Inhibition of the mitochondrial calcium uniporter prevents IL-13 and allergen-mediated airway epithelial apoptosis and loss of barrier function
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA (United States)
Highlights: • IL-13 promotes mitochondrial matrix Ca{sup 2+} 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. 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 Ca{sup 2+} uniporter (MCU) resides in the inner mitochondrial membrane and controls mitochondrial Ca{sup 2+} 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 Ca{sup 2+} 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 Ca{sup 2+} uptake through MCU as a key controller of epithelial cell viability in acute allergic asthma.
- OSTI ID:
- 23082498
- Journal Information:
- Experimental Cell Research, Vol. 362, Issue 2; Other Information: Published by Elsevier Inc.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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