Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction
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), w...
| الحاوية / القاعدة: | iScience |
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| المؤلفون الرئيسيون: | , , , , , , , , , , , , , , , , , |
| التنسيق: | مقال |
| اللغة: | الإنجليزية |
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Elsevier
2022-09-01
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| الموضوعات: | |
| الوصول للمادة أونلاين: | http://www.sciencedirect.com/science/article/pii/S2589004222012135 |
| _version_ | 1852699028199833600 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Fannie W. Chen |
| collection | DOAJ |
| container_title | iScience |
| description | 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. |
| format | Article |
| id | doaj-art-e19a65a93a4f4b3fb15bf654a093fa23 |
| institution | Directory of Open Access Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| spelling | doaj-art-e19a65a93a4f4b3fb15bf654a093fa232025-08-19T21:21:12ZengElsevieriScience2589-00422022-09-0125910494110.1016/j.isci.2022.104941Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunctionFannie W. Chen0Joanna P. Davies1Raul Calvo2Jagruti Chaudhari3Georgia Dolios4Mercedes K. Taylor5Samarjit Patnaik6Jean Dehdashti7Rebecca Mull8Patricia Dranchack9Amy Wang10Xin Xu11Emma Hughes12Noel Southall13Marc Ferrer14Rong Wang15Juan J. Marugan16Yiannis A. Ioannou17Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USACell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, 1250 1st Avenue, New York, NY 10065, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USAEarly Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA; Corresponding authorDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222012135Cell biologyCellular neuroscienceNeuroscience |
| spellingShingle | 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 Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction Cell biology Cellular neuroscience Neuroscience |
| title | Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction |
| title_full | Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction |
| title_fullStr | Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction |
| title_full_unstemmed | Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction |
| title_short | Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction |
| title_sort | activation of mitochondrial trap1 stimulates mitochondria lysosome crosstalk and correction of lysosomal dysfunction |
| topic | Cell biology Cellular neuroscience Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222012135 |
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