Department of Pharmacology & Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
PLoS One. 2013;8(1):e54914. doi: 10.1371/journal.pone.0054914. Epub 2013 Jan 31.
Normal axonal mitochondrial transport and function is essential for the maintenance of synaptic function. Abnormal mitochondrial motility and mitochondrial dysfunction within axons are critical for amyloid β (Aβ)-induced synaptic stress and the loss of synapses relevant to the pathogenesis of Alzheimer's disease (AD). However, the mechanisms controlling axonal mitochondrial function and transport alterations in AD remain elusive. Here, we report an unexplored role of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) in Aβ-impaired axonal mitochondrial trafficking. Depletion of CypD significantly protects axonal mitochondrial motility and dynamics from Aβ toxicity as shown by increased axonal mitochondrial density and distribution and improved bidirectional transport of axonal mitochondria. Notably, blockade of mPTP by genetic deletion of CypD suppresses Aβ-mediated activation of the p38 mitogen-activated protein kinase signaling pathway, reverses axonal mitochondrial abnormalities, improves synaptic function, and attenuates loss of synapse, suggesting a role of CypD-dependent signaling in Aβ-induced alterations in axonal mitochondrial trafficking. The potential mechanisms of the protective effects of lacking CypD on Aβ-induced abnormal mitochondrial transport in axon are increased axonal calcium buffer capability, diminished reactive oxygen species (ROS), and suppressing downstream signal transduction P38 activation. These findings provide new insights into CypD-dependent mitochondrial mPTP and signaling on mitochondrial trafficking in axons and synaptic degeneration in an environment enriched for Aβ.
正常的轴突线粒体运输和功能对于维持突触功能至关重要。轴突内异常的线粒体运动和线粒体功能障碍是淀粉样β（Aβ）诱导的突触应激和与阿尔茨海默病（AD）发病机制相关的突触丧失的关键。然而，控制 AD 中轴突线粒体功能和运输改变的机制仍不清楚。在这里，我们报告了亲环素 D（CypD）依赖性线粒体通透性转换孔（mPTP）在 Aβ损伤轴突线粒体运输中的一个未被探索的作用。CypD 的耗竭显着保护轴突线粒体的运动和动力学免受 Aβ毒性的影响，表现为轴突线粒体密度和分布增加，以及轴突线粒体的双向运输得到改善。值得注意的是，通过 CypD 基因缺失抑制 mPTP 可抑制 Aβ介导的 p38 丝裂原活化蛋白激酶信号通路的激活，逆转轴突线粒体异常，改善突触功能，并减轻突触丧失，表明 CypD 依赖性信号在 Aβ 诱导的轴突线粒体运输改变中起作用。缺乏 CypD 对 Aβ诱导的轴突异常线粒体运输的保护作用的潜在机制是增加轴突钙缓冲能力、减少活性氧（ROS）和抑制下游信号转导 P38 激活。这些发现为富含 Aβ 的环境中轴突线粒体 mPTP 和信号转导对线粒体运输和突触退化的 CypD 依赖性提供了新的见解。
