Journal article
Inhibition of the mitochondrial calcium uniporter prevents IL-13 and allergen-mediated airway epithelial apoptosis and loss of barrier function
Experimental cell research, Vol.362(2), pp.400-411
01/15/2018
DOI: 10.1016/j.yexcr.2017.12.003
PMCID: PMC6330015
PMID: 29225050
Abstract
Mitochondria are increasingly recognized as key mediators of acute cellular stress responses in asthma. However, the distinct roles of regulators of mitochondrial physiology on allergic asthma phenotypes are currently unknown. The mitochondrial Ca2+ uniporter (MCU) resides in the inner mitochondrial membrane and controls mitochondrial Ca2+ uptake into the mitochondrial matrix. To understand the function of MCU in models of allergic asthma, in vitro and in vivo studies were performed using models of functional deficiency or knockout of MCU. In primary human respiratory epithelial cells, MCU inhibition abrogated mitochondrial Ca2+ uptake and reactive oxygen species (ROS) production, preserved the mitochondrial membrane potential and protected from apoptosis in response to the pleiotropic Th2 cytokine IL-13. Consequently, epithelial barrier function was maintained with MCU inhibition. Similarly, the endothelial barrier was preserved in respiratory epithelium isolated from MCU-/- mice after exposure to IL-13. In the ovalbumin-model of allergic airway disease, MCU deficiency resulted in decreased apoptosis within the large airway epithelial cells. Concordantly, expression of the tight junction protein ZO-1 was preserved, indicative of maintenance of epithelial barrier function. These data implicate mitochondrial Ca2+ uptake through MCU as a key controller of epithelial cell viability in acute allergic asthma.
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•IL-13 promotes mitochondrial matrix Ca2+ uptake, ROS production and apoptosis in respiratory epithelium.•MCU inhibition blocks mitochondrial ROS production and membrane depolarization.•MCU inhibition prevents apoptosis and epithelial barrier dysfunction.•Inhibition of MCU reduces allergen-mediated epithelial cell death in vivo.
Details
- Title: Subtitle
- Inhibition of the mitochondrial calcium uniporter prevents IL-13 and allergen-mediated airway epithelial apoptosis and loss of barrier function
- Creators
- Sara C Sebag - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USAOlha M Koval - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USAJohn D Paschke - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USAChristopher J Winters - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USAAlejandro P Comellas - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USAIsabella M Grumbach - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Experimental cell research, Vol.362(2), pp.400-411
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.yexcr.2017.12.003
- PMID
- 29225050
- PMCID
- PMC6330015
- ISSN
- 0014-4827
- eISSN
- 1090-2422
- Grant note
- name: University of Iowa Carver College of Medicine Innovative Science
- Language
- English
- Date published
- 01/15/2018
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; ICTS; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984094312502771
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