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Mitochondrial dysfunction and calcium dysregulation in leigh syndrome induced pluripotent stem cell derived neurons

Galera-Monge, Teresa ; Zurita-Díaz, Francisco ; Canals, Isaac LU ; Hansen, Marita Grønning LU ; Rufián-Vázquez, Laura ; Ehinger, Johannes K. LU orcid ; Elmér, Eskil LU orcid ; Martin, Miguel A. ; Garesse, Rafael and Ahlenius, Henrik LU , et al. (2020) In International Journal of Molecular Sciences 21(9).
Abstract

Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in... (More)

Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Disease modeling, IPSC, Leigh syndrome, Mitochondrial disorder, MtDNA, Neuron, NSC
in
International Journal of Molecular Sciences
volume
21
issue
9
article number
3191
publisher
MDPI AG
external identifiers
  • scopus:85084061139
  • pmid:32366037
ISSN
1661-6596
DOI
10.3390/ijms21093191
project
Development of treatment for mitochondrial disorders
language
English
LU publication?
yes
id
0adc8c7c-1129-45e0-9ef2-3cfbc8da0f59
date added to LUP
2020-05-19 07:38:24
date last changed
2024-05-29 12:55:31
@article{0adc8c7c-1129-45e0-9ef2-3cfbc8da0f59,
  abstract     = {{<p>Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G&gt;A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.</p>}},
  author       = {{Galera-Monge, Teresa and Zurita-Díaz, Francisco and Canals, Isaac and Hansen, Marita Grønning and Rufián-Vázquez, Laura and Ehinger, Johannes K. and Elmér, Eskil and Martin, Miguel A. and Garesse, Rafael and Ahlenius, Henrik and Gallardo, M. Esther}},
  issn         = {{1661-6596}},
  keywords     = {{Disease modeling; IPSC; Leigh syndrome; Mitochondrial disorder; MtDNA; Neuron; NSC}},
  language     = {{eng}},
  number       = {{9}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Mitochondrial dysfunction and calcium dysregulation in leigh syndrome induced pluripotent stem cell derived neurons}},
  url          = {{http://dx.doi.org/10.3390/ijms21093191}},
  doi          = {{10.3390/ijms21093191}},
  volume       = {{21}},
  year         = {{2020}},
}