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

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 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 () and Alessandro Prigione ()
Additional contact information
Gizem Inak: Max Delbrück Center for Molecular Medicine (MDC)
Agnieszka Rybak-Wolf: Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine (MDC)
Pawel Lisowski: Max Delbrück Center for Molecular Medicine (MDC)
Tancredi M. Pentimalli: Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine (MDC)
René Jüttner: Max Delbrück Center for Molecular Medicine (MDC)
Petar Glažar: Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine (MDC)
Karan Uppal: Emory University
Emanuela Bottani: University of Verona
Dario Brunetti: University of Milan
Christopher Secker: Max Delbrück Center for Molecular Medicine (MDC)
Annika Zink: Max Delbrück Center for Molecular Medicine (MDC)
David Meierhofer: Max Planck Institute for Molecular Genetics
Marie-Thérèse Henke: Max Delbrück Center for Molecular Medicine (MDC)
Monishita Dey: Max Delbrück Center for Molecular Medicine (MDC)
Ummi Ciptasari: Max Delbrück Center for Molecular Medicine (MDC)
Barbara Mlody: Max Delbrück Center for Molecular Medicine (MDC)
Tobias Hahn: Max Delbrück Center for Molecular Medicine (MDC)
Maria Berruezo-Llacuna: Max Delbrück Center for Molecular Medicine (MDC)
Nikos Karaiskos: Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine (MDC)
Michela Virgilio: Max Delbrück Center for Molecular Medicine (MDC)
Johannes A. Mayr: University Children’s Hospital, Paracelsus Medical University (PMU)
Saskia B. Wortmann: University Children’s Hospital, Paracelsus Medical University (PMU)
Josef Priller: Charité - Universitätsmedizin Berlin, Department of Neuropsychiatry
Michael Gotthardt: Max Delbrück Center for Molecular Medicine (MDC)
Dean P. Jones: Emory University
Ertan Mayatepek: Heinrich Heine University
Werner Stenzel: Charité – Universitätsmedizin, Department of Neuropathology
Sebastian Diecke: Max Delbrück Center for Molecular Medicine (MDC)
Ralf Kühn: Max Delbrück Center for Molecular Medicine (MDC)
Erich E. Wanker: Max Delbrück Center for Molecular Medicine (MDC)
Nikolaus Rajewsky: Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine (MDC)
Markus Schuelke: Charité - Universitätsmedizin Berlin, Department of Neuropediatrics
Alessandro Prigione: Max Delbrück Center for Molecular Medicine (MDC)

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22117-z

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