Loss of ANT1 Increases Fibrosis and Epithelial Cell Senescence in Idiopathic Pulmonary Fibrosis.
Loss of ANT1 Increases Fibrosis and Epithelial Cell Senescence in Idiopathic Pulmonary Fibrosis.
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ANT1 的缺失会增加特发性肺纤维化中的纤维化和上皮细胞衰老。
DOI：
10.1165/rcmb.2022-0315oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Kliment,CorrineR
中科院分区：
文献类型：
--
作者：
Sui,Justin;Boatz,JenniferC;Shi,Jian;Hu,Qianjiang;Li,Xiaoyun;Zhang,Yingze;Königshoff,Melanie;Kliment,CorrineR
特发性肺纤维化（IPF）是一种间质性肺疾病，其特征是进行性肺瘢痕形成和重塑。尽管存在减缓疾病进展的治疗方法，但 IPF 是不可逆转的，并且无法治愈。细胞衰老是衰老的一个主要标志，与 IPF 发病机制有关，并且线粒体功能障碍越来越被认为是衰老的驱动因素。腺嘌呤核苷酸转位酶 (ANT) 是丰富的线粒体 ATP-ADP 转运蛋白，对于调节细胞命运和维持线粒体功能至关重要。我们试图确定 ANT 的改变如何影响肺纤维化中的细胞衰老。通过单细胞 RNA 测序和组织染色，我们发现 IPF 患者肺部中的 SLC25A4（溶质载体家族 25 成员 4）（ANT1）和 SLC25A5（ANT2）表达降低，特别是在肺泡 II 型（AT2）细胞内。肺上皮细胞中 siRNA 导致 ANT1 缺失，导致 β-半乳糖苷酶和 p21 等衰老标志物增加，烟酰胺腺嘌呤二核苷酸与还原型烟酰胺腺嘌呤二核苷酸的比例降低。与博莱霉素处理的对照细胞相比，博莱霉素处理的 ANT1 敲低细胞的衰老标记物也有所增加。 AT2 细胞中 ANT1 的缺失导致肺泡类器官生长减少，染色显示 p21 增加。在博来霉素和石棉诱导的肺纤维化小鼠模型中，ANT1的整体缺失导致肺纤维化恶化并加速衰老。总之，ANT1 的缺失通过线粒体功能障碍、衰老增加和 AT2 细胞再生能力下降导致 IPF 发病，从而导致肺纤维化加剧。 ANT 的调节提供了一种新的治疗途径，可以改变细胞衰老途径并限制肺纤维化。
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by progressive lung scarring and remodeling. Although treatments exist that slow disease progression, IPF is irreversible, and there is no cure. Cellular senescence, a major hallmark of aging, has been implicated in IPF pathogenesis, and mitochondrial dysfunction is increasingly recognized as a driver of senescence. Adenine nucleotide translocases (ANTs) are abundant mitochondrial ATP–ADP transporters critical for regulating cell fate and maintaining mitochondrial function. We sought to determine how alterations in ANTs influence cellular senescence in pulmonary fibrosis. We found thatSLC25A4(solute carrier family 25 member 4) (ANT1) andSLC25A5(ANT2) expression is reduced in the lungs of patients with IPF, particularly within alveolar type II (AT2) cells, by single-cell RNA sequencing and tissue staining. Loss of ANT1 by siRNA in lung epithelial cells resulted in increased senescence markers such as β-galactosidase and p21, with a reduction in the ratio of nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide. Bleomycin-treated ANT1 knockdown cells also had increased senescence markers compared with bleomycin-treated control cells. Loss of ANT1 in AT2 cells resulted in a reduction in alveolar organoid growth, with an increase in p21 by staining. Global loss of ANT1 resulted in worse lung fibrosis and increased senescence in the bleomycin- and asbestos-induced mouse models of pulmonary fibrosis. In summary, loss of ANT1 contributes to IPF pathogenesis through mitochondrial dysfunction, increased senescence, and decreased regenerative capacity of AT2 cells, resulting in enhanced lung fibrosis. Modulation of ANTs presents a new therapeutic avenue that may alter cellular senescence pathways and limit pulmonary fibrosis.