亨廷顿舞蹈症中Hsp60丢失诱发线粒体功能障碍(英)

Loss of Hsp60 elicits mitochondrial dysfunction in Huntington’s disease

亨廷顿舞蹈症(Huntington’s disease, HD)是一种典型的神经退行性疾病,其中纹状体神经元的线粒体障碍是导致其神经退行的重要原因。前期研究表明亨廷顿蛋白突变体(mutant huntingtin, mtHtt)抑制线粒体未折叠蛋白反应(mitochondrial unfolded protein response, UPRmt)导致线粒体碎片化,但其潜在分子机制尚不明确。本研究结果表明,UPRmt标志物热休克蛋白60(heat shock protein 60, Hsp60)缺失可导致纹状体细胞线粒体碎片化。采用慢病毒敲低纹状体细胞中的Hsp60,结果显示,线粒体动力相关蛋白1(dynamin-related protein 1, Drp1)与线粒体结合增强、Drp1 616位丝氨酸磷酸化和Drp1寡聚体水平升高。突变型纹状体细胞中过表达Hsp60抑制了Drp1过度激活。此外,Hsp60下调诱导活性氧生成和线粒体膜电位丢失。以上结果提示,HD中Hsp60与线粒体功能调节密切相关。

Huntington′s disease(HD) is a typical neurodegenerative disease with a primary etiology of mitochondrial disorder of striatal neurons. It has been demonstrated that mitochondrial unfolded protein response(UPRmt) was suppressed by the mutant huntingtin(mtHtt), which caused mitochondrial fragmentation. However, its underlying molecular mechanism is still unclear. Here, our results showed that deletion of the heat shock protein 60(Hsp60), a marker of UPRmt, could contribute to mitochondrial fragmentation in striatal cells. We found that knocking down Hsp60 with lentivirus increased the translocation of dynamin-related protein 1(Drp1) to mitochondria in striatal cells. Deletion of Hsp60 caused increased phosphorylation of Drp1 at the serine 616(S616) site and oligomerization of Drp1. The overexpression of Hsp60 in mutant striatal cells alleviated Drp1 hyperactivation. Moreover, downregulated Hsp60 induced reactive oxygen species(ROS) generation and mitochondrial membrane potential(MMP) reduction. Thus, our results indicate that Hsp60 is closely associated with the regulation of mitochondrial function in HD.