Department of Medical Science, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea.
Department of Microbiology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon 35015, Korea.
Cells. 2019 Oct 30;8(11):1355. doi: 10.3390/cells8111355.
Apoptosis is an important host defense mechanism against mycobacterial infection. However, the molecular mechanisms regulating apoptosis during mycobacterial infection are not well known. Recent reports suggest that bacterial infection regulates mitochondrial fusion and fission in various ways. Here, we investigated the role of mitochondria in (Mtb)-infected macrophages. Mtb H37Rv (Rv) infection induced mitofusin 2 (MFN2) degradation, leading to mitochondrial fission. Interestingly, Mtb H37Ra (Ra) infection induced significantly greater mitochondrial fragmentation than Rv infection. Mtb-mediated Parkin, an E3 ubiquitin ligase, contributed to the degradation of MFN2. To evaluate the role of endoplasmic reticulum stress in the production of Parkin during Mtb infection, we analyzed Parkin production in 4-phenylbutyric acid (4-PBA)-pretreated macrophages. Pretreatment with 4-PBA reduced Parkin production in Mtb-infected macrophages. In contrast, the level of MFN2 production recovered to a level similar to that of the unstimulated control. In addition, Ra-infected macrophages had reduced mitochondrial membrane potential (MMP) compared to those infected with Rv. Interestingly, intracellular survival of mycobacteria was decreased in siMFN2-transfected macrophages; in contrast, overexpression of MFN2 in macrophages increased Mtb growth compared with the control.
细胞凋亡是宿主抵抗分枝杆菌感染的重要防御机制。然而，分枝杆菌感染过程中调控细胞凋亡的分子机制尚不清楚。最近的报告表明，细菌感染以各种方式调控线粒体融合和裂变。在这里，我们研究了线粒体在分枝杆菌感染的巨噬细胞中的作用。分枝杆菌 H37Rv（Rv）感染诱导融合蛋白 2（MFN2）降解，导致线粒体裂变。有趣的是，分枝杆菌 H37Ra（Ra）感染诱导的线粒体碎片化程度明显高于 Rv 感染。分枝杆菌介导的泛素连接酶 Parkin 参与了 MFN2 的降解。为了评估内质网应激在分枝杆菌感染过程中产生 Parkin 中的作用，我们分析了 4-苯丁酸（4-PBA）预处理巨噬细胞中的 Parkin 产生情况。4-PBA 预处理降低了分枝杆菌感染巨噬细胞中的 Parkin 产生。相比之下，MFN2 的产生水平恢复到未刺激对照的相似水平。此外，Ra 感染的巨噬细胞的线粒体膜电位（MMP）比 Rv 感染的巨噬细胞降低。有趣的是，siMFN2 转染的巨噬细胞中分枝杆菌的细胞内存活减少；相反，与对照组相比，MFN2 在巨噬细胞中的过表达增加了 Mtb 的生长。
