Center for Translational Medicine and Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Free Radic Biol Med. 2021 Nov 20;176:335-344. doi: 10.1016/j.freeradbiomed.2021.10.006. Epub 2021 Oct 8.
Whether from known or unknown causes, loss of epithelial repair plays a central role in the pathogenesis of pulmonary fibrosis. Recently, diminished mitochondrial function has been implicated as a factor contributing to the loss of epithelial repair but the mechanisms mediating these changes have not been defined. Here, we investigated the factors contributing to mitochondrial respiratory dysfunction after bleomycin, a widely accepted agent for modeling pulmonary fibrosis in mice and in vitro systems. In agreement with previous reports, we found that mitochondrial respiration was decreased in lung epithelial cells exposed to bleomycin, but also observed that responses differed depending on the type of metabolic fuel available to cells. For example, we found that mitochondrial respiration was dramatically reduced when glucose served as the primary fuel. Moreover, this associated with a marked decrease in glucose uptake, expression of glucose uptake transport 1 and capacity to augment glycolysis to either glucose or oligomycin. Conversely, mitochondrial respiration was largely preserved if glutamine was present in culture medium. The addition of glutamine also led to increased intracellular metabolite levels, including multiple TCA cycle intermediates and the glycolytic intermediate lactate, as well as reduced DNA damage and cell death to bleomycin. Taken together, these findings indicate that glutamine, rather than glucose, supports mitochondrial respiration and metabolite production in injured lung epithelial cells, and suggest that this shift away from glucose utilization serves to protect the lung epithelium from injury.
无论是已知还是未知的原因，上皮细胞修复的丧失在肺纤维化的发病机制中起着核心作用。最近，线粒体功能的减弱被认为是导致上皮细胞修复丧失的一个因素，但介导这些变化的机制尚未确定。在这里，我们研究了博来霉素（一种广泛用于在小鼠和体外系统中模拟肺纤维化的药物）作用后导致线粒体呼吸功能障碍的因素。与之前的报告一致，我们发现暴露于博来霉素的肺上皮细胞中线粒体呼吸减少，但也观察到，由于细胞可利用的代谢燃料类型不同，反应也不同。例如，我们发现当葡萄糖作为主要燃料时，线粒体呼吸显著降低。此外，这与葡萄糖摄取、葡萄糖摄取转运蛋白 1 的表达以及糖酵解向葡萄糖或寡霉素的能力显著降低有关。相反，如果培养基中存在谷氨酰胺，线粒体呼吸则基本保持不变。添加谷氨酰胺还会导致细胞内代谢物水平升高，包括多种 TCA 循环中间产物和糖酵解中间产物乳酸，以及降低博来霉素引起的 DNA 损伤和细胞死亡。总之，这些发现表明，在受损的肺上皮细胞中，谷氨酰胺而不是葡萄糖支持线粒体呼吸和代谢物的产生，并表明这种从葡萄糖利用的转变有助于保护肺上皮免受损伤。
