m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity

Teun M. Klein Gunnewiek, Eline J.H. Van Hugte, Monica Frega, Gemma Solé Guardia, Katharina Foreman, Daan Panneman, Britt Mossink, Katrin Linda, Jason M. Keller, Dirk Schubert, David Cassiman, Richard Rodenburg, Noemi Vidal Folch, Devin Oglesbee, Ester Perales-Clemente, Timothy J. Nelson, Eva Morava, Nael Nadif Kasri, Tamas Kozicz

Research output: Contribution to journalArticle

Abstract

Epilepsy, intellectual and cortical sensory deficits, and psychiatric manifestations are the most frequent manifestations of mitochondrial diseases. How mitochondrial dysfunction affects neural structure and function remains elusive, mostly because of a lack of proper in vitro neuronal model systems with mitochondrial dysfunction. Leveraging induced pluripotent stem cell technology, we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background from patients with the common pathogenic m.3243A > G variant of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). iNeurons with high heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity, and fewer excitatory synapses. Micro-electrode array recordings of neuronal networks displayed reduced network activity and decreased synchronous network bursting. Impaired neuronal energy metabolism and compromised structural and functional integrity of neurons and neural networks could be the primary drivers of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease. Using human-inducible-pluripotent-stem-cell-derived neurons with high levels of m.3243A > G heteroplasmy, Klein Gunnewiek et al. show neuron-specific mitochondrial dysfunction as well as structural and functional impairments ranging from reduced dendritic complexity and fewer synapses and mitochondria to reduced neuronal activity and impaired network synchronicity.

Original languageEnglish (US)
Article number107538
JournalCell reports
Volume31
Issue number3
DOIs
StatePublished - Apr 21 2020

Keywords

  • MELAS
  • induced pluripotent stem cells
  • m.3243A > G
  • micro-electrode array
  • mitochondria
  • mitochondrial disease
  • network activity
  • neurodevelopment
  • neuron

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Klein Gunnewiek, T. M., Van Hugte, E. J. H., Frega, M., Guardia, G. S., Foreman, K., Panneman, D., Mossink, B., Linda, K., Keller, J. M., Schubert, D., Cassiman, D., Rodenburg, R., Vidal Folch, N., Oglesbee, D., Perales-Clemente, E., Nelson, T. J., Morava, E., Nadif Kasri, N., & Kozicz, T. (2020). m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity. Cell reports, 31(3), [107538]. https://doi.org/10.1016/j.celrep.2020.107538