Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD
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DOI：
10.1172/jci74985
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发表时间：
2014-09-01
影响因子：
15.9
通讯作者：
Choi, Augustine M. K.
中科院分区：
文献类型：
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作者：
Mizumura, Kenji;Cloonan, Suzanne M.;Choi, Augustine M. K.
慢性阻塞性肺疾病（COPD）的发病机制尚不清楚，但涉及肺泡表面积的损失（肺气肿）和气道炎症（支气管炎）作为香烟烟雾（CS）暴露的结果。以前，我们证明了自噬蛋白促进肺上皮细胞死亡，气道功能障碍，肺气肿响应CS，然而，潜在的机制尚未阐明。在这里，使用培养的肺上皮细胞和小鼠模型，我们证明，CS导致线粒体功能障碍，这是与线粒体膜电位降低。CS通过稳定线粒体自噬调节因子PINK 1诱导线粒体自噬，即线粒体的自噬依赖性消除。CS引起细胞死亡，通过施用坏死或坏死性凋亡抑制剂来减少。PINK 1和线粒体分裂/线粒体自噬抑制剂Mdivi-1的遗传缺陷在体外保护CS诱导的细胞死亡和线粒体功能障碍，并减少MLKL的磷酸化，MLKL是坏死性凋亡途径中RIP 3的底物。此外，Pink 1（-/-）小鼠在CS暴露期间受到保护，免受线粒体功能障碍、空域扩大和粘膜纤毛清除（MCC）破坏。Mdivi-1治疗还改善了CS暴露小鼠中CS诱导的MCC破坏。在人COPD中，肺上皮细胞显示PINK 1和RIP 3的表达增加。这些发现暗示了在肺气肿变化中响应于CS暴露的线粒体自噬依赖性坏死性凋亡，表明该途径是COPD的治疗靶点。
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.