Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays a key role in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis, according to a new study published in iScience. 

First author Fannie W. Chen and the coauthors of the study postulated that TRAP1 could, therefore, represent a potential therapeutic target for lysosomal storage disorders such as Pompe disease and many others including mitochondrial diseases and even neurodegenerative disorders since lysosomal and mitochondrial dysfunction are involved in a multitude of disorders. 

The team of researchers led by Yiannis A. Ioannou, PhD, from the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai in New York, New York, unexpectedly discovered that the activation of TRAP1, a mitochondrial chaperone, led to the correction of the lysosomal storage phenotype in cells obtained from patients with different lysosomal storage disorders including Pompe disease.

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The authors also showed that when they activated TRAP1 using specific small compound activators such as ML405 and 1685, lysosomal and mitochondrial health were restored. 

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“Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress,” the researchers wrote. This reduction, they said, “results in activation of [adenosine monophosphate-activated protein kinase] and ultimately stimulates lysosome recycling.”

TRAP1 belongs to the heat-shock protein 90 family of chaperones and seems to play a critical role in mitochondrial metabolic homeostasis, though its exact function remains unclear.

Pompe disease is a glycogen storage disease caused by a mutation in the gene coding for the acid alpha-glucosidase (GAA) enzyme. This enzyme normally cleaves glycogen and converts it into glucose. When the function of the GAA enzyme is disrupted due to a genetic mutation, glycogen accumulates inside tissues and causes damage, especially in the heart and skeletal muscles. 

Reference

Chen FW, Davies JP, Calvo R, et al. Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction. iScience. Published online August 14, 2022. doi:10.1016/j.isci.2022.104941

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