SIRT1 activation restores PINK1-dependent mitophagy to reverse airway barrier dysfunction in Acinetobacter baumannii infection.

Abstract

A. baumannii is one of the most widespread extensively drug-resistant pathogens in hospital environments. It exhibits robust resistance to a variety of adverse conditions and enables prolonged survival in clinical settings. However, the molecular pathogenesis and regulatory mechanisms of highly virulent A. baumannii strains remain incompletely elucidated. Here, novel evidence is presented indicating that A. baumannii induces mitochondrial damage while concurrently suppressing mitophagy. This suppression results in the accumulation of dysfunctional mitochondria, ultimately causing cellular barrier dysfunction and cell death. Furthermore, based on a mouse pneumonia model infected with A. baumannii, it is demonstrated that the pathogen impairs PINK1-dependent mitophagy in vivo. This impairment significantly increases inflammatory cell infiltration in the lungs and elevates the levels of inflammatory factors in peripheral blood and bronchoalveolar lavage fluid, thereby markedly increasing mortality rates. Importantly, the activation of SIRT1 partially restores cellular and airway barrier functions by up-regulating PINK1-dependent mitophagy, consequently attenuating the virulence and pathogenicity of A. baumannii. Our findings reveal that the maintenance of barrier integrity mediated by mitophagy plays a critical role in regulating the virulence of this pathogen. This discovery may contribute to the development of innovative therapeutic strategies targeting mitochondrial pathways to combat infections caused by A. baumannii strains.