MST1, a novel therapeutic target for Alzheimer's disease, regulates mitochondrial homeostasis by mediating mitochondrial DNA transcription and the PI3K-Akt-ROS pathway

作者：Dongqing Cui, Haixia Liu, Lili Cao, Xiaowei Du, Dingxin Liu, Zhi-Ping Liu, Tong Wang, Hui Yang, Xiaolei Zheng, Zhaohong Xie, Shunliang Xu, Jianzhong Bi, Ping Wang · 发表于：Journal of Translational Medicine · 年份：2024 · DOI：10.1186/s12967-024-05852-x · 被引用次数：23 · 研究领域：Hippo pathway signaling and YAP/TAZ、Microtubule and mitosis dynamics、Melanoma and MAPK Pathways

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 m...