m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
Summary: 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 mode...
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Elsevier
2020-04-01
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Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720304381 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity Cell Reports |
author_facet |
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 |
author_sort |
Teun M. Klein Gunnewiek |
title |
m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity |
title_short |
m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity |
title_full |
m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity |
title_fullStr |
m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity |
title_full_unstemmed |
m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity |
title_sort |
m.3243a > g-induced mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2020-04-01 |
description |
Summary: 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. Keywords: MELAS, mitochondrial disease, mitochondria, neuron, induced pluripotent stem cells, network activity, neurodevelopment, micro-electrode array, m.3243A > G |
url |
http://www.sciencedirect.com/science/article/pii/S2211124720304381 |
work_keys_str_mv |
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doaj-db72172982f844a182028f325789bcff2020-11-25T02:07:50ZengElsevierCell Reports2211-12472020-04-01313m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and SynchronicityTeun M. Klein Gunnewiek0Eline J.H. Van Hugte1Monica Frega2Gemma Solé Guardia3Katharina Foreman4Daan Panneman5Britt Mossink6Katrin Linda7Jason M. Keller8Dirk Schubert9David Cassiman10Richard Rodenburg11Noemi Vidal Folch12Devin Oglesbee13Ester Perales-Clemente14Timothy J. Nelson15Eva Morava16Nael Nadif Kasri17Tamas Kozicz18Department of Anatomy, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Clinical Neurophysiology, University of Twente, 7522 NB Enschede, the NetherlandsDepartment of Anatomy, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the NetherlandsDepartment of Hepatology, UZ Leuven, 3000 Leuven, BelgiumRadboud Center for Mitochondrial Disorders, Radboudumc, 6500 HB Nijmegen, the NetherlandsDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADivision of General Internal Medicine, Division of Pediatric Cardiology, Departments of Medicine, Molecular Pharmacology, and Experimental Therapeutics, Mayo Clinic Center for Regenerative Medicine, Rochester, MN 55905, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USADepartment of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Corresponding authorDepartment of Anatomy, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB Nijmegen, the Netherlands; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, 55905 Rochester, MN, USA; Corresponding authorSummary: 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. Keywords: MELAS, mitochondrial disease, mitochondria, neuron, induced pluripotent stem cells, network activity, neurodevelopment, micro-electrode array, m.3243A > Ghttp://www.sciencedirect.com/science/article/pii/S2211124720304381 |