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Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction. | LitMetric

AI Article Synopsis

  • - Numerous studies have linked dysfunctions in lysosomes and mitochondria to neurodegenerative diseases like Alzheimer's and Parkinson's.
  • - Researchers discovered that activating the mitochondrial chaperone TRAP1 can improve lysosomal function in cells from various lysosomal storage disorders, including Niemann-Pick C1 disease.
  • - Activation of TRAP1 enhances lysosomal and mitochondrial health by reducing oxidative stress and promoting lysosome recycling, suggesting TRAP1 could be a promising target for new treatments for several disorders.

Article Abstract

Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440283PMC
http://dx.doi.org/10.1016/j.isci.2022.104941DOI Listing

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