TY - JOUR
T1 - Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis
AU - Rimessi, Alessandro
AU - Pozzato, Chiara
AU - Carparelli, Lorenzo
AU - Rossi, Alice
AU - Ranucci, Serena
AU - de Fino, Ida
AU - Cigana, Cristina
AU - Talarico, Anna
AU - Wieckowski, Mariusz R.
AU - Ribeiro, Carla M.P.
AU - Trapella, Claudio
AU - Rossi, Giacomo
AU - Cabrini, Giulio
AU - Bragonzi, Alessandra
AU - Pinton, Paolo
N1 - Funding Information:
This study was supported initially by the Italian Cystic Fibrosis Research Foundation (grant FFC no. 19/2014 to P.P., FFC no. 20/2015 to A.R., and CFaCore to A.B.). Moreover, the Signal Transduction Laboratory is supported by the following: the local founds from University of Ferrara, FIR-2017, the Italian Ministry of Health (GR-2016-02364602), and the Italian Ministry of Education, University and Research (PRIN grant 2017XA5J5N) to A.R. and the Italian Association for Cancer Research (AIRC, IG-23670), Telethon (GGP11139B), local funds from the University of Ferrara, and the Italian Ministry of Education, University and Research (PRIN grant 2017E5L5P3) to P.P. M.R.W. was supported by the Polish National Science Centre (grant UMO-2014/15/NZ1/00490). P.P. is grateful to C. d. Scrovegni for continuous support.
Publisher Copyright:
Copyright © 2020 The Authors.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/5
Y1 - 2020/5
N2 - 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 Pseudomonasaeruginosainfection 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.
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 Pseudomonasaeruginosainfection 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.
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U2 - 10.1126/sciadv.aax9093
DO - 10.1126/sciadv.aax9093
M3 - Article
C2 - 32494695
AN - SCOPUS:85084936689
VL - 6
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 19
M1 - eaax9093
ER -