates the permeability transition pore to inhibit mitochondrial-associated cell death (Kang et al, 2007).…”