miR-128-3p alleviates airway inflammation in asthma by targeting SIX1 to regulate mitochondrial fission and fusion.

ABSTRACT

Bronchial asthma is known for airway inflammation, hyperresponsiveness, and remodeling.MicroRNAs (MiRNAs) have been involved in the development of asthma, whereas, the mechanism of various MiRNAs in asthma remains to be elucidated. In this study, we aim to explore the mechanism of miR-128-3p in asthma-related airway inflammation by targeting sine oculis homeobox homolog 1 (SIX1) to regulate the mitochondrial function. In an ovalbumin (OVA) asthma mouse model, miR-128-3p levels were found to be significantly diminished. Administration of miR-128-3p agomir decreased peribronchial inflammatory cell infiltration and improved airway inflammation. Afterwards, we used the luciferase reporter assay to predict and confirmed that SIX1 is a target gene of miR-128-3p. Overexpression of miR-128-3p attenuated IL-13-induced cellular inflammation and ROS production in bronchial epithelial cells (BEAS-2B). In vitro, overexpression of miR-128-3p and SIX1 knockdown mitigated mitochondrial fragmentation, reduced Drp1-mediated mitochondrial division, and upregulated mitochondrial membrane potential. Moreover, led to decreased production of ROS/mitochondrial ROS, P-Drp1(616) and Fis1 expression, while enhancing P-Drp1(637), MFN1, caspase-3/9, and Bax-mediated apoptosis. Our findings demonstrated that miR-128-3p could alleviate airway inflammation by downregulating SIX1 and improving mitochondrial function, positioning the miR-128-3p/SIX1/Drp1 signaling as a potential therapeutic target for asthma.