Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.246140v1?rss=1 Authors: Klein Gunnewiek, T. M., Verboven, A. H. A., Hogeweg, M., Schoenmaker, C., Renkema, H., Beyrath, J., Smeitink, J., De Vries, B. B. A., Kozicz, T., 't Hoen, P. A. C., Nadif Kasri, N. M. Abstract: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is often caused by an adenine to guanine mutation at m.3243 (m.3243A>G) of the MT-TL1 gene (tRNAleu(UUR)). To understand how this mutation 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 mutation. We combined micro-electrode array (MEA) measurements with RNA sequencing (MEA-seq) and found that the m.3243A>G mutation affects 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 II stage drug sonlicromanol (KH176) improved neuronal network activity in a patient-specific manner when treatment is initiated early in development. This was intricately linked with changes in the neural transcriptome. Overall, MEA-seq is a powerful approach to identify mechanisms underlying the m.3243A>G mutation and to study the effect of pharmacological interventions in iPSC-derived neurons. Copy rights belong to original authors. Visit the link for more info