Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction
Fannie W. Chen,
Joanna P. Davies,
Raul Calvo,
Jagruti Chaudhari,
Georgia Dolios,
Mercedes K. Taylor,
Samarjit Patnaik,
Jean Dehdashti,
Rebecca Mull,
Patricia Dranchack,
Amy Wang,
Xin Xu,
Emma Hughes,
Noel Southall,
Marc Ferrer,
Rong Wang,
Juan J. Marugan,
Yiannis A. Ioannou
Affiliations
Fannie W. Chen
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Joanna P. Davies
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Raul Calvo
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Jagruti Chaudhari
Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, 1250 1st Avenue, New York, NY 10065, USA
Georgia Dolios
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Mercedes K. Taylor
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
Samarjit Patnaik
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Jean Dehdashti
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Rebecca Mull
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Patricia Dranchack
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Amy Wang
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Xin Xu
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Emma Hughes
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Noel Southall
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Marc Ferrer
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
Rong Wang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Juan J. Marugan
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA; Corresponding author
Yiannis A. Ioannou
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding author
Summary: 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.
