Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle
Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle
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DOI：
10.1152/ajplung.00155.2013
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发表时间：
2014-05-01
影响因子：
4.9
通讯作者：
Prakash, Y. S.
中科院分区：
文献类型：
--
作者：
Aravamudan, Bharathi;Kiel, Alexander;Prakash, Y. S.
线粒体分裂和融合之间的平衡对于线粒体执行其正常细胞功能至关重要。我们假设香烟烟雾（CS）破坏了这种平衡，并增强了气道中的线粒体功能障碍。在非哮喘的人气道平滑肌（ASM）细胞中，CS提取物（CSE）诱导线粒体碎片化，并以浓度依赖性方式损害其网络形态，通过增加线粒体分裂蛋白动力蛋白相关蛋白1（Drp 1）的表达和减少融合蛋白线粒体融合蛋白（Mfn）2。CSE对Drp 1与Mfn 2和线粒体网络形态的影响涉及活性氧（ROS）、细胞外信号调节激酶（ERK）、磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（Akt）、蛋白激酶C（PKC）和蛋白酶体途径的激活，以及通过NF-κ B和核红细胞2相关因子2等因子的转录调节。抑制Drp 1可以防止CSE对线粒体网络和ROS产生的影响，而阻断Mfn 2则具有相反的有害作用。在哮喘患者的ASM中，线粒体在基线时表现出实质性的形态学缺陷，并显示Drp 1表达增加，但Mfn 2表达减少，CSE的影响加剧。总的来说，这些结果突出了线粒体网络及其调节在由炎症（如哮喘）或CS等损伤诱导的细胞变化背景下的重要性。改变的线粒体分裂/融合蛋白具有进一步影响与气道疾病相关的参数如ROS和细胞增殖和凋亡的潜力。
The balance between mitochondrial fission and fusion is crucial for mitochondria to perform its normal cellular functions. We hypothesized that cigarette smoke (CS) disrupts this balance and enhances mitochondrial dysfunction in the airway. In nonasthmatic human airway smooth muscle (ASM) cells, CS extract (CSE) induced mitochondrial fragmentation and damages their networked morphology in a concentration-dependent fashion, via increased expression of mitochondrial fission protein dynamin-related protein 1 (Drp1) and decreased fusion protein mitofusin (Mfn) 2. CSE effects on Drp1 vs. Mfn2 and mitochondrial network morphology involved reactive oxygen species (ROS), activation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C (PKC) and proteasome pathways, as well as transcriptional regulation via factors such as NF-kappa B and nuclear erythroid 2-related factor 2. Inhibiting Drp1 prevented CSE effects on mitochondrial networks and ROS generation, whereas blocking Mfn2 had the opposite, detrimental effect. In ASM from asmatic patients, mitochondria exhibited substantial morphological defects at baseline and showed increased Drp1 but decreased Mfn2 expression, with exacerbating effects of CSE. Overall, these results highlight the importance of mitochondrial networks and their regulation in the context of cellular changes induced by insults such as inflammation (as in asthma) or CS. Altered mitochondrial fission/fusion proteins have a further potential to influence parameters such as ROS and cell proliferation and apoptosis relevant to airway diseases.