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

Background Alzheimer's disease (AD) stands as one of the prevalent irreversible neurodegenerative conditions 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 aims to investigate the effect of MST1 on neuronal damage and cognitive impairment by regulating mitochondrial homeostasis in AD. Methods In this study, we selected 4- and 7-month-old 5xFAD mice to simulate the early and middle stages of AD, we assessed cognitive function, detected neuronal damage indicators, and evaluated mitochondrial morphology, dynamics, oxidative stress, ATP, and mitochondrial apoptosis-related indicators. We employed RNA-seq technology to explore potential mechanisms of action. In vitro studies were conducted to investigate the effects of MST1 on the viability and mitochondrial function of SH-SY5Y model cells, aiming to validate the potential molecular mechanisms of MST1. Results Overexpression of MST1 accelerated neuronal degeneration and cognitive deficits, alongside promoting oxidative stress and mitochondrial damage. Similarly, in cell models, MST1 overexpression facilitated apoptosis and mitochondrial dysfunction. Knockdown of MST1 expression and chemical inactivation of MST1 improved cognitive decline, mitochondrial dysfunction while reducing neuronal degeneration. In terms of mechanism, MST1 was found to regulate the transcription of mitochondrial genes, including MT-Nd4L, MT-ATP6, and MT-CO2, by binding to PGC1α. It influenced cellular oxidative stress through the PI3K-Akt-ROS pathway, ultimately disrupting mitochondrial homeostasis and mediating cell damage. Conclusion Overall, our results showed that MST1 primarily regulates mitochondrial DNA transcription levels by interacting with PGC1α and modulates cellular oxidative stress through the PI3K-Akt-ROS pathway, thereby disrupting mitochondrial homeostasis. This discovery can potentially enhance mitochondrial energy metabolism pathways by targeting MST1, thereby offering novel potential therapeutic targets for treating AD.