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

Authors
  • Lorenz, Carmen
  • Lesimple, Pierre
  • Bukowiecki, Raul
  • Zink, Annika
  • Inak, Gizem
  • Mlody, Barbara
  • Singh, Manvendra
  • Semtner, Marcus
  • Mah, Nancy
  • Auré, Karine
  • Leong, Megan
  • Zabiegalov, Oleksandr
  • Lyras, Ekaterini-Maria
  • Pfiffer, Vanessa
  • Fauler, Beatrix
  • Eichhorst, Jenny
  • Wiesner, Burkhard
  • Huebner, Norbert
  • Priller, Josef
  • Mielke, Thorsten
  • And 9 more
Type
Published Article
Journal
Cell Stem Cell
Publisher
Elsevier
Publication Date
Jul 15, 2017
Volume
20
Issue
5
Pages
659–674000000000
Identifiers
DOI: 10.1016/j.stem.2016.12.013
PMID: 28132834
Source
USPC - SET - SVS
License
White

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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