The mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid β-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid β-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

线粒体钙单向转运体 (MCU) 调节肺巨噬细胞的代谢重编程和肺纤维化的进展。纤维化进展与肺巨噬细胞的凋亡抗性有关；然而，发生细胞凋亡抗性的机制知之甚少。在这里，我们发现特发性肺纤维化 (IPF) 受试者的肺巨噬细胞中线粒体 B 细胞淋巴瘤 2 (Bcl-2) 显着增加。在博莱霉素损伤的野生型 ( WT ) 小鼠中观察到类似的发现，而在表达显性负性线粒体钙单向转运体 ( DN-MCU ) 的小鼠中 Bcl-2 显着降低）。肉碱棕榈酰转移酶 1a (Cpt1a) 是脂肪酸 β 氧化的限速酶，通过与其 BH3 结构域结合直接与 Bcl-2 相互作用，将 Bcl-2 锚定在线粒体中以减弱细胞凋亡。这种相互作用依赖于 Cpt1a 活性。来自 IPF 受试者的肺巨噬细胞在 CPT1A 和 Bcl-2 之间具有直接相关性，而缺乏结合会诱导细胞凋亡。巨噬细胞中 Bcl-2 的缺失可保护小鼠免于发展为肺纤维化。此外，当 Bcl-2 被删除或在纤维化建立后被 ABT-199 抑制时，小鼠有分辨率。这些观察结果表明巨噬细胞脂肪酸 β 氧化、细胞凋亡抗性和失调的纤维化重塑之间存在相互作用。