RRC ID 76074
Author Tjahjono E, Pei J, Revtovich AV, Liu TE, Swadi A, Hancu MC, Tolar JG, Kirienko NV.
Title Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases.
Journal Sci Rep
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.
Volume 11(1)
Pages 17733
Published 2021-9-6
DOI 10.1038/s41598-021-97148-z
PII 10.1038/s41598-021-97148-z
PMID 34489512
PMC PMC8421394
MeSH Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Mitochondria / drug effects Mitochondria / genetics Mitochondria / metabolism* Mitophagy / drug effects Mitophagy / physiology Neurodegenerative Diseases / genetics Neurodegenerative Diseases / metabolism* Neurons / drug effects Neurons / metabolism Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Proteostasis / drug effects Proteostasis / physiology* Sodium Selenite / pharmacology Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism
Resource
C.elegans tm1779