PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease.
PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease.
复制标题
朊病毒病中PINK1 - 帕金（Parkin）介导的神经元线粒体自噬缺陷 。
DOI：
10.1038/s41419-022-04613-2
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发表时间：
2022-02-18
影响因子：
9
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Li J;Lai M;Zhang X;Li Z;Yang D;Zhao M;Wang D;Sun Z;Ehsan S;Li W;Gao H;Zhao D;Yang L
受损线粒体的持续积累是朊病毒病发病机制的一部分。正常情况下，受损的线粒体通过一个主要途径清除，该途径涉及E3泛素连接酶parkin和PTEN诱导的激酶1（PINK 1），它们共同启动线粒体自噬，识别和消除受损的线粒体。然而，在朊病毒疾病中线粒体自噬的确切机制仍然很大程度上未知。使用朊病毒疾病细胞模型，我们观察到PINK 1-parkin介导的线粒体自噬缺陷，其中parkin耗竭加重阻断了线粒体与LC 3-II标记的自噬体的共定位，并显著增加了线粒体蛋白水平，从而导致线粒体自噬抑制。Parkin过表达直接诱导LC 3-II与线粒体共定位，并减轻有缺陷的线粒体自噬。此外，parkin介导的线粒体自噬依赖于PINK 1，因为PINK 1缺失阻断线粒体Parkin募集并降低视神经磷酸酶和LC 3-II蛋白水平，从而抑制线粒体自噬。PINK 1过表达诱导parkin募集到线粒体，然后刺激线粒体自噬。此外，过表达的parkin和PINK 1也保护神经元免于凋亡。此外，我们发现补充两种线粒体自噬诱导剂，烟酰胺单核苷酸（NMN）和尿石素A（UA），显着刺激PINK 1-parkin介导的线粒体自噬。然而，与NMN相比，UA不能减轻朊病毒诱导的线粒体断裂和功能障碍以及神经元凋亡。这些发现表明，PINK 1-parkin介导的线粒体自噬缺陷导致受损线粒体的积累，从而表明刺激线粒体自噬的干预措施可能是朊病毒疾病的潜在治疗靶点。
A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.
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影响因子：
4.8
作者：
Gu, YP;Fujioka, H;Singh, N
通讯作者：
Singh, N
DOI：
10.1196/annals.1299.114
发表时间：
2003-01-01
期刊：
APOPTOSIS: FROM SIGNALING PATHWAYS TO THERAPEUTIC TOOLS
影响因子：
--
作者：
Corsaro, A;Thellung, S;Florio, T
通讯作者：
Florio, T
DOI：
10.1007/s00018-015-2087-8
发表时间：
2016-02
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Hamacher-Brady A;Brady NR
通讯作者：
Brady NR
影响因子：
16
作者：
Heo JM;Ordureau A;Paulo JA;Rinehart J;Harper JW
通讯作者：
Harper JW
影响因子：
64.8
作者：
Hoshino, Atsushi;Wang, Wei-jia;Arany, Zoltan
通讯作者：
Arany, Zoltan