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.