Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress.

Benjamin E Clarke,Bernadett Kalmar,Linda Greensmith

doi:10.3390/ijms23031789

Abstract

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis. In primary murine motor neurons, shRNA-mediated knockdown of TRAP1 expression results in mitochondrial dysfunction but does not further exacerbate damage induced by oxidative stress alone. Together, these results show that TRAP1 may be a potential therapeutic target for neurodegenerative diseases such as ALS, where mitochondrial dysfunction has been shown to be an early marker of pathogenesis.

Highlights

TNF-receptor associated protein (TRAP1) is a mitochondrial-specific member of theHsp90 heat shock protein (Hsp) superfamily of protein chaperones
Knockdown of TRAP1 expression exacerbated reactive oxygen species (ROS) production and cell death, while overexpression protected melanoma cells against cell death induced by mitochondrial complex I inhibition [9,10]
In order to investigate the effects of TRAP1 on protecting mitochondrial function in motor neurons, lentiviral-induced overexpression of human TRAP1 was performed in primary motor neuron cultures (Supplementary Materials, Figure S1A)

Summary

Introduction

TNF-receptor associated protein (TRAP1) is a mitochondrial-specific member of theHsp heat shock protein (Hsp) superfamily of protein chaperones. TNF-receptor associated protein (TRAP1) is a mitochondrial-specific member of the. Hsp chaperones play a crucial role in the regulation of protein folding quality control, and under conditions of cell stress, they are cytoprotective [1]. Early studies found that TRAP1 is associated with the TNF-α receptor and retinoblastoma protein [2,3], TRAP1 is known to be a mitochondrial-specific Hsp chaperone, which is predominantly located in the intermembrane space and matrix of mitochondria [4,5]. While TRAP1 retains its chaperoning function, it only shares 60% sequence homology with its cytoplasmic paralogue Hsp and does not bind Hsp co-chaperones p23 or Hop, suggesting that TRAP1 is highly specialised to function in mitochondria [6]. Knockdown of TRAP1 expression exacerbated reactive oxygen species (ROS) production and cell death, while overexpression protected melanoma cells against cell death induced by mitochondrial complex I inhibition [9,10]

Methods

Results

Conclusion