SRT1720 Protects Against CSE-Induced Cellular Senescence via Accelerates of FOXO3-PINK1-mediated Mitophagy

Abstract BackgroundChronic obstructive pulmonary disease (COPD) is often associate with cigarette smoke extract (CSE)-introduced bronchial epithelial cell senescence, mitochondrial fragmentation. Sirtuin-1(Sirt1) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of CSE introduced bronchial epithelial cell senescence in COPD although the precise mechanism(s) remain elusive. Here we hypothesized that SRT1720, a pharmacological SIRT1720 activator, exerts protect against COPD by activating PINK1 mediated mitophagy, en route to preserved mitochondrial homeostasis.MethodsCOPD rats model was established by CS exposure. During 6 months of SRT1720 treatment, airway resistance, cellular senescence and mitochondrial injury, mitophagy in the lung tissues of model rats were examined by western blot(WB) and histochemical and immunofluorescence staining. Transmission electron microscopy was also carried to elucidate the effects of SRT1720.Human bronchial epithelial cells(HBEC) were used to clarify the underlying molecular mechanisms. ResultDuring the introduction of CSE in cellular or rats, administration of SRT1720 improved airway resistance, cellular senescence and mitochondrial injury, accompanied with suppressed autophagy and mitophagy. Mitochondrial damage, cellular senescence and lung injury under contrast exposure were more severe in FOXO3 or Pink1 deficient cells and mice than in SRT1720 groups. Activation of Sirt1 by treating with SRT1720 induces autophagy enhanced. A Decrease in sirt1 expression caused by selisistat treatment promotes senescence.ConclusionsTaken together, our data suggested that suppressed SIRT1/FOXO3/Pink1 signaling mediated mitophagy played a protective role in COPD by reducing mitochondrial reactive oxygen species (ROS).