Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome

• DOI: 10.1038/s41467-021-22117-z
• Publication Date: 2021-03-26T11:03:37Z
• Authors: Gizem Inak; Agnieszka Rybak-Wolf; Pawel Lisowski; Tancredi M. Penti...; René Jüttner; Petar Glažar; Karan Uppal; Emanuela Bottani; Dario Brunetti; Christopher Secker; Annika Zink; David Meierhofer; Marie-Thérèse Henke; Monishita Dey; Ummi Ciptasari; Barbara Mlody; Tobias Hahn; Maria Berruezo-Ll...; Nikos Karaiskos; Michela Di Virgilio; Johannes A. Mayr; Saskia B. Wortmann; Josef Priller; Michael Gotthardt; Dean P. Jones; Ertan Mayatepek; Werner Stenzel; Sebastian Diecke; Ralf Kühn; Erich E. Wanker; Nikolaus Rajewsky; Markus Schuelke; Alessandro Prigione
• Keywords: Organoid; Neuroepithelial cell

Abstract Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and currently incurable. The lack effective models hampers our understanding the mechanisms underlying neuronal pathology LS. Using patient-derived induced pluripotent stem cells CRISPR/Cas9 engineering, we developed human model LS caused by mutations complex IV assembly gene SURF1 . Single-cell RNA-sequencing multi-omics analysis revealed compromised morphogenesis mutant neural cultures brain organoids. defects emerged at level progenitor (NPCs), which retained glycolytic proliferative state that failed to instruct morphogenesis. NPCs carrying I NDUFS4 recapitulated defects. augmentation PGC1A induction via bezafibrate treatment supported metabolic programming NPCs, leading restored Our findings provide mechanistic insights suggest potential interventional strategies for rare disease.