Mitochondrial and Redox Modifications in Huntington Disease Induced Pluripotent Stem Cells Rescued by CRISPR/Cas9 CAGs Targeting

• DOI: 10.3389/fcell.2020.576592
• Publication Date: 2020-09-22T05:07:13Z
• Authors: Carla Lopes; Yang Tang; Sandra I. Anjo; Bruno Manadas; Isabel Onofre; Luís P. de Almeida; George Q. Daley; Thorsten M. Schla...; Ana Cristina Carv...
• Keywords: Mitochondrial disease

Mitochondrial deregulation has gained increasing support as a pathological mechanism in Huntington's disease (HD), genetic-based neurodegenerative disorder caused by CAG expansion the HTT gene. In this study, we thoroughly investigated mitochondrial-based mechanisms HD patient-derived iPSC (HD-iPSC) and differentiated neural stem cells (NSC) versus control cells, well subjected to CRISPR/Cas9-CAG repeat deletion. We analyzed mitochondrial morphology, function biogenesis, linked exosomal release of components, glycolytic flux, ATP generation cellular redox status. Mitochondria exhibited round shape fragmented morphology. Functionally, HD-iPSC HD-NSC displayed lower respiration, cytochrome c, decreased ATP/ADP, reduced PGC-1α complex III subunit expression activity, were highly dependent on glycolysis, supported pyruvate dehydrogenase (PDH) inactivation. mitochondria showed synthase reversal increased calcium retention. Enhanced reactive oxygen species (ROS) also observed HD-NSC, along with UCP2 mRNA levels. deletion derived ameliorated phenotypes. Data attests for intricate metabolic dysfunction transcriptional early events pathogenesis, which are alleviated following