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

Carmen Lorenz, Pierre Lesimple, Raul Bukowiecki, Annika Zink, Gizem Inak, Barbara Mlody, Manvendra Singh, Marcus Semtner, Nancy Mah, Karine Auré, Megan Leong, Oleksandr Zabiegalov, Ekaterini Maria Lyras, Vanessa Pfiffer, Beatrix Fauler, Jenny Eichhorst, Burkhard Wiesner, Norbert Huebner, Josef Priller, Thorsten MielkeDavid Meierhofer, Zsuzsanna Izsvák, Jochen C. Meier, Frédéric Bouillaud, James Adjaye, Markus Schuelke, Erich E. Wanker, Anne Lombès, Alessandro Prigione

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


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.

Original languageEnglish
Pages (from-to)659-674.e9
JournalCell Stem Cell
Issue number5
StatePublished - 4 May 2017
Externally publishedYes


  • NPCs
  • calcium
  • drug discovery
  • iPSCs
  • induced pluripotent stem cells
  • metabolism
  • mitochondria
  • mitochondrial disorders
  • mtDNA mutations
  • neural progenitors


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