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Human iPSC-derived neural progenitors are an effective drug discovery model for neurological mtDNA disorders

Official URL:https://doi.org/10.1016/j.stem.2016.12.013
PubMed:View item in PubMed
Creators Name:Lorenz, C. and Lesimple, P. and Bukowiecki, R. and Zink, A. and Inak, G. and Mlody, B. and Singh, M. and Semtner, M. and Mah, N. and Aure, K. and Leong, M. and Zabiegalov, O. and Lyras, E.M. and Pfiffer, V. and Fauler, B. and Eichhorst, J. and Wiesner, B. and Huebner, N. and Priller, J. and Mielke, T. and Meierhofer, D. and Izsvak, Z. and Meier, J.C. and Bouillaud, F. and Adjaye, J. and Schuelke, M. and Wanker, E.E. and Lombes, A. and Prigione, A.
Journal Title:Cell Stem Cell
Journal Abbreviation:Cell Stem Cell
Volume:20
Number:5
Page Range:659-674.e9
Date:4 May 2017
Keywords:Neural Progenitors, NPCs, Induced Pluripotent Stem Cells, iPSCs, Mitochondria, Metabolism, Calcium, Mitochondrial Disorders, mtDNA Mutations, Drug Discovery
Abstract:Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.
ISSN:1934-5909
Publisher:Cell Press / Elsevier (U.S.A.)
Item Type:Article

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