Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.
Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy.
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DOI：
10.1111/jnc.13412
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发表时间：
2016-01
影响因子：
4.7
通讯作者：
Gegg ME
中科院分区：
文献类型：
--
作者：
Ivankovic D;Chau KY;Schapira AH;Gegg ME
自噬-溶酶体途径的损伤与帕金森病（PD）中观察到的α-突触核蛋白和线粒体功能障碍的变化有关。受损的线粒体积累PINK 1，然后招募parkin，导致线粒体蛋白的泛素化。然后这些可以被自噬蛋白p62/SQSTM 1和LC 3结合，导致线粒体通过线粒体自噬降解。PINK 1和parkin基因突变是家族性PD的原因之一。我们发现，在人神经母细胞瘤SH‐ SY 5 Y细胞中诱导线粒体自噬后，p62/SQSTM 1 mRNA和蛋白的表达显著增加。p62蛋白不仅聚集在线粒体上，而且在胞浆中也大量增加。在PINK 1敲低细胞中，p62/SQSMT 1表达增加被阻止，表明p62表达增加是线粒体自噬诱导的结果。转录因子Nrf 2和TFEB分别在线粒体和溶酶体生物合成中发挥作用，可以调节p62/SQSMT 1。我们报告，Nrf 2和TFEB易位到细胞核后，线粒体自噬诱导和p62 mRNA水平的增加与Nrf 2或TFEB敲低的细胞显着受损。TFEB易位也增加了其自身和溶酶体蛋白如葡萄糖脑苷脂酶和组织蛋白酶D在线粒体自噬诱导后的表达。我们还报告了TFEB蛋白增加的细胞具有显著更高的PGC-1α mRNA水平，这是线粒体生物发生的调节因子，导致线粒体含量增加。我们的数据表明TFEB在线粒体自噬后被激活以维持自噬-溶酶体途径和线粒体生物合成。因此，增加TFEB的策略可以改善PD中α-突触核蛋白的清除和线粒体功能障碍。 受损的线粒体通过自噬-溶酶体途径降解，称为线粒体自噬。在线粒体自噬诱导后，转录因子Nrf 2和TFEB易位到细胞核，诱导编码自噬蛋白如p62以及溶酶体和线粒体蛋白的基因的转录。我们认为，这些事件维持自噬通量，补充溶酶体和取代线粒体。
Impairment of the autophagy–lysosome pathway is implicated with the changes in α‐synuclein and mitochondrial dysfunction observed in Parkinson's disease (PD). Damaged mitochondria accumulate PINK1, which then recruits parkin, resulting in ubiquitination of mitochondrial proteins. These can then be bound by the autophagic proteins p62/SQSTM1 and LC3, resulting in degradation of mitochondria by mitophagy. Mutations in PINK1 and parkin genes are a cause of familial PD. We found a significant increase in the expression of p62/SQSTM1 mRNA and protein following mitophagy induction in human neuroblastoma SH‐SY5Y cells. p62 protein not only accumulated on mitochondria, but was also greatly increased in the cytosol. Increased p62/SQSMT1 expression was prevented in PINK1 knock‐down cells, suggesting increased p62 expression was a consequence of mitophagy induction. The transcription factors Nrf2 and TFEB, which play roles in mitochondrial and lysosomal biogenesis, respectively, can regulate p62/SQSMT1. We report that both Nrf2 and TFEB translocate to the nucleus following mitophagy induction and that the increase in p62 mRNA levels was significantly impaired in cells with Nrf2 or TFEB knockdown. TFEB translocation also increased expression of itself and lysosomal proteins such as glucocerebrosidase and cathepsin D following mitophagy induction. We also report that cells with increased TFEB protein have significantly higher PGC‐1α mRNA levels, a regulator of mitochondrial biogenesis, resulting in increased mitochondrial content. Our data suggests that TFEB is activated following mitophagy to maintain autophagy–lysosome pathway and mitochondrial biogenesis. Therefore, strategies to increase TFEB may improve both the clearance of α‐synuclein and mitochondrial dysfunction in PD. Damaged mitochondria are degraded by the autophagy–lysosome pathway and is termed mitophagy. Following mitophagy induction, the transcription factors Nrf2 and TFEB translocate to the nucleus, inducing the transcription of genes encoding for autophagic proteins such as p62, as well as lysosomal and mitochondrial proteins. We propose that these events maintain autophagic flux, replenish lysosomes and replace mitochondria.