Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis
Alessandro Rimessi, Chiara Pozzato, Lorenzo Carparelli, Alice S. Rossi, Serena Ranucci, Ida De Fino, Cristina Cigana, Anna Maria Talarico, Mariusz R. Wiȩckowski, Carla M. P. Ribeiro, Claudio Trapella, Giacomo Rossi, Giulio Cabrini, Alessandra Bragonzi, Paolo Pinton
Abstract
infection increases endoplasmic reticulum-mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein-associated protein B-protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease.