Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
Department of Biology, Case Western Reserve University College of Arts and Sciences, Cleveland, OH, 44106, USA.
Biochem Biophys Res Commun. 2021 Sep 10;569:17-22. doi: 10.1016/j.bbrc.2021.06.079. Epub 2021 Jun 30.
The pathogenesis of Parkinson's disease (PD) remains elusive, but mitochondrial dysfunction is believed to be one crucial step in its pathogenesis. The mitochondrial unfolded protein response (UPR) is an important mitochondrial quality control strategy that maintains mitochondrial function in response to disturbances of mitochondrial protein homeostasis. Activation of the UPR and the beneficial effect of rescuing mitochondrial proteostasis have been reported in several genetic models of PD. However, the pathogenic relevance of the UPR in idiopathic PD is unknown. The present study examined the link between the UPR and mitochondrial dysfunction in 1-methyl-4-phenylpyridinium (MPP)-treated SH-SY5Y cells. Treatment with MPP induced activation of the UPR, reflected by an increase in the expression of UPR-related chaperones, proteases, and transcription mediators. UPR activation that was induced by overexpressing mutant ornithine transcarbamylase significantly reduced the production of mitochondrial reactive oxygen species (ROS) and improved cell survival in SH-SY5Y cells following MPP treatment. Moreover, the overexpression of activating transcription factor 5 (mammalian UPR transcription factor) conferred protection against MPP-induced ROS production and against cell death in SH-SY5Y cells. Overall, our results demonstrate the beneficial effect of UPR activation in MPP -treated cells, shedding new light on the mechanism of mitochondrial dysfunction in the pathogenesis of PD.
帕金森病（PD）的发病机制仍不清楚，但线粒体功能障碍被认为是其发病机制中的关键步骤之一。线粒体未折叠蛋白反应（UPR）是一种重要的线粒体质量控制策略，可在应对线粒体蛋白稳态紊乱时维持线粒体功能。在几种 PD 的遗传模型中，已经报道了 UPR 的激活及其对挽救线粒体蛋白稳态的有益作用。然而，UPR 在特发性 PD 中的发病相关性尚不清楚。本研究在 MPP 处理的 SH-SY5Y 细胞中检查了 UPR 与线粒体功能障碍之间的联系。用 MPP 处理诱导 UPR 的激活，这反映在 UPR 相关伴侣、蛋白酶和转录调节剂的表达增加。过表达突变的鸟氨酸氨甲酰转移酶诱导的 UPR 激活显著降低了 MPP 处理后 SH-SY5Y 细胞中线粒体活性氧（ROS）的产生，并提高了细胞存活率。此外，激活转录因子 5（哺乳动物 UPR 转录因子）的过表达赋予了 SH-SY5Y 细胞对 MPP 诱导的 ROS 产生和细胞死亡的保护作用。总的来说，我们的结果表明 UPR 激活在 MPP 处理的细胞中具有有益的作用，为 PD 发病机制中线粒体功能障碍的机制提供了新的见解。
