Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons.
Animals
Astrocytes
/ metabolism
Cell Culture Techniques
Cell Differentiation
/ drug effects
Cells, Cultured
Chromans
/ pharmacology
DNA, Mitochondrial
/ genetics
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation
/ drug effects
Genetic Predisposition to Disease
Heteroplasmy
/ genetics
Humans
Induced Pluripotent Stem Cells
/ cytology
Mitochondrial Encephalomyopathies
/ diagnosis
Neurons
/ cytology
Phenotype
RNA, Transfer, Leu
/ genetics
Rats
Transcriptome
MELAS
iPSC-derived neurons
micro-electrode arrays
mitochondria
neurons
sonlicromanol
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
30
07
2020
revised:
01
07
2021
accepted:
02
07
2021
pubmed:
31
7
2021
medline:
11
3
2022
entrez:
30
7
2021
Statut:
ppublish
Résumé
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is often caused by an adenine to guanine variant at m.3243 (m.3243A>G) of the MT-TL1 gene. To understand how this pathogenic variant affects the nervous system, we differentiated human induced pluripotent stem cells (iPSCs) into excitatory neurons with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function from MELAS patients with the m.3243A>G pathogenic variant. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found reduced expression of genes involved in mitochondrial respiration and presynaptic function, as well as non-cell autonomous processes in co-cultured astrocytes. Finally, we show that the clinical phase II drug sonlicromanol can improve neuronal network activity when treatment is initiated early in development. This was intricately linked with changes in the neuronal transcriptome. Overall, we provide insight in transcriptomic changes in iPSC-derived neurons with high m.3243A>G heteroplasmy, and show the pathology is partially reversible by sonlicromanol.
Identifiants
pubmed: 34329596
pii: S2213-6711(21)00327-1
doi: 10.1016/j.stemcr.2021.07.002
pmc: PMC8452519
pii:
doi:
Substances chimiques
Chromans
0
DNA, Mitochondrial
0
MT-TL1 tRNA, human
0
RNA, Transfer, Leu
0
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
S18UL9710X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2197-2212Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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