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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...

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Autores principales: Tjahjono, Elissa, Pei, Jingqi, Revtovich, Alexey V., Liu, Terri-Jeanne E., Swadi, Alisha, Hancu, Maria C., Tolar, Joe G., Kirienko, Natalia V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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