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 BrustovetskyEmail author


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.


Huntington’s disease Mitochondria Neurons Respiration Glycolysis Reactive oxygen species 



Mutant huntingtin


Wild-type huntingtin


Induced pluripotent stem cells


Human medium spiny neurons


Huntington’s disease


Reactive oxygen species


Brain-derived neurotrophic factor


Glia-derived neurotrophic factor




Oxygen consumption rates


Extracellular acidification rates


Tetramethylrhodamine, methyl ester


Tyrosine hydroxylase


Action potentials




Carbonyl cyanide p-trifluoromethoxyphenylhydrazone


Human embryonic stem cells




Antimycin A



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.

Funding Information

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.

Supplementary material

12035_2019_1734_MOESM1_ESM.docx (12.4 mb)
ESM 1 (DOCX 12674 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, School of MedicineIndiana UniversityIndianapolisUSA
  2. 2.Program in Medical Neuroscience, School of MedicineIndiana UniversityIndianapolisUSA
  3. 3.Paul and Carole Stark Neurosciences Research Institute, School of MedicineIndiana UniversityIndianapolisUSA
  4. 4.Department of Biology, School of ScienceIUPUIIndianapolisUSA
  5. 5.Indiana University School of MedicineIndianapolisUSA

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