| Literature DB >> 33771987 |
Gizem Inak1,2, Agnieszka Rybak-Wolf3, Pawel Lisowski1,2,4, Tancredi M Pentimalli3, René Jüttner1, Petar Glažar3, Karan Uppal5, Emanuela Bottani6, Dario Brunetti7,8, Christopher Secker1,9, Annika Zink1,2,10, David Meierhofer11, Marie-Thérèse Henke1,12, Monishita Dey1, Ummi Ciptasari1, Barbara Mlody1, Tobias Hahn1, Maria Berruezo-Llacuna1, Nikos Karaiskos3, Michela Di Virgilio1, Johannes A Mayr13, Saskia B Wortmann13,14, Josef Priller10,15,16, Michael Gotthardt1, Dean P Jones5, Ertan Mayatepek2, Werner Stenzel17, Sebastian Diecke1,18, Ralf Kühn1, Erich E Wanker1, Nikolaus Rajewsky19, Markus Schuelke20,21, Alessandro Prigione22,23.
Abstract
Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS caused by mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. SURF1 gene augmentation and PGC1A induction via bezafibrate treatment supported the metabolic programming of LS NPCs, leading to restored neuronal morphogenesis. Our findings provide mechanistic insights and suggest potential interventional strategies for a rare mitochondrial disease.Entities:
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Year: 2021 PMID： 33771987 DOI： 10.1038/s41467-021-22117-z
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919