Montelukast promotes mitochondrial biogenesis via CREB/PGC-1α in human bronchial epithelial cells

Abstract

Bronchial epithelial mitochondrial dysfunction including impaired mitochondrial biogenesis has been linked with the initiation and development of bronchial asthma. Montelukast, a robust antagonist of cysteinyl leukotriene receptors, has been widely applied for the therapies of bronchial asthma. However, the effects of montelukast in airway epithelial mitochondrial dysfunction are less reported. In the present study, we report that montelukast treatment in human bronchial epithelial cells of Beas-2b increased the expressions of PGC-1a, NRF-1 and TFAM. As expected, montelukast promoted mitochondrial biogenesis in Beas-2b cells through increasing mitochondrial mass, mtDNA/nDNA and the expression of cytochrome B. Importantly, we found that montelukast caused a functional gain in mitochondria of Beas-2b cells. Mechanistically, we found that montelukast treatment increased intracellular cAMP levels and activation of CREB. Blockage of CREB with H89 abolished montelukast-induced expression of PGC-1a. These findings report a novel pharmacological function of montelukast in stimulating mitochondrial biogenesis in Beas-2b cells, mediating by the CREB/PGC-1a pathway.

Effects of Hyperoxia on Mitochondrial Homeostasis: Are Mitochondria the Hub for Bronchopulmonary Dysplasia?

“…It can also regulate the key mitochondrial genes involved in adaptive thermogenesis by coordinating the expression of a large number of genes involved in glucose and fatty acid metabolism. Studies have shown that the clinical drugs used to improve breathing, such as aminophylline and montelukast, can promote the biogenesis of human alveolar epithelium mitochondria through cAMP responsive element binding protein (CREB)/PGC-1α (Wang et al, 2019;Wei et al, 2019). The use of the mitochondrial antioxidant resveratrol can protect mtDNA and reduce apoptosis through SIRT1-PGC-1a (Wang et al, 2020;Zhu et al, 2021).…”

Leukotriene Signaling as a Target in α-Synucleinopathies

“…Although the impact of LT signaling on autophagy or mitochondria is largely unresearched in neurodegenerative diseases, studies on non-neurological conditions suggest detrimental effects of LTs on the autophagic and mitochondrial system [113][114][115][116][117][118].…”

“…Notably, LT signaling seems to affect mitochondrial function at the CysLT 1 R as well as at the BLTR 1 level [116][117][118]. On the one hand, the intraperitoneal administration of the BLTR 1 inhibitor U75302 reversed mitochondrial complex I and II downregulation and attenuated mitochondrial impairment in the myocardium of an LPS-induced acute cardiac injury mouse model [116].…”

“…On the one hand, the intraperitoneal administration of the BLTR 1 inhibitor U75302 reversed mitochondrial complex I and II downregulation and attenuated mitochondrial impairment in the myocardium of an LPS-induced acute cardiac injury mouse model [116]. On the other hand, the idea of a possible therapeutic effect of LT inhibition on mitochondria is supported by in vitro studies on human bronchial epithelial cells showing that the CysLT 1 R antagonists Zafirlukast and MTK stimulate mitochondrial biogenesis via PGC-1α [117,118].…”

Montelukast Drug May Improve COVID-19 Prognosis: A Review of Evidence

“…These results support a role for oxidative stress during COVID-19. Importantly, protective effects of MK are not limited to inflammatory and microbial infectious attacks, but also include protection against chemotoxicity (bleomycin, cysplatin, doxorubicin, statin, paracetamol) (Hareedy et al, 2019) and radiotoxicity (Hormati et al, 2020) in animal experiments, which demonstrates some antioxidant properties resulting in increased mitochondrial mass and functionality, together with increased intracellular cyclic adenosine 3, 5′-monophosphate (cAMP) level and activation of the Krebs cycle (Wang et al, 2019).…”