Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
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DOI：
10.1038/cddis.2014.103
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发表时间：
2014-04-17
影响因子：
9
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中科院分区：
文献类型：
--
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线粒体伴侣死亡蛋白与帕金森病（PD）有关，因为其在PD患者大脑中的水平降低，以及与疾病相关的罕见遗传变异，这些变异未能在细胞敲除模型中挽救受损的线粒体完整性。为了揭示死亡蛋白相关神经变性的分子机制，我们剖析了与线粒体质量控制相关的细胞监视机制，在分子和细胞水平上定义了死亡蛋白功能降低的影响，并研究了死亡蛋白与Parkin和PINK1（两种参与线粒体稳态的PD相关蛋白）的功能相互作用。我们发现死亡蛋白功能降低导致：（1）线粒体未折叠蛋白反应（UPR（mt））的激活，（2）对线粒体内蛋白水解应激的易感性增加，（3）片段化线粒体的自噬降解增加，以及（4）体外和离体人类细胞中线粒体质量降低。这些改变导致细胞凋亡的脆弱性增加。蛋白毒性扰动引起的死亡蛋白或化学诱导的部分损失获救与天然死亡蛋白的互补，但不是疾病相关的死亡蛋白的变体，是独立的自噬途径的完整性。然而，Parkin和PINK1通过增加溶酶体介导的线粒体清除率挽救了死亡蛋白表型的损失，并需要完整的自噬机制。我们关于死亡蛋白功能丧失的研究结果揭示了受损的线粒体蛋白稳态、UPR（mt）和PD之间的直接联系，并表明通过遗传（PINK1和Parkin过表达）或药物干预（雷帕霉素）有效去除功能障碍的线粒体可能会补偿线粒体表型。
The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.
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影响因子：
5.3
作者：
Liang, Chang-Lin;Wang, Tom T.;German, Dwight C.
通讯作者：
German, Dwight C.
影响因子：
3.5
作者：
Hosokawa, Nao;Hara, Yukichi;Mizushima, Noboru
通讯作者：
Mizushima, Noboru
影响因子：
4.3
作者：
Liu, Y;Liu, W;Zuo, J
通讯作者：
Zuo, J
影响因子：
4.2
作者：
Freimann, Karen;Zschiedrich, Katja;Westenberger, Ana
通讯作者：
Westenberger, Ana
影响因子：
2
作者：
Diedrich, Madeleine;Kitada, Tohru;Mao, Lei
通讯作者：
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