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Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis
- Source :
- Science Advances
- Publication Year :
- 2020
- Publisher :
- American Association for the Advancement of Science, 2020.
-
Abstract
- Mitochondrial therapy offers an alternative strategy for attenuation of hyperinflammation in cystic fibrosis lung disease.<br />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.
- Subjects :
- autophagy
congenital, hereditary, and neonatal diseases and abnormalities
Cystic Fibrosis
inhibitor KB-R7943
molecular mechanisms
chemistry.chemical_element
receptors
Inflammation
Protein tyrosine phosphatase
Calcium
Mitochondrion
medicine.disease_cause
Cystic fibrosis
NO
resistance
Mitochondrial Proteins
03 medical and health sciences
CA2+
0302 clinical medicine
medicine
Humans
Health and Medicine
Research Articles
030304 developmental biology
0303 health sciences
Multidisciplinary
Pseudomonas aeruginosa
Endoplasmic reticulum
Autophagy
signals
SciAdv r-articles
Cell Biology
Pneumonia
respiratory system
medicine.disease
Cell biology
respiratory tract diseases
mitophagy
chemistry
NA+/CA2+ exchange
NA+/CA2+ exchange, molecular mechanisms, inhibitor KB-R7943, autophagy, CA2+, mitophagy, receptors, signals, complex, resistance
Calcium Channels
medicine.symptom
030217 neurology & neurosurgery
complex
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23752548
- Volume :
- 6
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi.dedup.....1208ef5acb1eb1da5aba07ac5c04a26a