Deficiency of Mitochondrial Fatty Acid Enzyme,
CPT1A
, Underlies Airway Epithelial Barrier Dysfunction in Severe Asthma
Muyun Wang, Haiyang Hu, Kun Wang, Di Wu, Ximing Liao, Jing Gao, Tian Li, Wujian Xu, Shaoyong Gao, Qiang Li, Pankaj Kumar Bhavsar, Wei Gao, Kian Fan Chung ABSTRACT
Background
Mitochondrial fatty acid oxidation through carnitine palmitoyltransferase‐1A (CPT1A) leads to ATP generation. We examined its role in regulating permeability and mitochondrial metabolic homeostasis of airway epithelial cells in asthma.
Methods
Primary nasal epithelial cells (NECs) from healthy controls and severe asthma (SA) patients in air‐liquid interface (ALI) were exposed to CPT1A siRNA/ CPT1A overexpression lentiviral/L‐carnitine (LCA). Epithelial TEER and FITC‐dextran transport were measured. Bronchial biopsies from healthy and SA subjects and house dust mite (HDM) asthma mouse model were also studied.
Results
In NECs‐ALI and in bronchial epithelial cells (BECs) from bronchial biopsies of SA, CPT1A expression was reduced compared to healthy controls. Knock‐down of CPT1A in healthy NECs reduced expression of Occludin and E‐cadherin and impaired epithelial barrier integrity (EBI), while upregulation of CPT1A with CPT1A overexpression lentiviral/LCA in SA‐NECs increased the barrier proteins with improved EBI. CPT1A knockdown in healthy BECs increased release of mtROS, with mitochondrial disruption and activation of ERK1/2‐NF‐κB signaling pathway. These were aggravated with HDM exposure but N‐acetyl‐cysteine and MitoTempo reduced p‐ERK1/2 and p‐P65 activation, as well as EBI with CPT1A knockdown and HDM. In the mouse model, there was decreased airway epithelial CPT1A protein expression, associated with reduced airway hyperreactivity and inflammation, and in Occludin and ZO‐1 expression, effects partly reversed by LCA, with restoration of mitochondrial integrity and EBI.
Conclusion
CPT1A maintains epithelial barrier function through restoration of mitochondrial function in asthmatic airway epithelial cells. Restoration of deficient epithelial CPT1A of SA may represent a new treatment approach.