Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer's neurons.
Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer's neurons.
复制标题
DOI：
10.1371/journal.pone.0054914
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yan SS
中科院分区：
文献类型：
--
作者：
Guo L;Du H;Yan S;Wu X;McKhann GM;Chen JX;Yan SS
正常的轴突线粒体运输和功能对突触功能的维持至关重要。轴突内线粒体运动异常和线粒体功能障碍对β淀粉样蛋白（Aβ）诱导的突触应激和突触丧失至关重要，与阿尔茨海默病（AD）的发病机制有关。然而，控制阿尔茨海默病轴突线粒体功能和转运改变的机制仍然难以捉摸。在这里，我们报道了亲环蛋白D （CypD）依赖的线粒体通透性过渡孔（mPTP）在a β受损的轴突线粒体运输中未被探索的作用。通过增加轴突线粒体密度和分布以及改善轴突线粒体的双向运输，CypD的缺失可以显著保护轴突线粒体的运动和动力学免受Aβ毒性的影响。值得注意的是，通过基因缺失CypD来阻断mPTP，可以抑制a β介导的p38丝裂原激活的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，减轻突触损失，这表明CypD依赖性信号在a β诱导的轴突线粒体运输改变中起作用。缺乏CypD对a β诱导的轴突线粒体异常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），抑制下游信号转导P38的激活。这些发现为研究cypd依赖性线粒体mPTP以及在Aβ富集环境中轴突线粒体运输和突触变性的信号传导提供了新的见解。
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.
登录
查看更多内容
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu
影响因子：
2.5
作者：
BANKER, GA;COWAN, WM
通讯作者：
COWAN, WM
征素介导的线粒体沿神经元过程的顺行转运。
影响因子：
7.8
作者：
Cai, Qian;Gerwin, Claudia;Sheng, Zu-Hang
通讯作者：
Sheng, Zu-Hang
影响因子：
4.2
作者：
Du H;Guo L;Zhang W;Rydzewska M;Yan S
通讯作者：
Yan S