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

• DOI: 10.1186/s12967-024-05852-x
• Publication Date: 2024-11-22T12:00:27Z
• Authors: Dongqing Cui; Haixia Liu; Lili Cao; Xiaowei Du; Dingxin Liu; Zhiping Liu; Tong Wang; Hui Yang; Xiaolei Zheng; Zhaohong Xie; Shunliang Xu; Jianzhong Bi; Ping Wang
• Keywords: Hippo signaling pathway; Cognitive Decline

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