Introducing Mitochondrial Stasis in Neurons

描述(申请人提供)：线粒体是动态的膜细胞器，经历分裂和融合。这些相反的活动之间的平衡对控制线粒体的结构和功能起着至关重要的作用。线粒体的分裂和融合是由保守的动力蛋白相关的GTP酶介导的，包括用于分裂的Drp1和用于融合的OPA1。抑制线粒体分裂会扩大由于正在进行的融合而导致的线粒体，同时抑制融合片段线粒体。线粒体分裂和融合的异常与许多神经退行性疾病有关，如常染色体显性视神经萎缩、Charcot-Marie-Tooth神经病、阿尔茨海默病、亨廷顿病和帕金森病。要了解这些疾病的发病机制，需要对线粒体动力学的生理功能有更深入的了解。在这项拟议的研究中，我们将确定线粒体动力学改变如何导致神经退化。具体地说，我们将测试两个未经检验的假设。第一种假设认为，线粒体动力学直接调节线粒体的功能。在这个模型中，线粒体必须不断地分裂和融合，以维持它们的功能，以维持神经元的生存。第二种假设认为，正常的线粒体结构，而不是动力学本身，对神经元至关重要。在第二个模型中，如果线粒体能够保持其结构独立于线粒体动力学，那么线粒体的分裂和融合是可有可无的。为了解决这个问题，我们开发了一种直接的方法，在小鼠的有丝分裂后神经元中引入线粒体停滞。在这些动物中，线粒体分裂和融合可以通过Cre/loxP介导的Drp1和OPA1基因敲除单独或同时被抑制。我们已经证明，缺乏Drp1和OPA1的神经元可以恢复正常的线粒体形态，使我们能够在不影响线粒体结构的情况下阻止线粒体的动力学，并清楚地区分上述两种假设。因此，这项研究将为许多家族性和散发性神经疾病的发病机制提供新的见解。

DESCRIPTION (provided by applicant): Mitochondria are dynamic membrane organelles that undergo division and fusion. The balance between these opposing activities plays a critical role in controlling mitochondrial structure and function. Mitochondrial division and fusion are mediated by conserved dynamin-related GTPases including Drp1 for division and Opa1 for fusion. Inhibition of mitochondrial division enlarges mitochondria due to ongoing fusion while inhibition of fusion fragments mitochondria. Abnormalities in mitochondrial division and fusion are associated with many neurodegenerative diseases such as autosomal dominant optic atrophy, Charcot-Marie- Tooth neuropathy, Alzheimer's disease, Huntington's disease, and Parkinson's disease. Understanding the pathogenesis of these diseases requires a deeper knowledge of the physiological functions of mitochondrial dynamics. In this proposed research, we will determine how altered mitochondrial dynamics causes neurodegeneration. Specifically, we will test two untested hypotheses. The first hypothesis states that mitochondrial dynamics directly regulates mitochondrial functions. In this model, mitochondria must continuously divide and fuse to maintain their functions for survival of neurons. The second hypothesis states that normal mitochondrial structures, but not dynamics per se, are critical in neurons. In this second model, mitochondrial division and fusion are dispensable if mitochondria can maintain their structure independent of mitochondrial dynamics. To attack this problem, we have developed a straightforward approach by introducing mitochondrial stasis in postmitotic neurons in mice. In these animal animals, mitochondrial division and fusion can be individually or simultaneously inhibited using Cre/loxP-mediated knockout for Drp1 and Opa1. We have shown that neurons lacking both Drp1 and Opa1 restore normal mitochondrial morphology, allowing us to block mitochondrial dynamics without affecting mitochondrial structures and clearly distinguish these two hypotheses described above. Therefore, this study will provide novel insight into the pathogenesis of many familial and sporadic neurological disorders.