TRAP1 rescues PINK1 loss-of-function phenotypes

Abstract

PTEN-induced kinase 1 (PINK1) is a serine/threonine kinase that is localized to mitochondria. It protects cells from oxidative stress by suppressing mitochondrial cytochrome c release, thereby preventing cell death. Mutations in Pink1 cause early-onset Parkinson's disease (PD). Consistently, mitochondrial function is impaired in Pink1-linked PD patients and model systems. Previously, in vitro analysis implied that the protective effects of PINK1 depend on phosphorylation of the downstream factor, TNF receptor-associated protein 1 (TRAP1). Furthermore, TRAP1 has been shown to mitigate α-Synuclein-induced toxicity, linking α-Synuclein directly to mitochondrial dysfunction. These data suggest that TRAP1 seems to mediate protective effects on mitochondrial function in pathways that are affected in PD. Here we investigated the potential of TRAP1 to rescue dysfunction induced by either PINK1 or Parkin deficiency in vivo and in vitro. We show that overexpression of human TRAP1 is able to mitigate Pink1 but not parkin loss-of-function phenotypes in Drosophila. In addition, detrimental effects observed after RNAi-mediated silencing of complex I subunits were rescued by TRAP1 in Drosophila. Moreover, TRAP1 was able to rescue mitochondrial fragmentation and dysfunction upon siRNA-induced silencing of Pink1 but not parkin in human neuronal SH-SY5Y cells. Thus, our data suggest a functional role of TRAP1 in maintaining mitochondrial integrity downstream of PINK1 and complex I deficits but parallel to or upstream of Parkin.

Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila

“…Recently published studies have also indicated a similar role of TRAP1 in regulating stress resistance in flies (Costa et al, 2013, Zhang et al, 2013). However, we further demonstrate that dosage modulation of TRAP1 has remarkable sex-specific influences and is correlated with the sex-specific activation the UPR mt .…”

“…TRAP1 also ameliorates cellular toxicity induced by α-synuclein in dopaminergic neurons (Butler et al . 2012) and expression of TRAP1 was able to rescue mitochondrial dysfunction in Pink1 deficient flies (Zhang et al , 2013; Costa et al , 2013). In summary, TRAP1 lies at an exciting intersection between ROS, aging, mitochondrial proteostasis and human disease.…”

Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

“…In another study, however, Zhang et al reported that overexpression of human TRAP1 was able to mitigate PINK1 but not PARKIN loss-offunction phenotypes in Drosophila. In human neuronal SH-SY5Y cells, TRAP1 also rescued mitochondrial fragmentation and dysfunction after siRNA-induced silencing of PINK1 but not PARKIN (Zhang et al 2013). This discrepancy in the relationships between PARKIN and TRAP1 remains poorly understood.…”

Flies with Parkinson's disease

“…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.…”

“…For example GST or removing Aconitase, a major mediator of ROS-induced toxicity in mitochondria are protective Kim and Yim, 2013;Whitworth et al, 2005). In addition, expression of Ret, TNF receptor-associated protein 1 (TRAP1) and near-infrared 808 nm light all turned out to improve mitochondrial function in Drosophila pink1 mutants thereby rescuing the cellular and behavioral defects in these animals Vos et al, 2013;Zhang et al, 2013). These strategies are thus paving the way to a new generation of therapeutic strategies in Pink1-dependent strategies.…”