Affiliation:
1. Department of Respiratory and Critical Care Medicine, The Geriatric Institute of Anhui, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R.China
2. Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R.China
Abstract
BACKGROUND:
Mitochondria are important in mediating airway inflammatory responses to cigarette smoke (CS). Removal of damaged or defective mitochondrial (mitophagy) may prevent the detrimental impact of CS extract (CSE) on airway and lung epithelial cells.
METHOD:
We studied the effect of a mitophagy activator (Urolithin A, UA) and a mitophagy inhibitor (Liensinine diperchlorate, Ld) on CSE-exposed alveolar (A549) and airway (BEAS-2B) epithelial cell proliferation, intracellular and mitochondrial ROS, inflammatory response, mitochondrial membrane potential (DYm), mitochondrial morphology, mitochondrial complex activities, and protein levels of mitochondrial fission (DRP1, MFF) and mitophagy (SQSTM1/p62, LC3B). In both cell types, CSE exposure led to increased intracellular and mitochondrial oxidative stress, decreased DYm and resulted in structural disruption of the mitochondrial network. CSE increased the expression of DRP1, MFF and SQSTM1/p62, while decreasing the ratio of LC3B-II/I protein expression. CSE also increased inflammatory (IL-1β, IL-6, IL-18, CXCL1, CXCL8) and necroptosis factors (RIPK1, RIPK3, MLKL) mRNA expression.
RESULT:
Pre-treatment with UA attenuated CSE-induced oxidative stress, inflammatory and necroptosis gene expression and restored mitochondrial structure and function. UA also prevented CSE-evoked increases in DRP1, MFF and SQSTM1/p62 protein expression and increased LC3B-II/I ratio.
CONCLUSION:
Conversely, pre-treatment with Ld aggravated CSE-induced cellular and mitochondrial responses. In conclusion, mitophagy mediates CSE-induced damage and inflammation to lung epithelial cells and may represent a therapeutic target in CS-driven diseases.
Publisher
Bentham Science Publishers Ltd.
Subject
Molecular Biology,Molecular Medicine,General Medicine,Biochemistry