Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease

James Hamilton, Jessica J. Pellman, Tatiana Brustovetsky, Robert Harris, Nikolai Broustovetski

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Abstract

Alterations in oxidativemetabolism and defects inmitochondrial Ca2+handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory.We investigated the effect of humanmHtt fragments on oxidativemetabolismand Ca2+handling in isolated brainmitochondria and cultured striatal neurons fromthe R6/2mouse model of HD. Non-synaptic and synapticmitochondria isolated fromthe brains of R6/2mice had similar respiratory rates and Ca2+uptake capacity compared withmitochondria from wild-type (WT)mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived fromR6/2mice compared with neurons fromWT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons fromR6/2 andWTmice was similar. Mitochondrial Ca2+accumulation was also evaluated in cultured striatal neurons fromR6/2 andWT animals. Our data obtained with striatal neurons derived fromR6/2 andWTmice showthat both glutamate-induced increases in cytosolic Ca2+and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca2+were similar betweenWT and R6/2, suggesting thatmitochondria in neurons derived from both types of animals accumulated comparable amounts of Ca2+. Overall, our data argue against respiratory deficiency and impaired Ca2+handling induced by humanmHtt fragments in both isolated brainmitochondria and cultured striatal neurons fromtransgenic R6/2mice.

Original languageEnglish (US)
Pages (from-to)2762-2775
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number13
DOIs
StatePublished - 2016

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Corpus Striatum
Huntington Disease
Mitochondria
Neurons
Brain
Cell Respiration
Smegmamorpha
Handling (Psychology)
Respiratory Rate
Glutamic Acid
Adenosine Triphosphate
Pathology

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease. / Hamilton, James; Pellman, Jessica J.; Brustovetsky, Tatiana; Harris, Robert; Broustovetski, Nikolai.

In: Human Molecular Genetics, Vol. 25, No. 13, 2016, p. 2762-2775.

Research output: Contribution to journalArticle

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