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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Mitochondrial Quality Control via the PGC1 alpha-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin
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Mitochondrial Quality Control via the PGC1 alpha-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin

机译：通过PGC1 alpha-TFEB信号通路的线粒体质量控制受到Parkin Q311X突变的损害，但雷帕霉素可独立恢复

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摘要

Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1 alpha) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1 alpha-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1 alpha-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1 alpha-TFEB signaling and that this can be independently restored via upregulation of TFEB function.
机译：在被PINK1激活后，帕金蛋白被募集到去极化的线粒体中，在那里泛素化线粒体外膜蛋白，从而启动溶酶体介导的这些细胞器的降解。编码parkin PARK2的基因中的突变导致帕金森氏病（PD）的家族和散发性形式，同时减少了受损线粒体的清除。与其他PARK2突变的报道相反，小鼠体内Q311X突变的表达似乎在溶酶体功能水平涉及自噬途径的下游步骤。这与增加的PARIS表达和涉及主线粒体调节剂过氧化物酶体增殖物激活受体-γ共激活剂（PGC1 alpha）和溶酶体调节因子转录因子EB（TFEB）的相互信号通路的表达降低相吻合。发现用雷帕霉素治疗可独立地恢复PGC1α-TFEB信号传导，而无需帕金森活性，并消除了与该体内模型相关的线粒体质量控制和神经退行性功能的损害。发现培养的大鼠DAergic细胞中表达与线粒体功能和细胞活力降低相关的Q311X突变的PGC1α-TFEB信号传导的损失是PARIS依赖性的，并由雷帕霉素以需要TFEB的方式独立恢复。在人类iPSC衍生的神经元中进行的研究表明，TFEB诱导可在线粒体受损的人类细胞模型中恢复线粒体功能和细胞活力。基于这些数据，我们建议帕金Q311X突变通过PARIS介导的PGC1α-TFEB信号传导的调节影响线粒体质量控制，并且可以通过上调TFEB功能独立地恢复。

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