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

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.

TRAP1 Chaperones the Metabolic Switch in Cancer

“…Mitoquinone has been demonstrated to have protective properties in various animal models of neurological maladies, such as traumatic brain injury [ 131 ], Huntington’s disease [ 132 ], amyotrophic lateral sclerosis (ALS) [ 133 ], and Alzheimer’s disease [ 134 ]. This finding is contradictory to the working model of TRAP1 function, especially considering that TRAP1 downregulation is observed in Alzheimer’s disease patients [ 135 ] and its overexpression is protective against oxidative stress in ALS [ 62 ]. These results highlight the need to understand the disease-specific contexts of TRAP1 function to identify appropriate disease models for the evaluation of TRAP1 inhibitors.…”

“…Mitochondrial respiration drives the production of reactive oxygen species (ROS) and is responsible for most cellular ROS ( Figure 3 ) [ 61 ]. In considering the role of TRAP1 in chaperoning SDH and COXII, TRAP1-mediated regulation of mitochondrial respiration suppresses ROS production [ 62 ], thereby contributing to the regulation of redox homeostasis, metabolic flux, and mitochondrial apoptosis.…”

The development of cancers research based on mitochondrial heat shock protein 90

“…In addition to its significant role in the development, metastasis, and maintenance of cancer, aberrant expression of TRAP1 has been associated with a number of diseases, including but not limited to the following: TRAP1 overexpression protects motor neurons from mitochondrial dysfunction and death under conditions of oxidative stress caused by amyotrophic lateral sclerosis (ALS) (110). Ramos Rego et al describe the role of TRAP1 in CNS cells under physiological and pathological conditions (111).…”

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

“…Although TRAP1 may have regulatory roles in organellar processes, whether it is ultimately cytoprotective in the context of neurodegenerative diseases or pro-neoplastic in the context of many cancers may reflect two sides of the same coin. This molecule has been reported to play a crucial role in inhibiting oxidative stress-induced tissue damage in the ischemic brain [ 34 ], hypoxia-induced injury in cardiomyocytes [ 35 ], myocardial ischemia/reperfusion injury [ 36 ], motor neuron degeneration in oxidative stress-induced amyotrophic lateral sclerosis (ALS) [ 37 ], and acidosis-induced injury in cardiomyocytes [ 38 ]. Likewise, TRAP1 appears to be protective in genetic models of neurodegeneration such as Parkinson’s disease [ 27 , 28 , 39 ] where protein quality control in mitochondria plays a critical role [ 40 ].…”