LncRNA NR_030777 promotes mitophagy by targeting CDK1-related mitochondrial fission and ATG12 to attenuate paraquat-induced Parkinson's disease

粒体自噬 线粒体分裂 基因敲除 第一季 神经退行性变 MFN2型 分子生物学 线粒体 生物 细胞生物学 医学 疾病 自噬 线粒体融合 细胞凋亡 线粒体DNA 生物化学 基因 病理
作者
Nengzhou Chen,Hong Hu,Jianping Tang,Fuli Zheng,Zhenkun Guo,Xinpei Lin,Michael Aschner,Wenya Shao,Guangxia Yu,Ping Cai,Wei-Chun Chou,Siying Wu,Huangyuan Li
出处
期刊:Environmental Pollution [Elsevier]
卷期号:349: 123875-123875 被引量:2
标识
DOI:10.1016/j.envpol.2024.123875
摘要

With the evidence emerging that abnormal expression of long noncoding RNAs (lncRNAs) are involved in onset of Parkinson's disease (PD), the role of NR_030777 contributing to this disease is of great interest. We recently found that a novel lncRNA "NR_030777" demonstrates protective effects on PQ-induced neurodegeneration. However, the underlying molecular mechanisms of NR_030777 in the regulation of mitochondrial fission and mitophagy involved in PQ-induced neuronal damage remain to be explored. NR_030777 brain conditional overexpressing mice as well as in vitro primary neuronal cells from cerebral cortex and Neuro2a cells were adopted. Immunofluorescence, Immunohistochemistry, qRT-PCR and Western blotting were used to evaluate the expression levels of RNA and proteins. RNA immunoprecipitation and RNA pulldown experiment were used to evaluate the interaction of NR_030777 with its target proteins. NR_030777 and mitophagy were increased, and tyrosine hydroxylase (TH) levels recovered after NR_030777 overexpression upon PQ treatment. The overexpression and knockdown of NR_030777 unveiled that NR_030777 positively regulated mitophagy such as the upregulation of LC3B-II:I, ATG12-ATG5, p62 and NBR1. Moreover, the application of mdivi-1, a DRP-1 inhibitor, in combination with NR_030777 genetic modified cells unveiled that NR_030777 promoted DRP1-mediated mitochondrial fission and mitophagy. Furthermore, NR_030777 were directly bound to CDK1 to increase p-DRP1 levels at the Ser616 site, leading to mitochondrial fission and mitophagy. On the other hand, NR_030777 acted directly on ATG12 within the ATG12-ATG5 complex in the 800–1400 nt region to modulate the membrane formation. Accordingly, NR_030777 deficiency in neuron cells compromised cell mitophagy. Finally, the above findings were confirmed using NR_030777-overexpressing mice. NR_030777 exerted a protective effect on PQ-exposed mice by enhancing mitophagy. Our data provide the first scientific evidence for the precise invention of PQ-induced PD. Our findings further propose a breakthrough for understanding the regulatory relationship between NR_030777, CDK1, ATG12 and mitophagy in PQ-induced PD.
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