Ca(2+) handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington's disease.
Ca(2+) handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington's disease.
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DOI：
10.1111/jnc.13165
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发表时间：
2015-08
影响因子：
4.7
通讯作者：
Brustovetsky N
中科院分区：
文献类型：
--
作者：
Pellman JJ;Hamilton J;Brustovetsky T;Brustovetsky N
我们研究了钙处理在分离的脑突触和非突触线粒体和培养的纹状体神经元的YAC 128小鼠模型的亨廷顿病（HD）。来自2月龄和12月龄YAC 128小鼠的突触和非突触线粒体比来自YAC 18和野生型FVB/NJ小鼠的线粒体具有更大的Ca 2+摄取能力。与来自2个月大的YAC 128小鼠和年龄匹配的YAC 18和FVB/NJ小鼠的线粒体相比，来自12个月大的YAC 128小鼠的突触线粒体具有进一步增强的Ca 2+容量。这种Ca 2+摄取能力的增加与12月龄YAC 128小鼠线粒体相关的突变亨廷顿蛋白（mHtt）量的增加相关。我们推测，这可能是由于mHtt介导的游离脂肪酸的螯合，从而增加线粒体对Ca 2+诱导的损伤的抵抗力。在对YAC 128和FVB/NJ小鼠纹状体神经元的实验中，短暂暴露于25或100μM谷氨酸会导致胞质Ca 2+一过性升高，随后恢复至接近静息水平。恢复胞质Ca 2+后，FCCP的线粒体去极化产生了相当的胞质Ca 2+升高，表明YAC 128和FVB/NJ小鼠神经元线粒体中的Ca 2+释放和Ca 2+负荷相似。总之，我们的数据反对mHtt对YAC 128小鼠脑线粒体中Ca 2+处理的有害影响。
We investigated Ca2+ handling in isolated brain synaptic and nonsynaptic mitochondria and in cultured striatal neurons from the YAC128 mouse model of Huntington’s disease (HD). Both synaptic and nonsynaptic 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 due to 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 100μM 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.