High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons

Boglarka H Varkuti; Ze Liu; Miklos Kepiro; Rodrigo Pacifico; Yunchao Gai; Ted Kamenecka; Ronald L Davis

doi:10.1016/j.isci.2020.100931

High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons

iScience. 2020 Mar 27;23(3):100931. doi: 10.1016/j.isci.2020.100931. Epub 2020 Feb 22.

Authors

Boglarka H Varkuti¹, Ze Liu¹, Miklos Kepiro¹, Rodrigo Pacifico¹, Yunchao Gai¹, Ted Kamenecka², Ronald L Davis³

Affiliations

¹ Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA.
² Department of Molecular Medicine, Scripps Research Institute Florida, Jupiter, FL 33458, USA.
³ Department of Neuroscience, Scripps Research Institute Florida, Jupiter, FL 33458, USA. Electronic address: rdavis@scripps.edu.

Abstract

We developed a high-throughput assay for modulators of mitochondrial function in neurons measuring inner mitochondrial membrane potential (ΔΨ_m) and ATP production. The assay was used to screen a library of small molecules, which led to the identification of structural/functional classes of mitochondrial modulators such as local anesthetics, isoflavones, COXII inhibitors, adrenergic receptor blockers, and neurotransmitter system effectors. Our results show that some of the isolated compounds promote mitochondrial health, enhance oxygen consumption rate, and protect neurons against toxic insults found in the cellular environment of Alzheimer disease. These studies offer a set of compounds that may provide efficacy in protecting the mitochondrial system in neurodegenerative disorders.

Keywords: Biochemistry; Chemistry; Molecular Neuroscience.

Grants and funding

R01 MH109957/MH/NIMH NIH HHS/United States