Ca<sup>2+</sup> handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington's disease

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

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

We investigated Ca<sup>2+</sup> handling in isolated brain synaptic and non-synaptic mitochondria and in cultured striatal neurons from the YAC128 mouse model of Huntington's disease. Both synaptic and non-synaptic mitochondria from 2- and 12-month-old YAC128 mice had larger Ca<sup>2+</sup> uptake capacity than mitochondria from YAC18 and wild-type FVB/NJ mice. Synaptic mitochondria from 12-month-old YAC128 mice had further augmented Ca<sup>2+</sup> capacity compared with mitochondria from 2-month-old YAC128 mice and age-matched YAC18 and FVB/NJ mice. This increase in Ca<sup>2+</sup> uptake capacity correlated with an increase in the amount of mutant huntingtin protein (mHtt) associated with mitochondria from 12-month-old YAC128 mice. We speculate that this may happen because of mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca<sup>2+</sup>-induced damage. In experiments with striatal neurons from YAC128 and FVB/NJ mice, brief exposure to 25 or 100 μM glutamate produced transient elevations in cytosolic Ca<sup>2+</sup> followed by recovery to near resting levels. Following recovery of cytosolic Ca<sup>2+</sup>, mitochondrial depolarization with FCCP produced comparable elevations in cytosolic Ca<sup>2+</sup>, suggesting similar Ca<sup>2+</sup> release and, consequently, Ca<sup>2+</sup> loads in neuronal mitochondria from YAC128 and FVB/NJ mice. Together, our data argue against a detrimental effect of mHtt on Ca<sup>2+</sup> handling in brain mitochondria of YAC128 mice. We demonstrate that mutant huntingtin (mHtt) binds to brain synaptic and nonsynaptic mitochondria and the amount of mitochondria-bound mHtt correlates with increased mitochondrial Ca<sup>2+</sup> uptake capacity. We propose that this may happen due to mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca<sup>2+</sup>-induced damage. We demonstrate that mutant huntingtin (mHtt) binds to brain synaptic and nonsynaptic mitochondria and the amount of mitochondria-bound mHtt correlates with increased mitochondrial Ca<sup>2+</sup> uptake capacity. We propose that this may happen due to mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca<sup>2+</sup>-induced damage.

Original languageEnglish
Article number13165
Pages (from-to)652-667
Number of pages16
JournalJournal of Neurochemistry
Volume134
Issue number4
DOIs
StatePublished - Aug 1 2015

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Mitochondria
Huntington Disease
Neurons
Brain
Mutant Proteins
Nonesterified Fatty Acids
Proteins
Corpus Striatum
Handling (Psychology)
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Recovery
Depolarization
Huntingtin Protein

Keywords

  • calcium
  • Huntington's disease
  • mitochondria
  • neuron
  • permeability transition pore
  • striatum

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Ca<sup>2+</sup> handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington's disease. / Pellman, Jessica J.; Hamilton, James; Brustovetsky, Tatiana; Broustovetski, Nikolai.

In: Journal of Neurochemistry, Vol. 134, No. 4, 13165, 01.08.2015, p. 652-667.

Research output: Contribution to journalArticle

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N2 - We investigated Ca2+ handling in isolated brain synaptic and non-synaptic mitochondria and in cultured striatal neurons from the YAC128 mouse model of Huntington's disease. Both synaptic and non-synaptic mitochondria from 2- and 12-month-old YAC128 mice had larger Ca2+ uptake capacity than mitochondria from YAC18 and wild-type FVB/NJ mice. Synaptic mitochondria from 12-month-old YAC128 mice had further augmented Ca2+ capacity compared with mitochondria from 2-month-old YAC128 mice and age-matched YAC18 and FVB/NJ mice. This increase in Ca2+ uptake capacity correlated with an increase in the amount of mutant huntingtin protein (mHtt) associated with mitochondria from 12-month-old YAC128 mice. We speculate that this may happen because of mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca2+-induced damage. In experiments with striatal neurons from YAC128 and FVB/NJ mice, brief exposure to 25 or 100 μM glutamate produced transient elevations in cytosolic Ca2+ followed by recovery to near resting levels. Following recovery of cytosolic Ca2+, mitochondrial depolarization with FCCP produced comparable elevations in cytosolic Ca2+, suggesting similar Ca2+ release and, consequently, Ca2+ loads in neuronal mitochondria from YAC128 and FVB/NJ mice. Together, our data argue against a detrimental effect of mHtt on Ca2+ handling in brain mitochondria of YAC128 mice. We demonstrate that mutant huntingtin (mHtt) binds to brain synaptic and nonsynaptic mitochondria and the amount of mitochondria-bound mHtt correlates with increased mitochondrial Ca2+ uptake capacity. We propose that this may happen due to mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca2+-induced damage. We demonstrate that mutant huntingtin (mHtt) binds to brain synaptic and nonsynaptic mitochondria and the amount of mitochondria-bound mHtt correlates with increased mitochondrial Ca2+ uptake capacity. We propose that this may happen due to mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca2+-induced damage.

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