title: Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.
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.
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Berlin Institute of Health (BIH), Berlin 10117, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lorenz
authors.affiliation: INSERM U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Paris 75006, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lesimple
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Raul
authors.initials: R
authors.lastname: Bukowiecki
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Charité - Universitätsmedizin, Berlin 10117, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Zink
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Gizem
authors.initials: G
authors.lastname: Inak
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mlody
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Manvendra
authors.initials: M
authors.lastname: Singh
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Semtner
authors.affiliation: Charité - Universitätsmedizin, Berlin 10117, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mah
authors.affiliation: INSERM U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Paris 75006, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Auré
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Megan
authors.initials: M
authors.lastname: Leong
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Zabiegalov
authors.affiliation: Charité - Universitätsmedizin, Berlin 10117, Germany.
authors.forename: Ekaterini-Maria
authors.initials: EM
authors.lastname: Lyras
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pfiffer
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Fauler
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie (FMP), Berlin 13125, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Eichhorst
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie (FMP), Berlin 13125, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Wiesner
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Huebner
authors.affiliation: Berlin Institute of Health (BIH), Berlin 10117, Germany; Charité - Universitätsmedizin, Berlin 10117, Germany; DZNE, Berlin 10117, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mielke
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Izsvák
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Zoological Institute, Braunschweig 38106, Germany.
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Meier
authors.affiliation: INSERM U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Paris 75006, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, Düsseldorf 40225, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
authors.affiliation: Charité - Universitätsmedizin, Berlin 10117, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: INSERM U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Paris 75006, France. Electronic address: anne.lombes@inserm.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Lombès
authors.affiliation: Max Delbrueck Center for Molecular Medicine (MDC), 13125 Berlin, Germany. Electronic address: alessandro.prigione@mdc-berlin.de.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics*; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D002118:Calcium
keywords: NPCs; calcium; drug discovery; iPSCs; induced pluripotent stem cells; metabolism; mitochondria; mitochondrial disorders; mtDNA mutations; neural progenitors