The Mitochondrial Fusion Promoter M1 Mitigates Cigarette Smoke-Induced Airway Inflammation and Oxidative Stress via the PI3K-AKT Signaling Pathway.

Abstract

Purpose: This study investigated the efficacy and underlying mechanism of the mitochondrial fusion promoter M1 in mitigating cigarette smoking (CS)-induced airway inflammation and oxidative stress both in vitro and in vivo models.

Methods: Cigarette smoke extract (CSE)-treated airway epithelial cells (BEAS-2B) and CS-exposed mice were pretreated with M1, followed by the measurement of proinflammatory cytokines, oxidative stress, mitochondrial fusion proteins (MFN2 and OPA1) and fission proteins (DRP1 and MFF). Molecular pathways were elucidated through transcriptomic analysis and Western blotting.

Results: M1 pretreatment in CSE-treated cells significantly reduced the release of inflammatory cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α); reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels; increased superoxide dismutase (SOD) activity; protected mitochondrial function by increasing the expression of mitochondrial fusion proteins (MFN2 and OPA1) and decreasing the expression of mitochondrial fission proteins (DRP1 and MFF). M1 attenuated CS-induced lung histologic damage and mucus hypersecretion in mice, relieved high oxidative stress and reduced the release of IL-6 and IL-8 in BALF. Similarly, it also protected mitochondrial function by regulating the CS-induced imbalance of mitochondrial dynamic proteins. Transcriptome sequencing and Western blotting showed that M1 inhibited CSE- or CS-induced activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway.

Conclusion: M1 plays a protective role in inflammation, oxidative stress and mitochondrial dynamics dysfunction caused by CS by inhibiting the PI3K-AKT signaling pathway; thus, it has therapeutic potential for the treatment of CS-induced airway disorders.