Energy Metabolism and Mitochondrial Superoxide Anion Production in Pre-symptomatic Striatal Neurons Derived from Human-Induced Pluripotent Stem Cells Expressing Mutant Huntingtin

James Hamilton, Tatiana Brustovetsky, Akshayalakshmi Sridhar, Yanling Pan, Theodore R. Cummins, Jason S. Meyer, Nickolay Brustovetsky

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In the present study, we investigated whether mutant huntingtin (mHTT) impairs mitochondrial functions in human striatal neurons derived from induced pluripotent stem cells (iPSCs). Striatal neurons and astrocytes derived from iPSCs from unaffected individuals (Ctrl) and Huntington’s disease (HD) patients with HTT gene containing increased number of CAG repeats were used to assess the effect of mHTT on bioenergetics and mitochondrial superoxide anion production. The human neurons were thoroughly characterized and shown to express MAP2, DARPP32, GABA, synapsin, and PSD95. In human neurons and astrocytes expressing mHTT, the ratio of mHTT to wild-type huntingtin (HTT) was 1:1. The human neurons were excitable and could generate action potentials, confirming successful conversion of iPSCs into functional neurons. The neurons and astrocytes from Ctrl individuals and HD patients had similar levels of ADP and ATP and comparable respiratory and glycolytic activities. The mitochondrial mass, mitochondrial membrane potential, and superoxide anion production in human neurons appeared to be similar regardless of mHTT presence. The present results are in line with the results obtained in our previous studies with isolated brain mitochondria and cultured striatal neurons from YAC128 and R6/2 mice, in which we demonstrated that mutant huntingtin at early stages of HD pathology does not deteriorate mitochondrial functions. Overall, our results argue against bioenergetic deficits as a factor in HD pathogenesis and suggest that other detrimental processes might be more relevant to the development of HD pathology.

Original languageEnglish (US)
Pages (from-to)668-684
Number of pages17
JournalMolecular Neurobiology
Issue number2
StatePublished - Feb 1 2020



  • Glycolysis
  • Huntington’s disease
  • Mitochondria
  • Neurons
  • Reactive oxygen species
  • Respiration

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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