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Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases
Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421394/ https://www.ncbi.nlm.nih.gov/pubmed/34489512 http://dx.doi.org/10.1038/s41598-021-97148-z |
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author | Tjahjono, Elissa Pei, Jingqi Revtovich, Alexey V. Liu, Terri-Jeanne E. Swadi, Alisha Hancu, Maria C. Tolar, Joe G. Kirienko, Natalia V. |
author_facet | Tjahjono, Elissa Pei, Jingqi Revtovich, Alexey V. Liu, Terri-Jeanne E. Swadi, Alisha Hancu, Maria C. Tolar, Joe G. Kirienko, Natalia V. |
author_sort | Tjahjono, Elissa |
collection | PubMed |
description | Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover. |
format | Online Article Text |
id | pubmed-8421394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84213942021-09-09 Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases Tjahjono, Elissa Pei, Jingqi Revtovich, Alexey V. Liu, Terri-Jeanne E. Swadi, Alisha Hancu, Maria C. Tolar, Joe G. Kirienko, Natalia V. Sci Rep Article Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover. Nature Publishing Group UK 2021-09-06 /pmc/articles/PMC8421394/ /pubmed/34489512 http://dx.doi.org/10.1038/s41598-021-97148-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tjahjono, Elissa Pei, Jingqi Revtovich, Alexey V. Liu, Terri-Jeanne E. Swadi, Alisha Hancu, Maria C. Tolar, Joe G. Kirienko, Natalia V. Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title | Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title_full | Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title_fullStr | Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title_full_unstemmed | Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title_short | Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
title_sort | mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421394/ https://www.ncbi.nlm.nih.gov/pubmed/34489512 http://dx.doi.org/10.1038/s41598-021-97148-z |
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