线粒体靶向HSP90抑制剂Gamitrinib-TPP（G-TPP）诱导PINK1 / Parkin依赖性线粒体吞噬,Oncotarget

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线粒体靶向HSP90抑制剂Gamitrinib-TPP（G-TPP）诱导PINK1 / Parkin依赖性线粒体吞噬
Oncotarget Pub Date : 2017-11-06 , DOI: 10.18632/oncotarget.22287
Fabienne C. Fiesel _{1,

2} , Elle D. James ₁ , Roman Hudec ₁ , Wolfdieter Springer _{1,

2}

Affiliation

PINK1或PARKIN的功能丧失突变与早发性帕金森氏病有关。线粒体受到压力后，PINK1和帕金蛋白共同介导一种保护细胞免受有害，受损线粒体积累的反应。上游激酶PINK1积累在线粒体表面，并在位募集E3泛素连接酶Parkin来泛素化底物蛋白。两者在线粒体表面上产生磷酸化的泛素链的联合活性诱导自噬受体的募集，并最终通过自噬清除整个细胞器。尽管通常认为这种途径是在线粒体化学解偶联后发生的，但人们对（病理）生理相关性提出了质疑。然而，很少有研究表明，过表达ΔOTC（鸟氨酸转氨甲酰酶）后，线粒体管腔中错误折叠的蛋白质积聚也会激活PINK1和Parkin。在这里，我们使用了靶向线粒体的HSP90抑制剂加米替尼-三苯基phosph（G-TPP）（一种抗癌剂）来化学干扰线粒体蛋白折叠。G-TPP处理诱导PINK1积累，Ser65处的泛素磷酸化，Parkin活化及其募集到线粒体对线粒体HSP90抑制具有特异性，并且在很大程度上与线粒体膜去极化无关。通过监测自噬受体募集和miteoKeima记者观察到了线粒体诱导。重要的是，不仅在癌细胞中还诱导了线粒体吞噬，而且还在原代人成纤维细胞及其转化的神经元中诱导了线粒体吞噬。

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Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy

Loss-of-function mutations in PINK1 or PARKIN are associated with early-onset Parkinson’s disease. Upon mitochondrial stress, PINK1 and Parkin together mediate a response that protects cells from the accumulation of harmful, damaged mitochondria. PINK1, the upstream kinase accumulates on the mitochondrial surface and recruits the E3 ubiquitin ligase Parkin on site to ubiquitylate substrate proteins. The joint activity of both to generate phosphorylated poly-ubiquitin chains on the mitochondrial surface induces the recruitment of autophagy receptors and eventually whole organelles are cleared by autophagy. While this pathway is generally accepted to occur upon chemical uncoupling of mitochondria, the (patho-) physiologic relevance has been questioned. However, few studies have indicated that PINK1 and Parkin are also activated upon accumulation of misfolded proteins in the mitochondrial lumen upon overexpression of ΔOTC (Ornithine transcarbamylase). Here, we used the mitochondrial targeted HSP90 inhibitor Gamitrinib-triphenylphosphonium (G-TPP), an anti-cancer agent, to chemically interfere with mitochondrial protein folding. G-TPP treatment induced PINK1 accumulation, ubiquitin phosphorylation at Ser65, Parkin activation and its recruitment to mitochondria was specific for mitochondrial HSP90 inhibition and largely independent of mitochondrial membrane depolarization. Mitophagy induction was observed by monitoring autophagy receptor recruitment and the mitoKeima reporter. Importantly, mitophagy was not only induced in cancer cells but also in primary human fibroblasts and thereof converted neurons. G-TPP treatment might represent a novel strategy to study PINK1 and Parkin-mediated mitochondrial quality control using a more physiologically relevant stress.

更新日期：2017-11-06

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