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Hum Mol Genet. 2016 Jul 1;25(13):2762-2775. Epub 2016 Apr 30.

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

Author information

1
Department of Pharmacology and Toxicology.
2
Department of Biochemistry and Molecular Biology.
3
Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
4
Department of Pharmacology and Toxicology nbrous@iu.edu.
5
Stark Neuroscience Research InstituteIndiana University School of Medicine, Indianapolis, IN, USA.

Abstract

Alterations in oxidative metabolism and defects in mitochondrial Ca2+ handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca2+ handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca2+ uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived from R6/2 mice compared with neurons from WT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons from R6/2 and WT mice was similar. Mitochondrial Ca2+ accumulation was also evaluated in cultured striatal neurons from R6/2 and WT animals. Our data obtained with striatal neurons derived from R6/2 and WT mice show that both glutamate-induced increases in cytosolic Ca2+ and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca2+ were similar between WT and R6/2, suggesting that mitochondria 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 human mHtt fragments in both isolated brain mitochondria and cultured striatal neurons from transgenic R6/2 mice.

PMID:
27131346
PMCID:
PMC5181640
DOI:
10.1093/hmg/ddw133
[Indexed for MEDLINE]
Free PMC Article

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