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Ca 2+ handling in isolated brain mitochondria and cultured neurons derived from the YAC 128 mouse model of Huntington's disease
Author(s) -
Pellman Jessica J.,
Hamilton James,
Brustovetsky Tatiana,
Brustovetsky Nickolay
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13165
Subject(s) - mitochondrion , huntingtin , cytosol , huntingtin protein , biology , glutamate receptor , huntington's disease , mutant , microbiology and biotechnology , biochemistry , medicine , gene , receptor , enzyme , disease
Abstract We investigated Ca 2+ handling in isolated brain synaptic and non‐synaptic mitochondria and in cultured striatal neurons from the YAC 128 mouse model of Huntington's disease. Both synaptic and non‐synaptic mitochondria from 2‐ and 12‐month‐old YAC 128 mice had larger Ca 2+ uptake capacity than mitochondria from YAC 18 and wild‐type FVB / NJ mice. Synaptic mitochondria from 12‐month‐old YAC 128 mice had further augmented Ca 2+ capacity compared with mitochondria from 2‐month‐old YAC 128 mice and age‐matched YAC 18 and FVB / NJ mice. This increase in Ca 2+ uptake capacity correlated with an increase in the amount of mutant huntingtin protein (mHtt) associated with mitochondria from 12‐month‐old YAC 128 mice. We speculate that this may happen because of mHtt‐mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca 2+ ‐induced damage. In experiments with striatal neurons from YAC 128 and FVB / NJ mice, brief exposure to 25 or 100 μM glutamate produced transient elevations in cytosolic Ca 2+ followed by recovery to near resting levels. Following recovery of cytosolic Ca 2+ , mitochondrial depolarization with FCCP produced comparable elevations in cytosolic Ca 2+ , suggesting similar Ca 2+ release and, consequently, Ca 2+ loads in neuronal mitochondria from YAC 128 and FVB / NJ mice. Together, our data argue against a detrimental effect of mH tt on Ca 2+ handling in brain mitochondria of YAC 128 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 2+ uptake capacity. We propose that this may happen due to mHtt‐mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca 2+ ‐induced damage.