Sonlicromanol improves neuronal network dysfunction and transcriptome changes linked to m.3243A>G heteroplasmy in iPSC-derived neurons

Teun M. Klein Gunnewiek, Anouk H.A. Verboven, Iris Pelgrim, Mark Hogeweg, Chantal Schoenmaker, Herma Renkema, Julien Beyrath, Jan Smeitink, Bert B.A. de Vries, Peter Bram A.C.’t Hoen, Tamas Kozicz, Nael Nadif Kasri

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2197-2212
Number of pages16
JournalStem Cell Reports
Volume16
Issue number9
DOIs
StatePublished - Sep 14 2021

Keywords

  • iPSC-derived neurons
  • MELAS
  • micro-electrode arrays
  • mitochondria
  • neurons
  • sonlicromanol

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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