Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice.
Mitochondrial quality control in alveolar epithelial cells damaged by S. aureus pneumonia in mice.
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DOI：
10.1152/ajplung.00197.2017
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发表时间：
2017-06
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影响因子：
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通讯作者：
H. Suliman;B. Kraft;Raquel R Bartz;Lingye Chen;K. Welty-Wolf;C. Piantadosi
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作者：
H. Suliman;B. Kraft;Raquel R Bartz;Lingye Chen;K. Welty-Wolf;C. Piantadosi
线粒体损伤在急性肺损伤（ALI）中经常被忽视，然而肺的大多数生理过程，例如气道张力、粘膜纤毛清除、通气-灌注（Va/Q）匹配和免疫监视需要有氧能量提供。由于细胞的线粒体质量控制（QC）过程调节受损线粒体的消除和替换以维持细胞存活，因此我们在经验证的金黄色葡萄球菌肺炎模型中连续评估了小鼠肺泡区域的线粒体生物发生和线粒体自噬。我们报告说，除了细胞裂解直接接触微生物，适度的上皮细胞死亡，尽管检测到显着的线粒体损伤。通过TdT介导的dUTP切口末端标记染色的细胞死亡发生在接种后第1天和第2天：在第1天和第2天存在通过半胱天冬酶-3切割显示的细胞凋亡，而在第1天，通过磷酸混合谱系激酶结构域样蛋白（MLKL）和受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK 1）水平的增加显示的坏死性凋亡存在于肺泡I型（AT 1）中的细胞死亡通过支气管肺泡灌洗液受体评估的晚期糖基化终点（AGEs）水平较高，但AT 2细胞死亡有限，同时诱导线粒体生物合成和线粒体自噬。这些线粒体QC机制主要在AT 2细胞中通过局部柠檬酸合酶含量增加、核线粒体生物合成调节因子核呼吸因子-1（NRF-1）和过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）增加以及轻链3B蛋白（LC 3-I）/LC 3 II比值增加进行评价。p62、Pink 1和Parkin蛋白水平的伴随变化表明线粒体自噬的激活。通过共聚焦显微镜，线粒体生物发生和线粒体自噬往往观察到在同一个AT 2细胞内的第1天。这些发现意味着肺炎损伤的AT 2细胞中的线粒体QC活化促进细胞存活以支持肺泡功能。
Mitochondrial damage is often overlooked in acute lung injury (ALI), yet most of the lung's physiological processes, such as airway tone, mucociliary clearance, ventilation-perfusion (Va/Q) matching, and immune surveillance require aerobic energy provision. Because the cell's mitochondrial quality control (QC) process regulates the elimination and replacement of damaged mitochondria to maintain cell survival, we serially evaluated mitochondrial biogenesis and mitophagy in the alveolar regions of mice in a validated Staphylococcus aureus pneumonia model. We report that apart from cell lysis by direct contact with microbes, modest epithelial cell death was detected despite significant mitochondrial damage. Cell death by TdT-mediated dUTP nick-end labeling staining occurred on days 1 and 2 postinoculation: apoptosis shown by caspase-3 cleavage was present on days 1 and 2, while necroptosis shown by increased levels of phospho- mixed lineage kinase domain-like protein (MLKL) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) was present on day 1 Cell death in alveolar type I (AT1) cells assessed by bronchoalveolar lavage fluid receptor for advanced glycation end points (RAGE) levels was high, yet AT2 cell death was limited while both mitochondrial biogenesis and mitophagy were induced. These mitochondrial QC mechanisms were evaluated mainly in AT2 cells by localizing increases in citrate synthase content, increases in nuclear mitochondrial biogenesis regulators nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and increases in light chain 3B protein (LC3-I)/LC3II ratios. Concomitant changes in p62, Pink 1, and Parkin protein levels indicated activation of mitophagy. By confocal microscopy, mitochondrial biogenesis and mitophagy were often observed on day 1 within the same AT2 cells. These findings imply that mitochondrial QC activation in pneumonia-damaged AT2 cells promotes cell survival in support of alveolar function.