Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons.
Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons.
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DOI：
10.1038/cddis.2014.511
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发表时间：
2014-11-27
影响因子：
9
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中科院分区：
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线粒体是维持细胞生命和死亡的关键细胞器，其形态受到持续和平衡的裂变和融合动力学的控制。这些事件之间的平衡对于正常的线粒体和神经元功能是强制性的，并且新出现的证据表明，在几种神经退行性疾病中，线粒体在程序性细胞死亡期间的早期阶段经历广泛的裂变。已经描述了一种通过自噬选择性降解受损线粒体的途径，称为线粒体自噬，并且对维持神经元活力特别重要。在目前的工作中，我们分析了自噬刺激对线粒体功能和动力学的影响，在局灶性小脑损伤后的远程变性模型。我们提供的证据表明，小脑半球病变导致轴突切断小脑前神经元线粒体去极化与PTEN诱导的推定激酶1积累和帕金易位线粒体，线粒体融合Mfn1降解，钙调磷酸酶活性增加和动力蛋白相关蛋白1易位到线粒体，随之而来的线粒体分裂。在这里，我们认为观察到的雷帕霉素的神经保护作用是双重作用的结果：（1）刺激自噬，导致受损的线粒体清除和（2）增强线粒体分裂，使其通过线粒体自噬消除。线粒体动力学和线粒体自噬与脑损伤的关系，特别是在急性局灶性脑损伤后的远程变性背景下，尚未得到研究，这些发现可能为治疗干预提供新的目标，以改善急性脑损伤后的功能结果。
Mitochondria are key organelles for the maintenance of life and death of the cell, and their morphology is controlled by continual and balanced fission and fusion dynamics. A balance between these events is mandatory for normal mitochondrial and neuronal function, and emerging evidence indicates that mitochondria undergo extensive fission at an early stage during programmed cell death in several neurodegenerative diseases. A pathway for selective degradation of damaged mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to sustain neuronal viability. In the present work, we analyzed the effect of autophagy stimulation on mitochondrial function and dynamics in a model of remote degeneration after focal cerebellar lesion. We provided evidence that lesion of a cerebellar hemisphere causes mitochondria depolarization in axotomized precerebellar neurons associated with PTEN-induced putative kinase 1 accumulation and Parkin translocation to mitochondria, block of mitochondrial fusion by Mfn1 degradation, increase of calcineurin activity and dynamin-related protein 1 translocation to mitochondria, and consequent mitochondrial fission. Here we suggest that the observed neuroprotective effect of rapamycin is the result of a dual role: (1) stimulation of autophagy leading to damaged mitochondria removal and (2) enhancement of mitochondria fission to allow their elimination by mitophagy. The involvement of mitochondrial dynamics and mitophagy in brain injury, especially in the context of remote degeneration after acute focal brain damage, has not yet been investigated, and these findings may offer new target for therapeutic intervention to improve functional outcomes following acute brain damage.