Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's disease
Age-dependent changes in the calcium sensitivity of striatal mitochondria in mouse models of Huntington's disease
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DOI：
10.1111/j.1471-4159.2005.03036.x
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发表时间：
2005-06-01
影响因子：
4.7
通讯作者：
Dubinsky, JM
中科院分区：
文献类型：
--
作者：
Brustovetsky, N;LaFrance, R;Dubinsky, JM
检查了敲入和转基因突变亨廷顿小鼠的纹状体和皮质线粒体对钙诱导通透性转变的敏感性，通透性转变是线粒体去极化和 ATP 损失的原因。通透性转变被认为导致亨廷顿病的细胞死亡。对具有不同长度的聚谷氨酰胺扩展（Q20、Q50、Q92、Q111）的缓慢进展的敲入小鼠模型和过度表达具有超过 110 个聚谷氨酰胺的人亨廷顿蛋白外显子 I 的快速进展的转基因 R6/2 小鼠进行了线粒体检查。正如之前在大鼠中观察到的，来自背景品系 CD1 和 C57BL/6 对照小鼠的纹状体线粒体比皮质线粒体对钙更敏感。敲入 Q92 小鼠的 5 至 12 个月和敲入 Q111 小鼠的 8 至 12 周之间，纹状体线粒体产生了抵抗力，变得与皮质线粒体对钙同样敏感，而 Q50 小鼠的纹状体线粒体则没有变化。皮质线粒体钙敏感性没有改变。在 R6/2 小鼠中，纹状体和皮质线粒体对 Ca2+ 具有同样的抵抗力，而同窝对照小鼠的纹状体线粒体则更容易受到影响。与对照组相比，亨廷顿病 (HD) 小鼠的线粒体中没有观察到钙敏感性增加。运动异常和亲环蛋白 D 的表达均不与线粒体敏感性的变化相对应。亨廷顿蛋白中的聚谷氨酰胺扩增导致纹状体线粒体早期对钙的抵抗力增加，这表明线粒体在钙敏感性方面发生代偿性变化，以响应聚谷氨酰胺扩增引起的许多细胞变化。
Striatal and cortical mitochondria from knock-in and transgenic mutant huntingtin mice were examined for their sensitivity to calcium induction of the permeability transition, a cause of mitochondrial depolarization and ATP loss. The permeability transition has been suggested to contribute to cell death in Huntington's Disease. Mitochondria were examined from slowly progressing knock-in mouse models with different length polyglutarnine expansions (Q20, Q50, Q92, Q111) and from the rapidly progressing transgenic R6/2 mice overexpressing exon I of human huntingtin with more than 110 polyglutamines. As previously observed in rats, striatal mitochondria from background strain CD1 and C57BL/6 control mice were more sensitive to calcium than cortical mitochondria. Between 5 and 12 months in knock-in Q92 mice and between 8 and 12 weeks in knock-in Q111 mice, striatal mitochondria developed resistance, becoming equally sensitive to calcium as cortical mitochondria, while those from Q50 mice were unchanged. Cortical mitochondrial calcium sensitivity did not change. In R6/2 mice striatal and cortical mitochondria were equally resistant to Ca2+ while striatal mitochondria from littermate controls were more susceptible. No increases in calcium sensitivity were observed in the mitochondria from Huntington's Disease (HD) mice compared to controls. Neither motor abnormalities, nor expression of cyclophilin D corresponded to the changes in mitochondrial sensitivity. Polyglutamine expansions in huntingtin produced an early increased resistance to calcium in striatal mitochondria suggesting mitochondria undergo compensatory changes in calcium sensitivity in response to the many cellular changes wrought by polyglutamine expansion.