RT Journal Article SR Electronic T1 Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaax9093 DO 10.1126/sciadv.aax9093 VO 6 IS 19 A1 Rimessi, Alessandro A1 Pozzato, Chiara A1 Carparelli, Lorenzo A1 Rossi, Alice A1 Ranucci, Serena A1 De Fino, Ida A1 Cigana, Cristina A1 Talarico, Anna A1 Wieckowski, Mariusz R. A1 Ribeiro, Carla M. P. A1 Trapella, Claudio A1 Rossi, Giacomo A1 Cabrini, Giulio A1 Bragonzi, Alessandra A1 Pinton, Paolo YR 2020 UL http://advances.sciencemag.org/content/6/19/eaax9093.abstract AB Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum–mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonas aeruginosa 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.