Implication of mitochondrial metabolism in smooth muscle remodeling in asthma

Abstract

Bronchial smooth muscle (BSM) remodeling has an important prognostic value in asthma. BSM cell hyperplasia has been related to an increased proliferation of asthmatic BSM cells in vitro and ex vivo. We demonstrated that this increase was related to an increased number of mitochondria in the BSM of severe asthmatic patients. However, the impact of this increased mitochondrial mass on asthmatic BSM cell metabolism remains to be elucidated. We then enrolled 18 asthmatic patients from the COBRA cohort, and 27 control subjects. Asthmatic patients were similar to control subjects in terms of sex ratio, age and BMI but presented a lower FEV-1. Energetic metabolism was modified in asthmatic BSM cells, since oxygen consumption was increased and less lactate was produced than in control with no difference in glucose consumption. Then, we explored the TCA cycle intermediates and highlighted a significant increased level of pyruvate, succinate and malate in asthmatic BSM cells. Those results indicated that asthmatic BSM cells shifted their metabolism for oxidative phosphorylation. Large-scale proteomic confirmed an altered expression of oxidative enzymes, and in particular an upregulation of CPT2, underlying this metabolic shift in asthmatic BSM cells. Moreover, we showed a significant increased fatty acid internalization in asthmatic BSM cells, demonstrating the importance of fatty acid consumption in asthmatic BSM. Finally, inhibition of CPT2, significantly decreased asthmatic BSM cell proliferation. Taken together asthmatic BSM cells shifted their metabolism and CPT2 enzyme was crucial for asthmatic BSM cell proliferation. Then CPT2 could be a new therapeutic target against BSM remodeling in asthma.