Li Xueyuan, Li Jie, Gou Fengting, Dai Yuexin, Zhao Mengyang, Wang Dongdong, Sun Zhixin, Wen Pei, Wang Jingjing, Fan Qing, Ma Tianying, Wang Xiaoyu, Zhao Deming, Yang Lifeng
Sanya Institute of China Agriculture University, China Agricultural University, Sanya 572024, China; National Key Laboratory of Veterinary Public Health and Safety, National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Sanya Institute of China Agriculture University, China Agricultural University, Sanya 572024, China; National Key Laboratory of Veterinary Public Health and Safety, National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Life Sci. 2025 Oct 15;379:123860. doi: 10.1016/j.lfs.2025.123860. Epub 2025 Jul 18.
PINK1-Parkin-dependent mitophagy dysfunction is a critical contributor to the accumulation of damaged mitochondria in prion disease, leading to impaired autophagy and neurons apoptosis. However, the specific molecular mechanisms underlying mitophagy dysfunction in prion disease remain unclear. Phosphorylation of Parkin at Ser65 (pSer65-Parkin) is a key determinant for the initiation of PINK1-Parkin-mediated mitophagy. In the prion disease cell model, we observed a significant reduction in pSer65-Parkin and pSer65-Ub expression. PTEN-L, an isoform of the PTEN family, has been implicated in the regulation of PINK1-Parkin-mediated mitophagy. Here, we demonstrate that PTEN-L acts as a phosphatase for Parkin and Ub, exerting a regulatory role in mitophagy in prion disease. We found that PTEN-L expression and mitochondrial translocation were elevated in PrP-treated SH-SY5Y cells. Increased PTEN-L dephosphorylates pSer65-Parkin pSer65-Ub, leading to reduced pSer65-Parkin and pSer65-Ub, then impaired mitophagy initiation. Overexpression of PTEN-L in SH-SY5Y cells mimicked the effects of PrP treatment, reducing Parkin mitochondrial translocation and pSer65-Parkin levels. PTEN-L knockout alleviates these deficits, restoring Parkin and ubiquitin recruitment to mitochondria and increasing Ser65 phosphorylation in prion disease cell models. Furthermore, PTEN-L deficiency mitigated mitophagy dysfunction and apoptosis in neurons exposed by PrP. These findings suggest that PrP upregulates PTEN-L, enhancing dephosphorylation of pSer65-Parkin and pSer65-Ub, thereby impairing mitophagy initiation. Targeting PTEN-L expression or activity may represent a novel therapeutic strategy for prion disease.
依赖PINK1 - Parkin的线粒体自噬功能障碍是朊病毒病中受损线粒体积累的关键因素，导致自噬受损和神经元凋亡。然而，朊病毒病中线粒体自噬功能障碍的具体分子机制仍不清楚。Parkin在Ser65位点的磷酸化（pSer65 - Parkin）是PINK1 - Parkin介导的线粒体自噬起始的关键决定因素。在朊病毒病细胞模型中，我们观察到pSer65 - Parkin和pSer65 - Ub表达显著降低。PTEN - L是PTEN家族的一种异构体，已被证明参与PINK1 - Parkin介导的线粒体自噬的调节。在此，我们证明PTEN - L作为Parkin和Ub的磷酸酶，在朊病毒病的线粒体自噬中发挥调节作用。我们发现，在经PrP处理的SH - SY5Y细胞中，PTEN - L的表达和线粒体转位增加。PTEN - L的增加使pSer65 - Parkin和pSer65 - Ub去磷酸化，导致pSer65 - Parkin和pSer65 - Ub减少，进而损害线粒体自噬起始。在SH - SY5Y细胞中过表达PTEN - L模拟了PrP处理的效果，减少了Parkin的线粒体转位和pSer65 - Parkin水平。PTEN - L基因敲除可缓解这些缺陷，恢复Parkin和泛素向线粒体的募集，并增加朊病毒病细胞模型中的Ser65磷酸化。此外，PTEN - L缺陷减轻了PrP暴露神经元中的线粒体自噬功能障碍和凋亡。这些发现表明，PrP上调PTEN - L，增强pSer65 - Parkin和pSer65 - Ub的去磷酸化，从而损害线粒体自噬起始。靶向PTEN - L的表达或活性可能代表一种治疗朊病毒病的新策略。
