PolyQ-Expansion Causes Mitochondria Fragmentation Independent of Huntingtin and Is Distinct from Traumatic Brain Injury (TBI)/Mechanical Stress-Mediated Fragmentation Which Results from Cell Death.
PolyQ-Expansion Causes Mitochondria Fragmentation Independent of Huntingtin and Is Distinct from Traumatic Brain Injury (TBI)/Mechanical Stress-Mediated Fragmentation Which Results from Cell Death.
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在许多亨廷顿病（HD）模型中已经报道了线粒体功能障碍;然而，尚不清楚这些缺陷是如何发生的。在这里，我们测试的假设，过量的致病性亨廷顿蛋白（HTT）损害线粒体稳态，使用果蝇遗传学和药理学抑制剂在HD和polyQ-扩张疾病模型和机械应激诱导的创伤性脑损伤（TBI）模型。与正常HTT相比，致病性HTT的表达导致线粒体片段化，但HTT在正常或致病条件下不与线粒体共定位。单独或在马查多约瑟夫病（MJD）的背景下表达致病性polyQ（127 Q）引起线粒体片段化。虽然线粒体片段化不依赖于polyQ积累的细胞位置，但伴侣蛋白的表达、过量的线粒体融合蛋白（MFN）或动力蛋白相关蛋白1（DRP 1）的缺失挽救了片段化。有趣的是，在polyQ表达的幼虫脑中观察到更高浓度的一氧化氮（NO），并抑制NO的产生拯救了polyQ介导的片段化线粒体，假设DRP 1亚硝基化可能导致过度分裂。此外，虽然抑制polyQ诱导的细胞死亡的过量PI 3 K没有拯救polyQ介导的片段化，但它确实拯救了由机械应力/TBI引起的片段化。总之，我们的观察结果表明，单独的致病性polyQ足以导致细胞死亡上游的DRP 1依赖性线粒体片段化，揭示了polyQ疾病和机械应力中线粒体功能障碍的不同生理机制。
Mitochondrial dysfunction has been reported in many Huntington’s disease (HD) models; however, it is unclear how these defects occur. Here, we test the hypothesis that excess pathogenic huntingtin (HTT) impairs mitochondrial homeostasis, using Drosophila genetics and pharmacological inhibitors in HD and polyQ-expansion disease models and in a mechanical stress-induced traumatic brain injury (TBI) model. Expression of pathogenic HTT caused fragmented mitochondria compared to normal HTT, but HTT did not co-localize with mitochondria under normal or pathogenic conditions. Expression of pathogenic polyQ (127Q) alone or in the context of Machado Joseph Disease (MJD) caused fragmented mitochondria. While mitochondrial fragmentation was not dependent on the cellular location of polyQ accumulations, the expression of a chaperone protein, excess of mitofusin (MFN), or depletion of dynamin-related protein 1 (DRP1) rescued fragmentation. Intriguingly, a higher concentration of nitric oxide (NO) was observed in polyQ-expressing larval brains and inhibiting NO production rescued polyQ-mediated fragmented mitochondria, postulating that DRP1 nitrosylation could contribute to excess fission. Furthermore, while excess PI3K, which suppresses polyQ-induced cell death, did not rescue polyQ-mediated fragmentation, it did rescue fragmentation caused by mechanical stress/TBI. Together, our observations suggest that pathogenic polyQ alone is sufficient to cause DRP1-dependent mitochondrial fragmentation upstream of cell death, uncovering distinct physiological mechanisms for mitochondrial dysfunction in polyQ disease and mechanical stress.
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