Premium
Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization
Author(s) -
Gu Linlin,
LarsonCasey Jennifer L.,
Carter A. Brent
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201601371r
Subject(s) - fibrosis , mitochondrion , uniporter , mitochondrial ros , microbiology and biotechnology , pulmonary fibrosis , macrophage polarization , reactive oxygen species , cancer research , chemistry , biology , medicine , macrophage , biochemistry , cytosol , in vitro , enzyme
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 Ca 2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca 2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca 2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca 2+ 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 Ca 2+ 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. FASEB J. 31, 3072–3083 (2017). www.fasebj.org