Munich Cluster for Systems Neurology, 80802 Munich, Germany.
J Neurosci. 2012 Nov 14;32(46):16203-12. doi: 10.1523/JNEUROSCI.1327-12.2012.
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.
线粒体提供 ATP，维持钙稳态，并调节细胞凋亡。由于神经元的体积大和复杂的几何形状，它们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认识，但我们对体内的认识仍然有限。为了解决这一不足，我们开发了在可光学访问的斑马鱼中体内研究线粒体动力学的工具。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”，并可识别线粒体动力学的药理学和遗传学调节剂。此外，我们还实时观察到斑马鱼 tau 病模型中严重的线粒体运输缺陷。通过使用 MARK2（微管亲和力调节激酶 2）来挽救这种表型，我们提供了直接的体内证据，证明这种激酶以 Tau 依赖的方式调节轴突运输。因此，我们的方法允许在正常和疾病条件下在其自然环境中对线粒体的动态进行详细研究。
