MST1 是阿尔茨海默病的一个新的治疗靶点，通过调节线粒体 DNA 转录和 PI3K-Akt-ROS 通路来调节线粒体稳态。

BACKGROUND: Alzheimer's disease (AD) is a prevalent irreversible neurodegenerative condition marked by gradual cognitive deterioration and neuronal loss. The mammalian Ste20-like kinase (MST1)-Hippo pathway is pivotal in regulating cell apoptosis, immune response, mitochondrial function, and oxidative stress. However, the association between MST1 and mitochondrial function in AD remains unknown. Therefore, this study investigates the effect of MST1 on neuronal damage and cognitive impairment by regulating mitochondrial homeostasis in AD. METHODS: In this study, 4- and 7-month-old 5xFAD mice were selected to simulate the early and middle stages of AD, respectively; age-matched wild-type mice served as controls for comparative analysis. Adeno-associated virus (AAV) was injected into the hippocampus of mice. Four weeks post-injection, cognitive function, neuronal damage indicators, and mitochondrial morphology, dynamics, oxidative stress, ATP, and apoptosis-related indicators were evaluated. Additionally, RNA-sequencing was performed on the hippocampal tissue of 5xFAD mice and MST1-knockdown 5xFAD mice. Subsequently, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on differentially expressed genes to elucidate the potential mechanism of MST1. In vitro studies were performed to investigate the effects of MST1 on SH-SY5Y model cell viability and mitochondrial function and validate the potential underlying molecular mechanisms. RESULTS: MST1 overexpression accelerated neuronal degeneration and cognitive deficits in vivo while promoting oxidative stress and mitochondrial damage. Similarly, in vitro, MST1 overexpression facilitated apoptosis and mitochondrial dysfunction. MST1 knockdown and chemical inactivation reduced cognitive decline, mitochondrial dysfunction, and neuronal degeneration. Mechanistically, MST1 regulated the transcription of mitochondrial genes, including MT-ND4L, MT-ATP6, and MT-CO2, by binding to PGC1α. Moreover, MST1 influenced cellular oxidative stress through the PI3K-Akt-ROS pathway, ultimately disrupting mitochondrial homeostasis and mediating cell damage. CONCLUSIONS: Cumulatively, these results suggest that MST1 primarily regulates mitochondrial DNA transcription levels by interacting with PGC1α and modulates cellular oxidative stress through the PI3K-Akt-ROS pathway, disrupting mitochondrial homeostasis. This discovery can be exploited to potentially enhance mitochondrial energy metabolism pathways by targeting MST1, offering novel potential therapeutic targets for treating AD.

背景：阿尔茨海默病（AD）是一种常见的不可逆神经退行性疾病，其特征是认知能力逐渐下降和神经元丧失。哺乳动物 Ste20 样激酶（MST1）-Hippo 通路在调节细胞凋亡、免疫反应、线粒体功能和氧化应激方面起着关键作用。然而，MST1 与 AD 中线粒体功能之间的关联尚不清楚。因此，本研究通过调节 AD 中线粒体的动态平衡，研究了 MST1 对神经元损伤和认知障碍的影响。

方法：本研究选择 4 月龄和 7 月龄的 5xFAD 小鼠分别模拟 AD 的早期和中期阶段，年龄匹配的野生型小鼠作为对照进行比较分析。将腺相关病毒（AAV）注入小鼠海马体。注射后 4 周，评估认知功能、神经元损伤标志物以及线粒体形态、动力学、氧化应激、ATP 和凋亡相关指标。此外，对 5xFAD 小鼠和 MST1 敲低 5xFAD 小鼠的海马组织进行 RNA 测序。随后，对差异表达基因进行基因本体论（GO）富集和京都基因与基因组百科全书（KEGG）通路分析，以阐明 MST1 的潜在机制。体外研究旨在探讨 MST1 对 SH-SY5Y 模型细胞活力和线粒体功能的影响，并验证潜在的分子机制。

结果：MST1 过表达加速了体内神经元退化和认知缺陷，同时促进了氧化应激和线粒体损伤。同样，在体外，MST1 过表达促进了细胞凋亡和线粒体功能障碍。MST1 敲低和化学失活减少了认知下降、线粒体功能障碍和神经元退化。机制上，MST1 通过与 PGC1α 结合，调节线粒体基因（包括 MT-ND4L、MT-ATP6 和 MT-CO2）的转录。此外，MST1 通过 PI3K-Akt-ROS 通路影响细胞内氧化应激，最终破坏线粒体稳态并介导细胞损伤。

结论：综上所述，这些结果表明，MST1 主要通过与 PGC1α 相互作用来调节线粒体 DNA 转录水平，并通过 PI3K-Akt-ROS 通路调节细胞氧化应激，破坏线粒体稳态。这一发现可用于通过靶向 MST1 增强线粒体能量代谢途径，为治疗 AD 提供新的潜在治疗靶点。