Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

Abstract 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 muta...

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Autores principales:	Elissa Tjahjono, Jingqi Pei, Alexey V. Revtovich, Terri-Jeanne E. Liu, Alisha Swadi, Maria C. Hancu, Joe G. Tolar, Natalia V. Kirienko
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/62602521c7314afcacbfc9edc4abc37a
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spelling	oai:doaj.org-article:62602521c7314afcacbfc9edc4abc37a2021-12-02T14:58:48ZMitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases10.1038/s41598-021-97148-z2045-2322https://doaj.org/article/62602521c7314afcacbfc9edc4abc37a2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97148-zhttps://doaj.org/toc/2045-2322Abstract 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.Elissa TjahjonoJingqi PeiAlexey V. RevtovichTerri-Jeanne E. LiuAlisha SwadiMaria C. HancuJoe G. TolarNatalia V. KirienkoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elissa Tjahjono Jingqi Pei Alexey V. Revtovich Terri-Jeanne E. Liu Alisha Swadi Maria C. Hancu Joe G. Tolar Natalia V. Kirienko Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases
description	Abstract 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	article
author	Elissa Tjahjono Jingqi Pei Alexey V. Revtovich Terri-Jeanne E. Liu Alisha Swadi Maria C. Hancu Joe G. Tolar Natalia V. Kirienko
author_facet	Elissa Tjahjono Jingqi Pei Alexey V. Revtovich Terri-Jeanne E. Liu Alisha Swadi Maria C. Hancu Joe G. Tolar Natalia V. Kirienko
author_sort	Elissa Tjahjono
title	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_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_sort	mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/62602521c7314afcacbfc9edc4abc37a
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Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

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