Mitochondrial fission in Huntington's disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and Reactive Oxygen Species (ROS) homeostasis
Mitochondrial fission in Huntington's disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and Reactive Oxygen Species (ROS) homeostasis
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DOI：
10.1016/j.nbd.2020.104741
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发表时间：
2020-03-01
影响因子：
6.1
通讯作者：
Gines, Silvia
中科院分区：
文献类型：
--
作者：
Cherubini, Marta;Lopez-Molina, Laura;Gines, Silvia
线粒体相关膜（MAMs）是内质网（ER）和线粒体之间沟通的动态结构，允许钙在这两个细胞器之间转移。由于钙调节失调是几种神经退行性疾病的重要标志，因此推测MAMs的破坏有助于与这些神经退行性过程相关的病理特征。在亨廷顿氏病（HD）中，突变的亨廷顿蛋白诱导纹状体中中等棘神经元的选择性损失。这种特殊易感性的原因尚不清楚。然而，线粒体动力学和生物能量学上的缺陷被认为是导致线粒体碎片化积累和随后的Ca2+稳态改变的关键因素。在目前的工作中，我们发现在HD突变小鼠的纹状体中，drpl介导的线粒体断裂异常，迫使线粒体远离内质网，破坏内质网-线粒体的关联，因此导致Ca2+外排的缺陷和线粒体超氧化物的过度产生。因此，通过Mdivi-1处理抑制Drp1活性可以恢复er -线粒体接触、线粒体功能障碍和Ca2+稳态。总之，我们的研究结果为线粒体动力学缺陷如何导致HD纹状体易损性提供了新的见解，并强调MAMs功能障碍是HD纹状体病理的一个重要因素。
Mitochondria-associated membranes (MAMs) are dynamic structures that communicate endoplasmic reticulum (ER) and mitochondria allowing calcium transfer between these two organelles. Since calcium dysregulation is an important hallmark of several neurodegenerative diseases, disruption of MAMs has been speculated to contribute to pathological features associated with these neurodegenerative processes. In Huntington's disease (HD), mutant huntingtin induces the selective loss of medium spiny neurons within the striatum. The cause of this specific susceptibility remain unclear. However, defects on mitochondrial dynamics and bioenergetics have been proposed as critical contributors, causing accumulation of fragmented mitochondria and subsequent Ca2+ homeostasis alterations. In the present work, we show that aberrant Drpl-mediated mitochondrial fragmentation within the striatum of HD mutant mice, forces mitochondria to place far away from the ER disrupting the ER-mitochondria association and therefore causing drawbacks in Ca2+ efflux and an excessive production of mitochondria superoxide species. Accordingly, inhibition of Drp1 activity by Mdivi-1 treatment restored ER-mitochondria contacts, mitochondria dysfunction and Ca2+ homeostasis.In sum, our results give new insight on how defects on mitochondria dynamics may contribute to striatal vulnerability in HD and highlights MAMs dysfunction as an important factor involved in HD striatal pathology.