Screen for Small Molecules Increasing the Mitochondrial Membrane Potential
| Autor: | Noe Salazar, Julien P. Fey, Christine R. Montague, Bradley M. Hover, Aileen Fitzmaurice |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Proteomics
G6PC Mitochondrion Biology Biochemistry Analytical Chemistry Small Molecule Libraries chemistry.chemical_compound Adenosine Triphosphate Yeasts Drug Discovery Animals Humans Respiratory function Membrane Potential Mitochondrial Membrane potential Drug discovery Gene Expression Profiling Hep G2 Cells Yeast High-Throughput Screening Assays Mitochondria Cell biology chemistry Molecular Medicine Adenosine triphosphate Function (biology) Biotechnology |
| Zdroj: | SLAS Discovery. 19:387-398 |
| ISSN: | 2472-5552 |
| DOI: | 10.1177/1087057113495295 |
| Popis: | The identification of small molecules that positively modulate the mitochondrial respiratory function has broad applications in fundamental research, therapeutic target validation, and drug discovery. We present an approach in which primary screens for mitochondrial function in yeast are used to efficiently identify a subset of high-value compounds that can in turn be rapidly tested against a broad range of mammalian cell lines. The ability of the yeast assay to successfully identify in a high-throughput format hit compounds that increase the mitochondrial membrane potential and adenosine triphosphate (ATP) levels by as little as 15% was demonstrated. In this study, 14 hits were identified from a collection of 13,680 compounds. Secondary testing with myotubes, fibroblasts, and PC-12 and HepG2 cells identified two compounds increasing ATP levels in hepatocytes and two other compounds increasing ATP in fibroblasts. The effect on hepatocytes was further studied using genomic and mitochondrial proteomic tools to characterize the changes induced by the two compounds. Changes in the accumulation of a series of factors involved in early gene response or apoptosis or linked to metabolic functions (i.e., β-Klotho, RORα, PGC-1α, G6PC, IGFBP1, FTL) were discovered. |
| Databáze: | OpenAIRE |
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