Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Department of Neurology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, China.
Dis Markers. 2022 May 10;2022:5186252. doi: 10.1155/2022/5186252. eCollection 2022.
Mutations in PINK1 and Parkin are a major cause of Parkinson's disease (PD) pathogenesis. In addition, PINK1 and Parkin are two mitochondrial proteins that jointly contribute to mitochondrial homeostasis via mitophagy. Mitochondrial dysfunction is the most significant mechanism underlying PD pathogenesis. Thus, understanding the regulatory mechanism of PINK1 and Parkin expression is beneficial to the treatment of PD. In this study, we found that miR-421 expression was upregulated in mice treated with MPTP, as well as in SH-SY5Y cells treated with methyl-4-phenylpyridine (MPP+). Inhibition of miR-421 alleviated neurodegeneration in MPTP-treated mice and promoted mitophagy in MPP+-treated SH-SY5Y cells. Bioinformatics software predicted that Pink1 is a downstream target protein of miR-421. In addition, miR-421-induced Pink1 and Parkin inhibition negatively modulates mitophagy in MPP+-treated SH-SY5Y cells. In addition, our study confirmed that Pink1/Parkin is responsible for miR-421-regulated cell mitophagy. Overall, this study revealed that miR-421 regulates nerve cell mitophagy through the Pink1/Parkin pathway.
突变的 PINK1 和 Parkin 是帕金森病（PD）发病机制的主要原因。此外，PINK1 和 Parkin 是两种线粒体蛋白，它们通过线粒体自噬共同促进线粒体的稳态。线粒体功能障碍是 PD 发病机制的最重要机制。因此，了解 PINK1 和 Parkin 表达的调控机制有利于 PD 的治疗。在这项研究中，我们发现 MPTP 处理的小鼠以及 MPP+处理的 SH-SY5Y 细胞中 miR-421 的表达上调。miR-421 的抑制可减轻 MPTP 处理的小鼠的神经退行性变，并促进 MPP+处理的 SH-SY5Y 细胞中的线粒体自噬。生物信息学软件预测 Pink1 是 miR-421 的下游靶蛋白。此外，miR-421 诱导的 Pink1 和 Parkin 抑制负调控 MPP+处理的 SH-SY5Y 细胞中的线粒体自噬。此外，我们的研究证实 Pink1/Parkin 负责 miR-421 调节的细胞线粒体自噬。总之，本研究揭示了 miR-421 通过 Pink1/Parkin 通路调节神经细胞的线粒体自噬。
