PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.
PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.
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DOI：
10.1371/journal.pbio.0050172
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发表时间：
2007-07
期刊：
影响因子：
9.8
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Pridgeon JW;Olzmann JA;Chin LS;Li L
PTEN诱导假定激酶1（PINK1）基因的突变导致一种常染色体隐性形式的帕金森病（PD）。到目前为止，尚未有PINK1底物的相关报道，而且PINK1突变导致神经退行性变的机制尚不清楚。在此我们报道将肿瘤坏死因子受体相关蛋白1（TRAP1），一种也被称为热休克蛋白75（Hsp75）的线粒体分子伴侣，鉴定为PINK1激酶的细胞底物。PINK1在线粒体中与TRAP1结合并共定位，并且在体外和体内都使TRAP1磷酸化。我们表明PINK1通过抑制线粒体中细胞色素c的释放来防止氧化应激诱导的细胞死亡，并且PINK1的这种保护作用依赖于其使TRAP1磷酸化的激酶活性。此外，我们发现与帕金森病相关的PINK1 G309D、L347P和W437X突变会损害PINK1促进TRAP1磷酸化和细胞存活的能力。我们的研究结果表明了一种新的途径，即PINK1磷酸化下游效应物TRAP1以防止氧化应激诱导的细胞凋亡，并暗示这种线粒体途径的失调在帕金森病的发病机制中起作用。
帕金森病（PD）的特征是中脑多巴胺能神经元的选择性缺失。尽管帕金森病的病因尚不清楚，但病理分析表明氧化应激和线粒体功能障碍与其有关。最近，一种早发性帕金森病的遗传形式与编码线粒体蛋白PINK1的基因的两个拷贝的突变有关。此外，越来越多的证据表明PINK1的单拷贝突变是晚发性帕金森病发展的一个重要风险因素。在此我们表明PINK1是一种蛋白激酶，它使线粒体分子伴侣TRAP1磷酸化以促进细胞存活。我们发现PINK1通常通过抑制线粒体中细胞色素c的释放来防止氧化应激诱导的细胞死亡。与帕金森病相关的PINK1突变损害了PINK1使TRAP1磷酸化和促进细胞存活的能力。我们的研究结果揭示了一种新的抗凋亡信号通路，该通路被PINK1的突变所破坏。我们认为该通路在帕金森病的发病机制中起作用，并且可能是治疗干预的一个靶点。
编码PINK1的基因的突变导致一种常见形式的帕金森病。在此作者表明PINK1使TRAP1磷酸化，这抑制了线粒体中细胞色素c的凋亡性释放。
Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis. Parkinson disease (PD) is characterized by the selective loss of midbrain dopaminergic neurons. Although the cause of PD is unknown, pathological analyses have suggested the involvement of oxidative stress and mitochondrial dysfunction. Recently, an inherited form of early-onset PD has been linked to mutations in both copies of the gene encoding the mitochondrial protein PINK1. Furthermore, increasing evidence indicates that single-copy mutations in PINK1 are a significant risk factor in the development of later-onset PD. Here we show that PINK1 is a protein kinase that phosphorylates the mitochondrial molecular chaperone TRAP1 to promote cell survival. We find that PINK1 normally protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria. The PINK1 mutations linked to PD impair the ability of PINK1 to phosphorylate TRAP1 and promote cell survival. Our findings reveal a novel anti-apoptotic signaling pathway that is disrupted by mutations in PINK1. We suggest that this pathway has a role in PD pathogenesis and may be a target for therapeutic intervention. Mutations in the gene that codes for PINK1 cause a common form of Parkinson disease. Here the authors show that PINK1 phosphorylates TRAP1, which suppresses apoptotic release of cytochrome c from mitochondria.
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