Acinetobacter baumannii (A. baumannii) is one of the most common pathogens causing hospital-acquired infections. It exhibits robust environmental resilience and rapid acquisition of multidrug resistance, posing a serious threat in clinical settings [1]. The coexistence of multi-drug resistance and high virulence worsens the prognosis of clinically infected patients. Currently, the global prevalence of multidrug-resistant, extensively drug-resistant, and even completely drug-resistant A. baumannii is on an upward trajectory, posing a huge risk of the unavailability of effective drugs for clinical treatment. However, there is still a lack of effective research and exploration on the molecular pathogenic mechanism of A. baumannii.

Silencing information regulator 1 (SIRT1) is a NAD+ dependent deacetylase, and its role in mitochondrial function regulation has been widely studied. Our previous research has indicated that SIRT1 can repair mitochondrial oxidative stress damage induced by A. baumannii [2]. Mitochondria are important organelles for maintaining normal cellular physiological functions and play crucial roles in defending against pathogens, generating energy, reducing inflammation, and regulating cell death [3]. Dysfunctional mitochondria can be eliminated through various pathways (such as mitophagy) to maintain intracellular homeostasis [4]. Activation of autophagy can enhance the host's defense function and control infections caused by Mycobacterium tuberculosis [5]. The outer membrane vesicles of Neisseria gonorrhoeae can enhance their intracellular survival ability by inducing autophagy in epithelial cells and reducing reactive oxygen species (ROS) production [6]. In addition, Burkholderia pseudomallei hijacks the host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD [7]. Therefore, mitochondrial function and autophagy play a key role in various stress conditions, including infection, inflammation, and antimicrobial responses [8]. Autophagy sequesters cytoplasmic contents into double-layer membrane autophagy, which then fuse with lysosomes, leading to the degradation and recycling of the contents. This mechanism can protect cells from death, which is of great significance for maintaining epithelial barrier function and protecting the body from pathogens [9].

The airway epithelial barrier, encompassing tight junctions and adherens junctions, serve as the main protective structure against pathogens [10]. Regulating barrier function and enhancing mucosal defense are effective strategies for preventing infections associated with high morbidity and mortality. Destroying the integrity of airway epithelial cells will reduce epithelial resistance, increase permeability, and provide more opportunities for pathogen invasion. Intestinal epithelial tight junction proteins are considered to regulate the barrier permeability to bacterial toxins and pathogens [11]. SIRT1-mediated activation of mitophagy can promote the clearance of damaged mitochondria and improve the intestinal barrier function in mice [12]. Curcumin can improve H2O2-induced mitochondrial damage and intestinal barrier damage by promoting Parkin-dependent mitophagy [13]. Autophagy maintains cell barrier function by inhibiting epithelial cell necrosis, indicating that defective autophagy is a potential contributor to cell permeability. The above research shows that there is a close relationship between SIRT1 and mitophagy, and mitophagy is involved in the regulation of barrier function, which may become a novel target for the prevention and control of infectious diseases. However, the specific mechanism by which SIRT1 regulates mitophagy and the airway barrier, as well as its role in the pathogenesis of A. baumannii, remains unclear.

In this study, A. baumannii destroyed the normal structure and function of mitochondria and impeded the mitophagy process, resulting in the excessive accumulation of abnormal mitochondria and cell death by inducing cell barrier dysfunction. Moreover, it also caused airway barrier dysfunction by inhibiting the mitophagy process in mouse lung tissue, and increased the inflammation levels in broncho-alveolar lavage fluid (BALF) and peripheral blood as well as the mortality rate of mice. However, the activation of SIRT1 can drive the mitophagy process in BEAS-2B cells and mouse lung tissue, reduce cell damage, repair airway barrier dysfunction, and reduce the inflammation levels induced by A. baumannii. This reveals a previously unrecognized function of SIRT1-regulated mitophagy in the host defense against A. baumannii, and regulating such a process may become a new method to prevent and control A. baumannii infections.