In Vivo Imaging of Disease-Related Mitochondrial Dynamics in a Vertebrate Model System
In Vivo Imaging of Disease-Related Mitochondrial Dynamics in a Vertebrate Model System
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DOI：
10.1523/jneurosci.1327-12.2012
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发表时间：
2012-11-14
影响因子：
5.3
通讯作者：
Misgeld, Thomas
中科院分区：
文献类型：
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作者：
Plucinska, Gabriela;Paquet, Dominik;Misgeld, Thomas
线粒体提供ATP，维持钙稳态，并调节细胞凋亡。神经元由于其大小和复杂的几何形状，特别依赖于线粒体的正常功能和分布。因此，这些细胞器及其运输的中断在广泛的神经退行性疾病中起着核心作用。虽然体外研究极大地扩展了我们对线粒体动力学的了解，但我们对体内的理解仍然有限。为了解决这个缺点，我们开发了工具来研究线粒体动力学在光学可访问斑马鱼体内。我们在这里证明，我们新生成的工具，包括转基因“MitoFish”，可用于研究线粒体的体内“生命周期”，并允许识别线粒体动力学的药理学和遗传调节剂。此外，我们观察到深刻的线粒体转运赤字在真实的时间在斑马鱼tau蛋白病模型。通过使用MARK2（微管亲和力调节激酶2）拯救这种表型，我们提供了直接的体内证据，证明这种激酶以Tau依赖性方式调节轴突运输。因此，我们的方法允许在正常和疾病条件下详细研究线粒体在其自然环境中的动力学。
Mitochondria provide ATP, maintain calcium homeostasis, and regulate apoptosis. Neurons, due to their size and complex geometry, are particularly dependent on the proper functioning and distribution of mitochondria. Thus disruptions of these organelles and their transport play a central role in a broad range of neurodegenerative diseases. While in vitro studies have greatly expanded our knowledge of mitochondrial dynamics, our understanding in vivo remains limited. To address this shortcoming, we developed tools to study mitochondrial dynamics in vivo in optically accessible zebrafish. We demonstrate here that our newly generated tools, including transgenic "MitoFish," can be used to study the in vivo "life cycle" of mitochondria and allows identifying pharmacological and genetic modulators of mitochondrial dynamics. Furthermore we observed profound mitochondrial transport deficits in real time in a zebrafish tauopathy model. By rescuing this phenotype using MARK2 (microtubule-affinity regulating kinase 2), we provide direct in vivo evidence that this kinase regulates axonal transport in a Tau-dependent manner. Thus, our approach allows detailed studies of the dynamics of mitochondria in their natural environment under normal and disease conditions.