1. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders
- Author
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Josef Priller, Manvendra K. Singh, Nancy Mah, Carmen Lorenz, Pierre Lesimple, Anne Lombès, Gizem Inak, Zsuzsanna Izsvák, Ekaterini-Maria Lyras, Erich E. Wanker, Marcus Semtner, James Adjaye, Raul Bukowiecki, Megan Leong, Barbara Mlody, Karine Auré, Norbert Huebner, Jochen C. Meier, David Meierhofer, Thorsten Mielke, Jenny Eichhorst, Annika Zink, Alessandro Prigione, Markus Schuelke, Frédéric Bouillaud, Vanessa Pfiffer, Beatrix Fauler, Burkhard Wiesner, and Oleksandr Zabiegalov
- Subjects
0301 basic medicine ,Mitochondrial DNA ,Mitochondrial disease ,methods [Drug Discovery] ,metabolism [Neural Stem Cells] ,Mitochondrion ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,ddc:570 ,Genetics ,medicine ,Humans ,metabolism [Calcium] ,cytology [Neural Stem Cells] ,Progenitor cell ,Induced pluripotent stem cell ,Mutation ,cytology [Induced Pluripotent Stem Cells] ,Cell Biology ,medicine.disease ,genetics [DNA, Mitochondrial] ,Phenotype ,Molecular biology ,Neural stem cell ,Cell biology ,metabolism [Induced Pluripotent Stem Cells] ,030104 developmental biology ,Cardiovascular and Metabolic Diseases ,Molecular Medicine ,Calcium ,genetics [Mitochondria] ,Function and Dysfunction of the Nervous System ,030217 neurology & neurosurgery - 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.
- Published
- 2017
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