Gu Linlin, Larson-Casey Jennifer L, Carter A Brent
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA;
FASEB J. 2017 Jul;31(7):3072-3083. doi: 10.1096/fj.201601371R. Epub 2017 Mar 28.
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 levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca 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 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.
包括肝脏、肾脏和肺在内的多个器官的纤维化通常继发于环境暴露。接触石棉是肺纤维化的一个重要环境原因。尽管肺泡巨噬细胞中的线粒体氧化应激对纤维化发展至关重要，但介导纤维化的机制尚未完全了解。线粒体钙水平可能与活性氧的产生有关。在这里，我们表明与正常患者相比，石棉沉着病患者的线粒体钙水平更高。线粒体钙单向转运体（MCU）是一种高度选择性的离子通道，可将钙转运到线粒体基质中以调节代谢。接触石棉增加了野生型小鼠而非MCU基因敲除小鼠的肺泡巨噬细胞中的线粒体钙内流。接触石棉后，MCU的表达使巨噬细胞极化为促纤维化表型，并且促纤维化极化由MCU介导的ATP产生调节。当MCU缺失或其活性被阻断时，促纤维化极化被消除。更重要的是，MCU基因敲除小鼠可免受肺纤维化的影响。线粒体钙的调节表明，MCU可能在纤维化发展中起关键作用，并且可能是肺纤维化的治疗靶点。——顾，L.，拉森-凯西，J.L.，卡特，A.B.巨噬细胞利用线粒体钙单向转运体进行促纤维化极化。
