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  Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

Lorenz, C., Lesimple, P., Bukowiecki, R., Zink, A., Inak, G., Mlody, B., et al. (2017). Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders. Cell Stem Cell, 20(5): e9, pp. 659-674. doi:10.1016/j.stem.2016.12.013.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-5A75-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-D419-9
Genre: Journal Article

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 Creators:
Lorenz, Carmen, Author
Lesimple, Pierre, Author
Bukowiecki, Raul, Author
Zink, Annika, Author
Inak, Gizem , Author
Mlody, Barbara, Author
Singh, Manvendra , Author
Semtner, Marcus , Author
Mah, Nancy, Author
Auré, Karine, Author
Leong, Megan , Author
Zabiegalov, Oleksandr , Author
Lyras, Ekaterini-Maria , Author
Pfiffer, Vanessa , Author
Fauler, Beatrix1, Author              
Eichhorst, Jenny, Author
Wiesner, Burkhard , Author
Huebner, Norbert, Author
Priller, Josef, Author
Mielke, Thorsten1, Author              
Meierhofer, David2, Author              Izsvák, Zsuzsanna, AuthorMeier, Jochen C. , AuthorBouillaud, Frédéric , AuthorAdjaye, James , AuthorSchuelke, Markus, AuthorWanker, Erich E., AuthorLombès, Anne, AuthorPrigione, Alessandro , Author more..
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: NPCs; calcium; drug discovery; iPSCs; induced pluripotent stem cells; metabolism; mitochondria; mitochondrial disorders; mtDNA mutations; neural progenitors
 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.

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Language(s): eng - English
 Dates: 2017-01-262017-05-04
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.stem.2016.12.013
 Degree: -

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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Elsevier B. V.
Pages: - Volume / Issue: 20 (5) Sequence Number: e9 Start / End Page: 659 - 674 Identifier: -