title: Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.
abstract: Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Gu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larson-Casey
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; bcarter1@uab.edu.|Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA.
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001195:Asbestosis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D011658:Pulmonary Fibrosis; D017382:Reactive Oxygen Species; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: ATP; MCU; asbestos; pulmonary fibrosis; reactive oxygen species