Abstract
Mitochondrial deregulation has gained increasing support as a pathological mechanism in Huntington’s disease (HD), a genetic-based neurodegenerative disorder caused by CAG expansion in the HTT gene. In this study, we thoroughly investigated mitochondrial-based mechanisms in HD patient-derived iPSC (HD-iPSC) and differentiated neural stem cells (NSC) versus control cells, as well as in cells subjected to CRISPR/Cas9-CAG repeat deletion. We analyzed mitochondrial morphology, function and biogenesis, linked to exosomal release of mitochondrial components, glycolytic flux, ATP generation and cellular redox status. Mitochondria in HD cells exhibited round shape and fragmented morphology. Functionally, HD-iPSC and HD-NSC displayed lower mitochondrial respiration, exosomal release of cytochrome c, decreased ATP/ADP, reduced PGC-1α and complex III subunit expression and activity, and were highly dependent on glycolysis, supported by pyruvate dehydrogenase (PDH) inactivation. HD-iPSC and HD-NSC mitochondria showed ATP synthase reversal and increased calcium retention. Enhanced mitochondrial reactive oxygen species (ROS) were also observed in HD-iPSC and HD-NSC, along with decreased UCP2 mRNA levels. CRISPR/Cas9-CAG repeat deletion in HD-iPSC and derived HD-NSC ameliorated mitochondrial phenotypes. Data attests for intricate metabolic and mitochondrial dysfunction linked to transcriptional deregulation as early events in HD pathogenesis, which are alleviated following CAG deletion.
Highlights
Huntington’s disease is caused by CAG repeat expansion in the HTT gene, encoding for mutant huntingtin (mHTT) (No authors listed, 1993), with expanded polyglutamine stretch at the N-terminal
The decreased bioenergetic capacity in huntington’s disease (HD)-induced pluripotent stem cells (iPSC)-derived striatal neurons was attributed to defects in glycolysis rather than mitochondrial defects, as it was reverted with pyruvate (Hd iPSC Consortium, 2020)
Mitochondrial round shape was predominant in iPSC and neural stem cells (NSC), the percentage of mitochondria with rod shape was significantly reduced in HD-iPSC and HD neural stem cells (HD-NSC), when compared to Ctr cells (Figures 2A,C)
Summary
Huntington’s disease is caused by CAG repeat expansion in the HTT gene, encoding for mHTT (No authors listed, 1993), with expanded polyglutamine (polyQ) stretch at the N-terminal. Striatal-like MSN displayed altered electrophysiology, metabolism, cell adhesion and cell death for lines with long CAG, up to 180 repeats (Hd iPSC Consortium, 2012). The decreased bioenergetic capacity in HD-iPSC-derived striatal neurons was attributed to defects in glycolysis rather than mitochondrial defects, as it was reverted with pyruvate (Hd iPSC Consortium, 2020). Oxidative stressrelated proteins, such as SOD1 (superoxide dismutase 1) and peroxiredoxin were shown to be affected in HD-iPSC (Chae et al, 2012; Lu et al, 2014; Szlachcic et al, 2015)
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