The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis.
The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis.
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DOI：
10.1038/srep46416
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发表时间：
2017-04-12
影响因子：
4.6
通讯作者：
Weaver TE
中科院分区：
文献类型：
--
作者：
Yang L;Na CL;Luo S;Wu D;Hogan S;Huang T;Weaver TE
线粒体合成精选的磷脂，但缺乏合成最丰富的线粒体磷脂——磷脂酰胆碱（PC）的机制。尽管磷脂转移蛋白 Stard7 促进线粒体对 PC 的摄取，但该途径对于线粒体和细胞稳态的重要性仍存在重大的知识差距。 Stard7 的单倍体不足与小鼠过敏性气道疾病的显着恶化有关，包括上皮屏障通透性的增加。为了检验 Stard7 缺陷导致线粒体功能障碍下游屏障结构/功能改变的假设，在细支气管上皮细胞系 (BEAS-2B) 中敲低 Stard7 表达，并在小鼠肺上皮细胞 (Stard7epiΔ/Δ) 中明确删除 Stard7 表达。 Stard7 缺陷与体外和体内线粒体大小和膜组织的改变有关。线粒体结构的改变伴随着线粒体稳态的破坏，包括有氧呼吸减少、氧化应激增加和线粒体 DNA 损伤，而线粒体 DNA 损伤反过来又与屏障完整性和功能的改变有关。通过将 Stard7 靶向线粒体或用靶向线粒体的抗氧化剂处理上皮细胞，线粒体和屏障缺陷都得到了很大程度上纠正。这些研究表明，Stard7 介导的 PC 转移对于线粒体稳态至关重要，并且线粒体功能障碍会导致 Stard7 缺陷小鼠的屏障通透性改变。
Mitochondria synthesize select phospholipids but lack the machinery for synthesis of the most abundant mitochondrial phospholipid, phosphatidylcholine (PC). Although the phospholipid transfer protein Stard7 promotes uptake of PC by mitochondria, the importance of this pathway for mitochondrial and cellular homeostasis represents a significant knowledge gap. Haploinsufficiency for Stard7 is associated with significant exacerbation of allergic airway disease in mice, including an increase in epithelial barrier permeability. To test the hypothesis that Stard7 deficiency leads to altered barrier structure/function downstream of mitochondrial dysfunction, Stard7 expression was knocked down in a bronchiolar epithelial cell line (BEAS-2B) and specifically deleted in lung epithelial cells of mice (Stard7epi∆/∆). Stard7 deficiency was associated with altered mitochondrial size and membrane organization both in vitro and in vivo. Altered mitochondrial structure was accompanied by disruption of mitochondrial homeostasis, including decreased aerobic respiration, increased oxidant stress, and mitochondrial DNA damage that, in turn, was linked to altered barrier integrity and function. Both mitochondrial and barrier defects were largely corrected by targeting Stard7 to mitochondria or treating epithelial cells with a mitochondrial-targeted antioxidant. These studies suggest that Stard7-mediated transfer of PC is crucial for mitochondrial homeostasis and that mitochondrial dysfunction contributes to altered barrier permeability in Stard7-deficient mice.