Inhibition of MTERF4 disrupts mitochondrial function and attenuates amyloidogenic APP processing via HSDL2-mediated apoptosis and autophagy
Abstract
Abnormal proteolytic cleavage events and mitochondrial dysfunction are implicated in the neuropathology of Alzheimer’s disease (AD). Mitochondrial transcription factor 4 (MTERF4) is essential for mitochondrial ribosome assembly and translational regulation. In this study, we investigated the role of MTERF4 in mitochondrial dysfunction and amyloid precursor protein (APP) processing. MTERF4 knockdown (KD) significantly reduced adenosine triphosphate (ATP) production, mitochondrial DNA (mtDNA) copy number, and mitochondrial membrane potential (MMP) in HEK293-APPswe cells. To uncover the fundamental mechanisms, RNA sequencing (RNA-seq) analysis was conducted to screen for differentially expressed genes (DEGs). Notably, we demonstrated an upregulation of Hydroxysteroid dehydrogenase-like protein 2 (HSDL2), consistent with RNA-seq analysis, which has been implicated in apoptosis and autophagy regulation. Flow cytometry (FCM) analysis demonstrated that MTERF4 KD significantly reduced apoptosis, and subsequent experimental validation revealed that this effect was mediated via the Bcl-2/Bax/Caspase-3 pathway. Furthermore, MTERF4 KD notably raised the protein levels of Beclin-1 and ATG5, elevated the LC3Ⅱ/LC3Ⅰ ratio, and decreased P62 protein expression, thereby promoting autophagy. Additionally, MTERF4 KD resulted in reduced levels of APP, ADAM10, and secreted Aβ42. Moreover, MTERF4 KD reduced both α- and β-cleavage of APP. In conclusion, our study highlights the crucial role of MTERF4 in mitochondrial dysfunction and its regulatory effect on HSDL2 expression in HEK293-APPswe cells. MTERF4 inhibition suppresses apoptosis via the Bcl-2/Bax/Caspase-3 pathway and attenuates APP processing by enhancing autophagy. These findings indicate that MTERF4 is critically involved in AD pathogenesis and may serve as a potential therapeutic target.
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