The airway smooth muscle sodium/calcium exchanger NCLX is critical for airway remodeling and hyperresponsiveness in asthma

Abstract

The structural changes of airway smooth muscle (ASM) that characterize airway remodeling (AR) are crucial to the pathogenesis of asthma. During AR, ASM cells dedifferentiate from a quiescent to a proliferative, migratory, and secretory phenotype. Calcium (Ca²⁺) is a ubiquitous second messenger that regulates many cellular processes, including proliferation, migration, contraction, and metabolism. Furthermore, mitochondria have emerged as major Ca²⁺ signaling organelles that buffer Ca²⁺ through uptake by the mitochondrial Ca²⁺ uniporter and extrude it through the Na⁺/Ca²⁺ exchanger (NCLX/Slc8b1). Here, we show using mitochondrial Ca²⁺-sensitive dyes that NCLX only partially contributes to mitochondrial Ca²⁺ extrusion in ASM cells. Yet, NCLX is necessary for ASM cell proliferation and migration. Through cellular imaging, RNA-Seq, and biochemical assays, we demonstrate that NCLX regulates these processes by preventing mitochondrial Ca²⁺ overload and supporting store-operated Ca²⁺ entry, activation of Ca²⁺/calmodulin-dependent kinase II, and transcriptional and metabolic reprogramming. Using small animal respiratory mechanic measurements and immunohistochemistry, we show that smooth muscle-specific NCLX KO mice are protected against AR, fibrosis, and hyperresponsiveness in an experimental model of asthma. Our findings support NCLX as a potential therapeutic target in the treatment of asthma.

Keywords: CaMKII; NCLX; SOCE; airway fibrosis; airway hyperresponsiveness; airway remodeling; asthma; calcium signaling; metabolism; mitochondrial calcium.