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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.


Gizem Inak, Agnieszka Rybak-Wolf, Pawel Lisowski, Tancredi M Pentimalli, 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-Llacuna, 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. Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. Nature communications. 2021 Mar 26;12(1):1929

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PMID: 33771987

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