摘要：SummaryNumerous 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.Graphical abstractDisplay OmittedHighlights•Small molecules ML405 and 1685 correct the lipid storage in LSDs including NPC1•These molecules are agonists of the mitochondrial chaperone TRAP1•TRAP1 agonists ameliorate mitochondrial stress and improve lysosomal function•TRAP1 agonists reduce lipid storage in a mouse model of Fabry diseaseCell biology; Cellular neuroscience; Neuroscience
