Energy Metabolism and Mitochondrial Superoxide Anion Production in Pre-symptomatic Striatal Neurons Derived from Human-Induced Pluripotent Stem Cells Expressing Mutant Huntingtin
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.
KeywordsHuntington’s disease Mitochondria Neurons Respiration Glycolysis Reactive oxygen species
Induced pluripotent stem cells
Human medium spiny neurons
Reactive oxygen species
Brain-derived neurotrophic factor
Glia-derived neurotrophic factor
Oxygen consumption rates
Extracellular acidification rates
Tetramethylrhodamine, methyl ester
Carbonyl cyanide p-trifluoromethoxyphenylhydrazone
Human embryonic stem cells
We are very thankful to Dr. George Daley (Harvard University, Cambridge, MA) and Dr. David Gamm (University of Wisconsin, Madison, WI) for providing human undifferentiated induced pluripotent stem cells.
This study was supported by National Institutes of Health grant R01 NS098772 and in part by a grant from Indiana Traumatic Spinal Cord & Brain Injury Research Fund to N.B.
Compliance with Ethical Standards
Conflict of Interests
The authors declare that they have no conflict of interests.
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